International Journal of Innovative Pharmaceutical ...ijipsr.com/sites/default/files/articles/IJIPSRMN-80 (1).pdf · 2Department of Pharmacy, SBS PG Institute of Biomedical Sciences,

REVIEW ARTICLE Abhijit et.al / IJIPSR / 3 (6), 2015, 663-687

Department of Pharmaceutical Technology ISSN (online) 2347-2154

Available online: www.ijipsr.com June Issue 663

PATHOPHYSIOLOGICAL BASIS OF ERECTILE

DYSFUNCTION IN DIABETES MELLITUS: A REVIEW

1Abhijit De*,

2Mamta Farswan Singh,

3Vinod Singh,

2Veerma Ram,

2Shradha Bisht

1Department of Pharmaceutical Technology, Bengal School of Technology, Sugandha,

West Bengal, INDIA 2Department of Pharmacy, SBS PG Institute of Biomedical Sciences, Balawala, Dehradun,

INDIA 3Faculty of Pharmacy, Gurukul Kangri University, Haridwar, INDIA

Corresponding Author

Abhijit De

Assistant Professor, Dept. of Pharmaceutical Technology

Bengal School of Technology, Sugandha, West Bengal, INDIA

Email: [email protected]

Phone: +91 8274847571

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

Erectile dysfunction is a common complication of diabetes mellitus and also is the first symptom of as yet

undiagnosed diabetes. The Massachusetts Male Aging Study (MMAS) was the first major epidemiological

investigation to study the prevalence of ED in diabetes. According to MMAC the incidence of ED was correlated

with glycemic control and increases with increasing age, duration of diabetes and deteriorating metabolic control,

and was higher in individuals with type 2 diabetes than those with type 1 diabetes. The pathophysiology of ED in

diabetes is multifactorial including vascular and neural factors being equally implicated. In diabetic men,

peripheral vasculopathy and neuropathy are intimately involved in the development of ED. Diabetic patients

associated with insufficient control of glycemic level extremely suffer from disruption of endothelial functions,

generation of increased level of free radicals, loss of control in the parasympathetic and non adrenergenic non

cholinergic nerves (NANC). In diabetic patients hypogonadism, autonomic neuropathy, arterial insufficiency, low

testosterone, changes in expression of protein kinase C, RhoA-Rho kinase Ca2+

-sensitization pathway results in

vascular damages of penile smooth muscle which are more or less related to erectile dysfunction. Penile tissue

from diabetic men with ED demonstrates impaired neurogenic and endothelium-mediated relaxation of smooth

muscle, increased accumulation of advanced glycation end products (AGEs) and upregulation of arginase which

lead to decrease in the level of NO in corpora cavernosa. Still there is a need to understand the pathophysiology of

ED in diabetic patients and to make an effort to diagnose and treat ED for improving the quality of life of the

patients of diabetes. This review aimed to provide an update of the normal physiology of penile erection and the

pathophysiological mechanisms of erectile dysfunction (ED) in diabetes patients.

Keywords: Diabetes Mellitus, Erectile dysfunction, Oxidative stress, Advanced glycation end products,

Arginase, Rho Kinase, Tumor Necrosis Factor.

mailto:[email protected]




INTRODUCTION

Diabetes mellitus is one of the major risk factor for cardiovascular mortality and morbidity.

Diabetes mellitus has been shown to be an important risk factor for ED in several studies [1].

Based on the types of diabetes whether type I or type II, still it is a controversial point that which

type of diabetes actually play a vital role in altering sexual behavior of human. Male sexual

dysfunction among diabetic patients can include disorders of libido, ejaculatory problems, and

erectile dysfunction (ED) [2,3,4]. In diabetes mellitus erectile dysfunction is mainly associated

with increasing age and time of evolution of diabetes [5,6,7,8]. Chronic hyperglycemia in diabetic

patients may lead to micro- and macrovasculopathy, including endothelial dysfunction [9,10].

DM is responsible for several biochemical and homeostasis alterations that may result in male

subfertility and or infertility [11].

Hypogonadism, autonomic neuropathy, and arterial insufficiency are associated with a higher

likelihood of ED in cross-sectional and longitudinal studies of men with diabetes [12,13,14].

Androgen deficiency in diabetic rats is associated with downregulation of the neuronal isoforms

of nitric oxide synthase, suggesting a trophic effect of testosterone on peripheral erectile tissues.

Relaxation of penile tissue requires nitric oxide from nonadrenergic-noncholinergic neurons and

the endothelium [15]. Penile tissue from diabetic men with ED demonstrates impaired neurogenic

and endothelium-mediated relaxation of smooth muscle, [16] increased accumulation of advanced

glycation end products (AGEs),[17] and upregulation of arginase, a competitor with nitric oxide

synthase for its substrate L-arginine [18]. Erectile dysfunction is defined as the ability of the male

to attain and maintain penile erection which is sufficient to permit sexual intercourse upto

satisfactory level [19]. Epidemiological data focused that majority of men with DM is prone to

ED. In a study done in 541 DM men aged 20-59 years, 35% of ED was reported [20]. This

condition has been estimated to affect 150 million individuals worldwide and data from the

ENIGMA study in 2004 suggested that the condition is prevalent in approximately 17% of all

European men [21,22].

Approximately 20–30 million men in the United States and approximately 0.5 million men in the

UK have ED of varying severity. According to the Massachusetts Male Aging Study, 52% of men

in the United States between the ages of 40 and 70 years have ED [23].

The incidence is approximately 32% in the United Kingdom, 26% in Japan and 19% in Denmark

[24,25,26]. In the same study, it was found that the risk of cardiovascular complication was higher




in patients with non-insulin dependent diabetes that suffered from ED compared with the diabetic

patients who did not have ED [27].

In this article, we will discuss the factors and

pathophysiological mechanisms responsible for erectile dysfunction in diabetic patients.

BASIC PHYSIOLOGY OF PENILE ERECTION

Erection is a neurovascular event that involves spinal and supra spinal pathways. Penile erection

can arise from various stimuli include tactile stimuli to penis leading to reflex erection, the second

mechanism include erotic stimuli, whether visual, auditory, olfactory or imaginative also produce

erection through the stimulation of paraventricular nucleus and medial preoptic area of the

hypothalamus and the third mechanism involved in the production of nocturnal erection during

REM sleep [28]. The final common pathway involves the release of nitric oxide (NO) from both

endothelial cells and neurons, which acts as a vasodilator causing penile engorgement and

erection. Studies over the past years supports the vital role of endothelial-derived NO from eNOS

in the regulation of penile erection both in normal physiology and in pathological disease states.

Penile erection is elicited by neural signals from the spinal cord, which increases nNOS activity

and the production of NO from NANC nerves, thereby causing an increase in blood flow to the

cavernosal tissue [29,30]. eNOS is then activated by increased blood flow from the arteries

supplying the corpora and expansion of the sinusoidal spaces of the corpora and thereby causing

penile erection REF. Hurt and colleagues (2002), by using selective pharmacological inhibitors

and eNOS knockout mice, showed that penile erection-dependent processes to cavernosal nerve

stimulation and drug-induced relaxation of the corpus cavernosum are mediated by

phosphatidylinositol 3-kinase (PI3-kinase) and activation of the serine/ threonine protein kinase

Akt [31].

This pathway phosphorylates eNOS to increase endothelial-derived NO [32].

The use of pharmacological inhibitors of PI3- kinase in the penis of rats demonstrated that these

inhibitors were able to reduce erections to electrical nerve stimulation. This signaling pathway

was furthermore shown to be responsible for sustained NO production via a PI3 kinase/ Akt-

dependent activation of eNOS with subsequent increases in the release of endothelial-derived NO.

NO then diffuses to the underlying smooth muscle cells where it activates the soluble form of

guanylate cyclase and elevates intracellular levels of cGMP and the activity of cGKI protein

kinase. The NO/cGMP-signaling cascade reduces contractile activity and promotes cavernosal

smooth muscle relaxation REF.




Fig. 1: Schematic representation of normal physiology of penile erection. NO released from

non-adrenergic noncholinergic (NANC) nerves binds to soluble guanylate cyclase and

increases cyclic guanosine monophosphate (cGMP) levels and cGMP-dependent protein

kinase-1 (PKG-1) activity, leading to smooth muscle cell relaxation and cavernosal dilation.

MECHANISMS OF ERECTILE DYSFUNCTION IN DIABETES

There are several ways of classifying the causes of ED including organic, psychogenic or mixed

organic and psychogenic, among which organic ED being the common form [30]. In diabetic

men, peripheral vasculopathy and neuropathy are intimately involved in the development of ED.

Chronic hyperglycemia may lead to micro- and macrovasculopathy, including endothelial

dysfunction. The risk factors for diabetic ED include glycemic control, advanced age, duration of

diabetes, and diabetic complications such as retinopathy. Hyperlipidemia, hypertension, and

obesity are also all independent risk factors for diabetic men [31,33]. The decrease in NO

bioavailability in endothelial dysfunction may be caused by reductions in the enzyme endothelial

NO synthase (eNOS, NOS3), a lack of substrate or cofactors for eNOS, alterations in intracellular




signaling such that eNOS is not appropriately activated or uncoupled or accelerated degradation

of NO by reactive oxygen species (ROS), such as superoxide anion. Endothelial dysfunctions,

venous occlusion, decrease in nitric oxide level, failure of mechanisms of vasodilation and

formation of advanced glycation end products can be contributing factor for diabetes induced ED

[34].

DIABETES AND ENDOTHELIAL DYSFUNCTION

The term Endothelial dysfunction refers to a condition in which the healthy endothelial monolayer

diminishes its physiologic properties and impair dilatory mechanism by shifting towards a

vasoconstrictor and proinflammatory state [35].

The importance of endothelium was first

identified by its effect in limiting the vascular tone [36]. Various vasoconstricted and vasodilated

agents are involved in the physiology of penile erection. Cavernosal smooth muscle cells in the

penis are predominately found in the contracted state with minimal blood flowing through the

cavernous sinuses. The balance between known contractile systems (RhoA/Rho-kinase, a-

adrenergic, endothelin, angiotensin, thromboxane A2) and vasodilatory second-messenger

systems (adenylate cyclase-cyclic AMP and guanylate cyclase-cyclic GMP) determines the

overall tone of corpora cavernosa smooth muscle of the penis [37,38]. Damaged to endothelial-

dependent vasoreactivity has been demonstrated in various animal models. Various studies

performed on human and animal models indicates that in diabetes upregulation of endothelin 1

and Ag-II takes place which further causes contraction of the smooth muscles of corpora

cavernosa and flaccidity of penis. Jesmin et al observed a decrease of the immunofluroscent

staining of e NOS and the expression of this enzyme in the penile tissue of obese rats with respect

to controls [39]. Three contributing sources to endothelial dysfunction in diabetes include

alteration of endothelial function directly by hyperglycemia and its biochemical product,

alteration of endothelial function by high glucose through the synthesis of growth factors and

vasoactive agents in other cells which then alter the vascular permeability and alteration of

endothelial function by components of metabolic syndrome [40]. Endothelial dysfunction is

mainly related to decreased expression or activity of eNOS which results in decreased

bioavailability of NO and associated signaling molecules such as protein kinase C. Various

molecules are involved in the pathogenesis of endothelial dysfunction in diabetes such as free

radicals, arginase, NO, Rho-rho kinase, protein kinase C, tumour necrosis factor - α (TNF- α) and

advanced glycation end products.




OXIDATIVE STRESS AND ERECTILE DYSFUNCTION

ROS may modify endothelial function directly by activating several transcription factors leading

to the upregulation of adhesion molecules to platelets and leukocytes and decreasing the

bioavailability of NO or indirectly by increasing the formation of advanced glycation end

products (AGEs) or increasing oxidation of low density lipoprotein [41,42].

The common sources of free radicals in hyperglycemia have been shown in fig 2.

Fig. 2: Pathway for the generation of reactive oxygen species (ROS) and oxidative stress.

Asterisks indicate possible sites of inhibition by novel AGE inhibitors.

Reactive oxygen species (ROS) are formed at the time of regular metabolism due to reduction of

univalent oxygen molecule [43]. The most important ROS is superoxide (O2). The effect of a

superoxide anion-generating agent on in vitro NO-mediated cavernosal smooth muscle relaxation

demonstrated that acetylcholine-mediated relaxation was impaired in the rat corpus cavernosum

in the presence of increased production of superoxide anion, suggesting that superoxide anion can

impair endothelial-derived NO in normal erectile tissue [44]. Peroxy nitrite (OONO-), hydrogen

peroxide (H2O2) hypochlorous acid (HOCl-), ozone (O3) nitronium anion (NO2

+) are other

important free radicals which plays a major role in the pathophysiological mechanism of

endothelial dysfunction. NO and ROS after interaction between each other contribute a major

imbalance between the vaso-contraction and relaxation of the corpora cavernosa muscle in the

penis [45]. The enzymatic antioxidant, superoxide dismutase is known to catalyses the




dismutation of superoxide to hydrogen peroxide and oxygen. This enzyme mainly involves in the

removal of superoxide radicals from the human body and hence prevents the adverse effects of

superoxide in vasculature. It was hypothesized that the administration of the superoxide dismutase

(SOD) mimetic Tempol (4- hydroxy-2, 2, 6, 6-tetramethylpiperidine 1-oxyl) may reverse

diabetes-induced erectile dysfunction. To test this hypothesis, reactive oxygen species-related

genes (SOD1, SOD2, GP-1, CAT, NOS2, and NOS3) were tested and erectile functional studies

and immunohistochemical analysis were carried out in diabetic rats treated with or without

Tempol [46,47]. A decrease in CAT mRNA expression was observed in diabetes but there was no

change in CAT protein levels between control and diabetes whereas NOS2 (iNOS) mRNA and

protein levels were increased in diabetic rats [48]. Administration of Tempol to diabetic rats

inhibited superoxide overproduction. It also reversed the increase of iNOS mRNA expression in

rat crura and release of nitric oxide from endothelial cells leading to decreased formation of

peroxynitrite. Hyperglycemia in diabetes also favors increased expression of iNOS (NOS2)

through the activation of stress sensitive pathways such as NF-eˆB, which can increase the

generation of NO [49]. Superoxide immediately interacts with NO, generating cytotoxic

peroxynitrite (OONO-), thereby reducing the efficacy of the potent endothelium-derived

vasodilator system that participates in the homeostatic regulation of the vasculature [50,51].

Pathophysiologially peroxynitrite after reacting with tyrosyl residue of proteins inactivates SOD

which further leads to increased level of superoxide. Moreover superoxide and peroxynitrite

combinely play a major role in the apoptosis of the endothelium causes reduction in the

availability of NO. This reduced NO concentration promotes the adhesion of neutrophils to

platelets as well as endothelium by the expression of co-adhesion molecules. Peroxynitrite also

act as a driving force for more adhesion of platelets and neutrophils which causes release of

vasoconstricting substances such as serotonin and thromboxane A2 and vasculopathic erectile

dysfunction [52]. It was reported that antioxidants mainly alpha tocopherol and melatonin

improved the DM induced sexual impairment in male rats [53]. The corpus cavernosa of diabetic

rats and men with ED possess lipid peroxidation quantitatively in a high level along with up

regulation of superoxide anion and reduced antioxidants levels [54]. ROS have also been

implicated in over expression of arginase activity which further causes uncoupling of eNOS by

suppressing L-arginine [55]. This uncoupled eNOS utilizes molecular oxygen to generate

superoxide and increasing ROS formation [56]. In diabetics ROS also causes the overexpression

of Rho kinase which contributes a promising role in ED.




ROLE OF ARGINASE AND NO IN ERECTILE DYSFUNCTION

L-Arginine is a cationic, semi essential amino acid that is necessary precursor for the synthesis of

L-proline, L-orthinine, polyamines and proteins [57,58] L-Arginine requires the arginase enzyme

and it is also a substrate for production of NO through eNOS activation. Arginase catalyzes the

divalent cation dependent hydrolysis of L-Arginine to form orthinine and urea and exists in two

major isoforms: Arginase I and Arginase II [59,60]. Arginase I, a cytosolic enzyme abundantly

expressed in the liver which control the majority of total body arginase activity but arginase II is a

mitochondrial protein mainly expressed in wide variety of tissue, mostly expressed in the kidney

and prostrate and poorly expressed in the liver [61,62]. L-Arginine acts as a common substrate

which induces competition between arginase and eNOS [63]. In DM increased arginase activity

lead to eNOS dysfunction [64]. Experimentally it had been showed that vascular arginase activity

was increased in diabetic rats and TNF acts as a mediator to promote arginase activity [64,65]. In

diabetic patients, increased arginase expression in the penis reduces the availability of L-arginine

as substrate which further decreases the coupling of NOS and causes less release of NO. The

decreased bioavailability of NO contributes to vasculopathic erectile dysfunction. Studies have

demonstrated that animals with chemically induced and genetic diabetes have significant

decreases in penile eNOS and nNOS protein/gene expression and cavernosal cGMP levels which

is responsible for impaired mating behavior [66,67,68,69,70,71]. Interestingly, endothelium-

independent cavernosal smooth muscle relaxation is also impaired in animal models of diabetes

which suggests that diabetes attenuates endothelial and neurogenic- NO neurotransmission but

may also affect smooth muscle reactivity and the downstream second messengers like soluble

guanylate cyclase, cGMP, or protein kinase cGKI [72]. Impairment in NO biosynthesis can be

potentiated by the fact that long-term oral administration of L-arginine to rabbits with diabetes

increased endothelium-dependent corporal smooth muscle relaxation by increasing the

availability of substrate L-arginine for conversion to L-citrulline and NO. In the presence of

ABH, an arginase inhibitor, the calcium-dependent conversion of L-arginine to L-citrulline was

increased significantly in diabetic cavernosal tissue. These data may suggest that the elevated

arginase expression/activity reduces eNOS activity by competing the eNOS for L-arginine, and

that inhibition of arginase by ABH shifts the availability of L-arginine to eNOS, thus resulting in

increased conversion of the substrate to NO. It has been shown in the rats that sodium nitrite

(NaNO2) administered intra-cutaneously increases ICP and decreases systemic arterial pressure.




The ability of nitrite to enhance erectile activity suggests further investigation in the use of nitrite

as a therapeutic agent for ED.

ROLE OF RHO KINASE

Flaccidity of penis is due to contraction of cavernosal smooth muscles [73]. Contraction of

cavernosal smooth muscle is primarily mediated by the Ca21- dependent activation of MLC

kinase, resulting in the phosphorylation of MLC, and subsequent actin/myosin cross-bridge

formation. In addition, recent evidence has established the important role of myosin phosphatase

in regulating the MLC mediated smooth muscle contraction. Myosin phosphatase by

phosphorylating MLCK prevents the phosphorylation of MLC and thereby contributes to smooth

muscle relaxation. A principle regulator of MLC phosphatase activity is the serine/threonine

kinase, Rho-kinase. Although the role of RhoA/Rho-kinase has been well outlined in numerous

forms of smooth muscle, recent evidence has demonstrated its importance in the regulation of

cavernosal smooth muscle tone [74,75,76,77]. Rho kinase by phosphorylating inactivates myosin

phosphatase and thereby causes smooth muscle contraction. In diabetic patients upregulation of

Rho Kinase causes more inactivation of myosin phosphatase and leads to more contraction of

cavernosal muscles and erectile dysfunction. In diabetic patients RhoA activation also leads to

increased arginase activity. Under physiological conditions NO by inhibiting Rho Kinase causes

MLCK phosphorylation and smooth muscle relaxation. However in diabetic patients decrease in

the level of NO is not able to regulate the activity of Rho kinase and therefore leads to muscle

contraction. It was proposed that NO can inhibit the RhoA/ Rho-kinase pathway in the normal

physiology of erectile response [78,79,80].

Rats with STZ-induced diabetes also have an

increased level of RhoA and Rho-kinase in diabetic corpus cavernosum at a time when eNOS

protein and activity is reduced [81]. Role of Rho-kinase in the maintenance of cavernosal smooth

muscle vasoconstriction has been supported by the evidence that administration of the Rho kinase

inhibitor, Y-27632, directly into the cavernosal sinuses of rats caused dose-dependent increase in

intracavernosal pressure [74]. Y-27632, a Rho kinase inhibitor when given intracutaneously

along with pretreatment with NOS inhibitors (L-NMA and L-NAME) or sGC inhibitor

(Methylene blue) in rats resulted in increased erectile activity due to nerve stimulation,

independent of NO [82]. Bivalacqua et al found that erectile activity, cGMP levels, constitutive

NOS activity and cavernosal eNOS protein were restored to normal level when the diabetic

animals were transfected with a dominant negative RhoA mutant [83]. Fasudil, a Rho kinase

inhibitor after chronic administration was shown to treat vasculogenic erectile dysfunction [84]. A




most recent study concluded that diabetes associated erectile dysfunction enhances Akt activity

due to upregulation of RhoA/ Rho-kinase pathway, which directly leads to apoptosis of

cavernosal tissue [85]. In a study of diabetes induced erectile dysfunction by streptozotocin or

alloxan in rats and rabbits, Rho kinase inhibitor SAR407899 was found to cause relaxation of

corpora cavernosa invivo [86].

ROLE OF PROTEIN KINASE C AND TNF-ALPHA

Protein kinase C is an enzyme mainly activated by high glucose concentration and high TNF [87].

DM causes de novo synthesis of diacylglycerol which leads to the PKC activation [88]. Diabetes

induced translocation of PKC-alpha to renal membrane was associated with increased

nicotinamide adenine dinucleotide phosphate oxidase-dependent superoxide generation and

kidney damage [89]. Of the various isoforms PKC in vascular cells, it is found by immunoblotting

studies that the PKC β and δ isoforms in the aorta and heart of diabetic rats get activated on

exposure to high glucose [90,91]. Hyperglycemia in DM generates Tumor Necrosis Factor (TNF)

and then the cytokine upregulates the endothelial arginase activity [92,93]. TNF binds to different

receptors TNF-R1 (soluble TNF has the highest affinity) and TNF-R2 (Membrane bound TNF has

the highest affinity) [94,95]. Except TNF-R2, TNF-R1 consists of death domain which gets

activated during apoptosis signal [96]. TNF-R2 though not carry death domain is involved in

regulation of apoptosis in micro vascular endothelial cells [97]. Up regulation of TNF in diabetics

decreases eNOS expression and thus affect NO production [98]. It also promotes ROS production

in endothelial cells through NADPH oxidase and uncoupled NOS [99,100,101]. Moreover, PKC

activation leads to TNF mediated increase in permeability of endothelial monolayers and

endothelial dysfunctions [102]. TNF-α levels are increased in serum of patients with moderate to

severe ED [103,104,105] and

TNF-α is inversely associated with sexual performance [103].

Experimental studies have demonstrated that TNF-α knockout mouse exhibited changes in

cavernosal reactivity that would facilitate erectile responses, decreased responses to adrenergic

nerve stimulation and increased NANC and endothelium-dependent relaxation that are associated

with increased corporal eNOS and nNOS protein levels [106]. The penile smooth muscle cells

synthesizes endothelin-1 (ET-1), its converting enzyme (ECE-1), and both ETA and ETB receptor

subtypes [107,108,109]. ET-1 induces vasoconstriction and also stimulates the expression of

adhesion molecules and activates transcriptional factors responsible for the coordinated increase

in the expression of many cytokines and enzymes, which can in turn lead to the production of

inflammatory mediators [110,111]. Angiotensin II, ET-1 and other inflammatory mediators have




been shown to increase TNF-α levels [112,113,114,115]. However further studies are essential to

determine whether TNF-α plays a detrimental role in ED associated with CVD such as

hypertension, diabetes, CAD, and heart failure. Finally, a key role for TNF-α in mediating smooth

muscle and endothelial dysfunction is of interest not only because markedly elevated serum levels

of TNF-α have been documented in patients with ED, but also because we now have access to

targeted anti-TNF-α therapies.

ADVANCED GLYCATED END PRODUCTS

Among the various proposed mechanisms for ED in DM patients, the role of elevated

concentration of Advanced Glycated End Product is one of the common mechanism

[116,117,118,119,120]. AGEs are accumulated during the process of aging and diabetes. The

level of AGEs is markedly increased in diabetes as a consequence of an increase in glucose [121].

AGEs are formed abundantly when glucose remains high for prolonged periods [122,119]. There

are various consequences which takes place after the formation of AGE and directly or indirectly

contributes to the pathophysiology of DM induced ED. During the process of diabetes, AGE

accumulates and causes structural and functional changes in plasma and extracellular matrix

proteins which leads to enhanced formation of ROS and activation of nuclear factor- kB as well

as release of proinflammatory cytokines, GFs and adhesion molecules [123,124,125,126,127].

Fig. 3: Pathway showing formation of AGE




In diabetes through the process of glycation, glucose reacts with amino groups producing Schiff

base, which is modified to form more stable amadori products [128]. AGE acts through surface

receptors such as Receptor for AGE (RAGE), 80 kH phosphoprotein (R-2), scavenger receptor II,

lactoferrin like polypeptide and CD-36 [129]. AGE can also form covalent bonds with vascular

collagen which leads to thickening of blood vessels, decreased elasticity, endothelial dysfunction

and atherosclerosis. AGE at the molecular level acts on various channels and receptors in

cavernosal smooth muscle cells especially on k+ channel which help in the release of intracellular

Ca++

ion and cause cavernosal smooth muscle relaxation. AGE damages this physiology of K+ ion

channel and thus disrupting the relaxation capacity of cavernosal smooth muscle and leads to

early onset of DM induced ED [130]. AGE also increases the expression of major

vasoconstrictors such as ET1 and VEGF [131]. Along with AGE, receptor for advanced glycated

end product (RAGE) also contribute the overexpression of ET1 in the cavernosal tissue [132]. It

has been proposed that AGEs through the generation of ROS and cell damage decrease the level

of cGMP which affect the smooth muscle relaxation [133,134]. AGEs accumulate in endothelial

and smooth muscle cells and cause sustained cellular activation of various proteins and generation

of oxygen- derived free radicals. It is now proposed that AGE inhibitors can repair the

vasoconstrictory mechanism of cavernosal smooth muscle by various mechanisms as depicted

possibly in fig 2. Aminoguanidine, a novel inhibitor of AGE formation and ALT-711, a

compound that breaks down AGE, has been demonstrated to play a major role in treating DM

induced ED and observed that there is a major improvement in the endothelium-dependent

cavernosal smooth muscle relaxation in vitro and erectile responses in vivo [132,134].

Additionally, aminoguanidine also prevent diabetes-induced changes in the connective tissue

composition of the microvascular wall of the arterioles supplying the penis, thus improving

arterial inflow to the penis. Taken together, the deleterious effects of AGEs seem to be involved

in the pathogenesis of endothelial dysfunction as it relates to diabetes.

CONCLUSION

Normal penile erection is dependent on the integrity of the endothelium. Endothelial-derived NO

plays an important role in the physiological mechanism of erection. Alteration in the

concentration of NO due to damage to endothelium or due to increased destruction appears to be

the most important causes for ED. Diabetes Mellitus is a most important risk for the development

of erectile dysfunction. A major factor contributing to diabetic ED in human corporal tissue is a




reduction in the number of nitrergic NOS containing nerve fibers, constitutive NOS activity, and

impaired endothelial and neurogenic mediated smooth muscle relaxation. The detectable changes

in diabetes associated with ED are endothelial abnormality which causes loss of the normal

homeostatic mechanisms. Hyperglycemia in diabetes collectively induces endothelial

dysfunction, oxidative stress, disturbance in NANC pathway, formation of advanced glycated end

products, over expression of arginase enzyme and TNF-alpha, activation of protein kinase C and

endothelin1 which ultimately leads to ED as consequence. Various animal and human

experimental data have demonstrated that diabetic vasculopathy and neuropathy contribute

significantly to diabetes-associated ED. Impairments in endothelium-dependent and NANC-

mediated cavernosal smooth muscle relaxation are well established in diabetic corpus cavernosum

in vitro and in vivo. Recent evidence suggests that oxidative stress may play a major role in

diabetic endothelial dysfunction of the penile vascular bed. Studies on the use of a Rho Kinase

inhibitor for treatment of STZ induced ED also indicate the involvement of Rho Kinase in

diabetic erectile dysfunction. The correlation among these molecules has revealed the most

possible mechanism underlying diabetes induced ED. Discovery of the pathophysiological

mechanisms involved in disease associated ED will undoubtedly lead to prevention strategies and

new therapies for ED. Still researches are going on investigating the proper treatment targeting

these molecules which may lead to novel strategies for curing ED in the future.

REFERENCES

1. K. Kohei, “Pathophysiology of type II diabetes and its treatment policy,” Japanese Medical

Association Journal, vol. 53, no. 1, pp. 41-46, 2010.

2. R. Lucas, R. Caldwell, and G. Yang, “Novel mechanisms of endothelial dysfunction in

diabetes.” Journal of Cardiovascular Disease Research, vol. 1, no. 2, pp. 117-119, 2010.

3. P.J. Grant, “Diabetes Mellitus as a prothrombotic condition”. Journal of Internal Medicine,

vol. 262, no. 2, pp. 152-157, 2007.

4. D.D. Eulises, “Erectile dysfunction: A chronic complication of diabetes mellitus”.

Complementary and Alternative Medicine, pp. 69-78, 2012.

5. R. Klein, B.E. Klein, K.E. Lee, S.E. Moss, and K.J. Cruickshanks, “Prevalence of self

reported erectile dysfunction in people with long term IDDM”. Diabetes care, vol. 19, no. 2,

pp. 135-141, 1996.




6. D. Fedele, C. Coscelli, D. Cucinotta, G. Forti, F. Santeusanio et al., “Incidence of erectile

dysfunction in Italian men with diabetes”. Journal of Urology, vol. 166, no. 4, pp. 1368-1371,

2001.

7. D.K. McCulloch, I.W. Campbell, F.C. Wu, R.J. Prescott, and B.F. Clarke, “The prevalence of

diabetic impotence”. Diabetologia, vol.18, no. 4, pp. 279-283, 1980.

8. A. Roth, O. Kalter-Leibovici, Y. Kerbis, J. Chen, T. Sobol et al., “Prevalence and risk factors

for erectile dysfunction in men with diabetes, hypertension or both diseases: a community

survey among 1,412 Israeli men”. Clinical Cardiology, vol. 26, no. 1, pp. 25-30, 2003.

9. K.P. Kleinman, H.A. Feldman, C.B. Johannes, C.A. Derby, and J.B. McKinlay, “A new

surrogate variable for erectile dysfunction status in the Massachusetts male aging study”.

Journal of Clinical Epidemiology, vol. 53, no. 1, pp. 71-78, 2000.

10. J.H. Romeo, A.D. Seftel, Z.T. Madhun, and D.C. Aron, “Sexual function in men with diabetes

type 2: association with glycemic control”. Journal of Urology, vol. 163, no. 3, pp. 788-791,

2000.

11. R. Leite, “Targets for the treatment of erectile dysfunction is NO/c GMP still the answer?”

Recent Patents on Cardiovascular Drug Discovery, vol. 2, no. 2, pp. 119-132, 2007.

12. B.L. Meena, D.K. Kochar, T.D. Aggarwal, R. Chaudhary, and A. Kochar, “Association

between erectile dysfunction and cardiovascular risk in individuals with type 2 diabetes

without overt cardiovascular disease”. International Journal of Diabetes in Developing

Countries, vol. 29, no. 4, pp. 150-154, 2009.

13. NIH Consensus Conference. Impotence. The Journal of the American Medical Association,

vol. 270, no. 1, pp. 83-90, 1993.

14. I. Eardley, “Pathophisiology of erectile dysfunction”. The British Journal of Diabetes and

Vascular Disease, vol. 2, no. 4, pp. 272-276, 2002.

15. R. Maas, E. Schwedhelm, J. Albsmeier, and B.H. Boger, “The pathophysiology of erectile

dysfunction related to endothelial dysfunction and mediators of vascular functions”. Vascular

Medicine, vol. 7, no. 3, pp. 213-225, 2002.

16. Z. Colakoglu, E. Kutluay, C. Ertekin, B. Altay, R. Killi et al., “Autonomic nerve involvement

and venous leakage in diabetic men with impotence”. International Journal of Urology, vol.

83, no. 4, pp. 453-456, 1999.

17. M.A. Potenza, S. Gagliardis, and C. Nacci, “Endothelial dysfunction in diabetes: from

mechanism to therapeutics targets”. Current Medical Chemistry, vol. 16, pp. 94-112, 2009.




18. J.E. Deanfield, J.P. Halcox, and T.J. Rabelink, “Endothelial function and dysfunction: testing

and clinical relevance”. Circulation, vol. 115, pp. 1285-1295, 2007.

19. S. Jesmin, I. Sakuma, and K. Nonomura, “Diminished penile expression of vascular

endothelial growth factor and its receptor at the insulin-resistant stage of a type II diabetic rat

model: a possible cause of erectile dysfunction in diabetes”. Journal of Molecular

Endocrinology, vol. 31, no. 3, pp. 401-418, 2003.

20. C.G. Schalkwijk, and C.D. Stehouwer, “Vascular complications in diabetes mellitus: the role

of endothelial dysfunction”. Clinical Science London, vol. 109, no. 2, pp. 143-59, 2005.

21. S. Rahbar, and J.L. Figarola, “Novel inhibitors of advanced glycated end products. Archives

of Biochemistry & Biophysics, vol. 419, no. 1, pp. 63-79, 2003.

22. J.S. Beckman, and W.H. Koppenol, “Nitric oxide, superoxide and peroxynitrite: the good, the

bad, and ugly”. American Journal of Physiology, vol. 271, pp. 1424-1437, 1996.

23. J.Y. Jeremy, G.D. Angelini, M. Khan, D.P. Mikhailidis, and C.S. Thopson, “Platelets, oxidant

stress and erectile dysfunction, an hypothesis”. Cardiovascular Research, vol. 46, no. 1, pp.

50-54, 2000.

24. A.S. De Vreise, T.J. Verbeuren, J. Van de Voorde, N.H. Lameire, and P.M. Vanhoutte,

“Endothelial dysfunction in diabetes”. British Journal of Pharmacology, vol. 130, no. 5, pp.

963-974, 2000.

25. F. Fiordaliso, I. Cuccovillo, R. Bianchi, A. Bai, M. Doni, and M. Salio, “Cardiovascular

oxidative stressis reduced by an ACE inhibitor in a rat model of streptozotocin induced

diabetes”. Life Science, vol. 79, pp. 121-129, 2006.

26. H.E. Tawfik, A.B. Remessy, S. Matragoon, G. Ma, R.B. Caldwell, and R.W. Caldwell,

“Simvastatin improves diabetes induced coronary endothelial dysfunction. Journal of

Pharmacology and Experimental Therapeutics, vol. 319, no. 1, pp. 386-395, 2006.

27. A. Ceriello, “Oxidative stress and diabetes associated complications”. Endocrine Practice, vol.

12, no. 1, pp. 60-62, 2006.

28. Z.T. Bloomgarden, “American Diabetes Association Annual Meeting. Endothelial

dysfunction, neuropathy and the diabetic foot, diabetic mastopathy, and erectile dysfunction”.

Diabetes Care, vol. 21, pp. 83-89, 1998.

29. R.B. Moreland, G. Hsieh, M. Nakane, and J.D. Brioni, “The biochemical and neurologic basis

for the treatment of male erectile dysfunction”. Journal of Pharmacology and Experimental

Therapeutics, vol. 296, no. 2, pp. 225-234, 2001.




30. S.K. Agarwal, A. Prakash, and N.P. Singh, “Erectile dysfunction in diabetes mellitus: Novel

treatments”. International Journal of Diabetes in Developing Countries, vol. 23, pp. 94-98,

2003.

31. K.J. Hurt, B. Musicki, M.A. Palese, J.K. Crone, R.E. Becker, J.L. Moriarity, S.H. Snyder, and

A.L. Burnett, “Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates

penile erection”. Proceedings of the National Academy of Sciences of the United State of

America, vol. 99, no. 6, pp. 4061-4066, 2002.

32. B.J. Michell, J.E. Griffiths, and K.I. Mitchelhill et al., “The Akt kinase signals directly to

endothelial nitric oxide synthase”. Current Biology, vol. 9, no. 15, pp. 845-848, 1999.

33. K. Paskaloglu, G. Sener, and G. Ayanoglu-Dulger, “Melatonin treatment protects against

diabetes –induced functional and biochemical changes in rat aorta and corpus cavernosum”.

European Journal of Pharmacology, vol. 499, pp. 345-354.

34. T.J. Bivalacqua, M.F. Usta, M. Kendirci, L. Pradhan, X. Alvarez, H.C. Champion, P.J.

Kadowitz, and W.J. Hellstrom, “Superoxide anion production in the rat penis impairs erectile

function in diabetes: influence of in vivo extracellular superoxide dismutase gene therapy”.

The Journal of Sexual Medicine, vol. 2, no. 2, pp. 187-197, 2005.

35. H. Tsubouchi, T. Inoguchi, T. Sato, N. Sato et al., “Statin attenuates high glucose induced and

diabetes induced oxidative stress in vitro and in vivo evaluated by electron spin resonance

measurement”. Free Radical Biology and Medicine, vol. 39, no. 4, pp. 444-452, 2005.

36. S. Kimura, G.X. Zhang, T. Shokoji, I. Yao, Y.Y. Fan et al., “Role of NAD(P)H oxidase and

mitochondria derived reactive oxygen species in cardioprotection of ischemic reperfusion

injury by angiotensin II”. Hypertension, vol. 45, pp. 860-866.

37. K.E. Andersson, “Neurophysiology/pharmacology of erection”. International Journal of

Impotence Research, vol. 13(suppl 3), pp. S8-S17, 2001.

38. T.M. Mills, K. Chitaley, R.W. Lewis, and R.C. Webb, “Nitric oxide inhibits RhoA/ Rho-

kinase signaling to cause penile erection”. European Journal of Pharmacology, vol. 439, no. 1,

pp. 173-174, 2002.

39. B. Barbul, “Arginine: biochemistry, physiology, and therapeutic implications”. Journal of

Parenteral and Enteral Nutrition, vol. 10, pp. 227-238, 1986.

40. G. Wu, and S.M. Morris, “Arginine metabolism: NO and beyond”. Biochemical Journal, vol.

336, no. 1, pp. 1-17, 1998.




41. E. David, “Arginine metabolism: Enzymology, Nutrition and Clinical Significance”.

American Society of Nutritional Science, 2004.

42. W. Zhang, B. Baban, M. Rojas, S. Tofigh, C. Patel et al., “Arginase activity mediates retinal

inflammation in endotoxin induced uveitis”. American Journal of Pathology, vol. 175, pp.

891-902, 2009.

43. J.G. Vockley, C.P. Jenkinson, H. Shukla, and R.M. Kern, “Cloning and characterization of

human type II human arginase gene”. Genomics, vol. 38, no. 2, pp. 118-123, 1996.

44. J.J. Cartledge, I. Eardley, and J.F. Morrison, “Impairment of corpus cavernosal smooth

muscle relaxation by glycosylated human haemoglobin”. British Journal of Urology

International, vol. 85, no. 6, pp. 735-741, 2000.

45. S.M. Morris, and D. Bhamidipati, “Human type II arginase: sequence analysis and tissue

specific expression”. Gene, vol. 193, no. 2, pp. 157-161, 1997.

46. A. Ceriello, “New insights on oxidative stress and diabetic complications may lead to a

„causal‟ antioxidant therapy”. Diabetes Care, vol. 26, no. 5, pp. 1589-1596, 2003.

47. M.M. Spitaler, and W.F. Graier, “Vascular targets of redox signaling in diabetes mellitus”.

Diabetologia, vol. 45, pp. 476-494, 2002.

48. F.G. Soriano, L. Virag, P. Jagtap, E. Szabo, J.G. Mabley, and L. Liaudet, “Diabetic

endothelial dysfunction: the role of poly (ADP-ribose) polymerase activation”. Nature

Medicine, vol. 7, pp. 108-113, 2001.

49. M.F. Usta, T.J. Bivalacqua, D.Y. Yang, A. Ramanitharan, D.R. Sell, and A. Viswanathan et

al., “The protective effect of aminoguanidine on erectile function in streptozotocin diabetic

rats”. Journal of Urology, vol. 170, no. 4, pp. 1437-1442, 2003.

50. A.R. White, S. Ryoo, H.C. Champion, J. Steppan, D. Wang et al., “Knockdown of arginase I

restores NO signaling in the vasculature of old rats”. Hypertension, vol. 47, no. 2, pp. 245-

251, 2006.

51. M.J. Romero, and R.B. Caldwell, “Does elevated arginase activity contributes to diabetes-

induced endothelial dysfunction”. Federation of American Societies for Experimental

Biology, vol. 20, pp. 1125-1129, 2006.

52. M.J. Romero, D.H. Platt, H.E. Tawfik, and M. Bartoli, “Diabetes induced coronary vascular

dysfunction involves increased arginase activity”. Circulation Research, vol. 102, pp. 95-102,

2008.




53. X. Gao, X. Xu, S. Belmandi, Y. Park, Z. Tang et al., “TNF alpha Contributes to the

endothelial dysfunction by upregulating arginase in ischaemia/ reperfusion injury”.

Arteriosclerosis, Thrombosis and Vascular Biology, vol. 27, pp. 1269- 1275, 2007.

54. K.E. Andersson, and G. Wagner, “Physiology of penile erection”. Physiological Reviews, vol.

75, no. 1, pp. 191-236, 1995.

55. M.P. Walsh, “The Ayerst Award Lecture 1990. Calcium dependent mechanisms of regulation

of smooth muscle contraction”. Biochemistry and Cell Biology, vol. 69, pp. 771-800, 1991.

56. A.P. Somlyo, and A.V. Somlyo, “Signal transduction by G-proteins, Rho-kinase and protein

phosphatase to smooth muscle and non-muscle myosin II”. Journal of Physiology, vol. 522,

no. 2, pp. 177-185, 2000.

57. R.W. Rees, T. Zeissen, D.J. Ralph, P. Kell, S. Moneada et al., “Human and rabbit cavernosal

smooth muscle cells express Rho-kinase”. International Journal of Impotence Research, vol.

14, no. 1, pp. 1-7, 2002.

58. H. Wang, M. Eto, W.D. Steers, A.P. Somlyo, and A.V. Somlyo, “RhoA mediated Ca2+

sensitization in erectile function”. The Journal of Biological Chemistry, vol. 277, no. 34, pp.

14-21, 2002.

59. K. Chitaley, R.C. Webb, T.M. Mills et al., “RhoA/Rhokinase: a novel player in the regulation

of penile erection”. International Journal of Impotence Research, vol. 13, pp. 67-72, 2001.

60. T.M. Mills, K. Chitaley, R.W. Lewis, and R.C. Webb, “Nitric oxide inhibits RhoA/Rho-

kinase signaling to cause penile erection”. European Journal of Pharmacology, vol. 439, no.1 ,

pp. 173-174, 2002.

61. K. Chitaley, C.J. Wingard, R. Clinton et al., “Antagonism of Rho-kinase stimulates rat penile

erection via a nitric oxide-independent pathway”. Nature Medicine, vol. 7, no. 1, pp. 119-122,

2001.

62. T.G. Bivalacqua, T.C. Champion, M.F. Usta et al., “RhoA/Rho-kinase suppresses endothelial

nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction”.

Proceedings of the National Academy of Sciences of the United States of America, vol. 101,

no. 24, pp. 9121-9126, 2004.

63. K. Park, S.W. Kim, S.W. Rhu, and J.S. Paick, “Chronic administration of an oral Rho Kinase

inhibitor prevents the development of vasculogenic erectile dysfunction in a rat model”. The

Journal of Sexual Medicine, vol. 3, no. 6, pp. 996-1003, 2006.




64. W.J. Li, K. Park, J.S. Paick, and S.W. Kim, “Chronic treatment with an oral Rho-kinase

inhibitor restores erectile function by suppressing corporal apoptosis in diabetic rats”. The

Journal of Sexual Medicine, vol. 8, no. 2, pp. 400-410, 2011.

65. M. Uehata, T. Ishizaki, H. Satoh, J. Ono, T. Kawahara et al., “Calcium sensitization of smooth

muscle mediated by a Rho-associated protein kinase in hypertension”. Nature, vol. 389, pp.

990-994, 1997.

66. G. Ari, Y. Vardi, and J.P. Finberg, “Nitric oxide and penile erection in streptozotocin-diabetic

rats”. Clinical Science London, vol. 96, pp. 365-371, 1999.

67. A.I. El-Sakka, C.S. Lin, R.M. Chui, R. Dahiya, and T.F. Lue, “Effects of diabetes on nitric

oxide synthase and growth factor genes and protein expression in an animal model”.

International Journal of Impotence Research, vol. 11, no. 3, pp. 123-132, 1999.

68. A.G. Akingba, and A.L. Burnett, “Endothelial nitric oxide synthase protein expression,

localization, and activity in the penis of the alloxan-induced diabetic rat”. Molecular Urology,

vol. 5, no. 4, pp. 189-197, 2001.

69. C.S. Thompson, F.H. Mumtaz, M.A. Khan, R.M. Wallis, D.P. Mikhailidis, R.J. Morgan, G.D.

Angelini, and J.Y. Jeremy, “The effect of sildenafil on corpus cavernosal smooth muscle

relaxation and cyclic GMP formation in the diabetic rabbit”. European Journal of

Pharmacology, vol. 425, no. 1, pp. 57-64, 2001.

70. A. Escrig, R. Marin, P. Abreu, J.L. Gonzalez-Mora, and M. Mas, “Changes in mating

behavior, erectile function, and nitric oxide levels in penile corpora cavernosa in

streptozotocin-diabetic rats”. Biology of Reproduction, vol. 66, no. 1, pp. 185-189, 2002.

71. T.J. Bivalacqua, M.F. Usta, H.C. Champion, D. Adams, D.B. Namara, A.B. Abdel- Mageed,

P.J. Kadowitz, and W.J. Hellstrom, “Gene transfer of endothelial nitric oxide synthase

partially restores nitric oxide synthesis and erectile function in streptozotocin diabetic rats”.

Journal of Urology, vol. 169, no. 5, pp. 1911-1917, 2003.

72. K.J Way, and J.J. Reid, “The effects of diabetes on nitric oxide-mediated responses in rat

corpus cavernosum”. European Journal of Pharmacology, vol. 376, no. 1, pp.73-82, 1999.

73. A.P. Somlyo, and A.V. Somlyo, “Signal transducing by G-proteins, Rho-kinase and protein

phosphatase to smooth muscle and non muscle myosin II”. Journal of Physiology, vol. 522,

no. 2, pp. 177-185, 2000..




74. K. Chitaley, C.J. Wingard, R.W. Clinton, H. Branam, V.S. Stopper, R.W. Lewis, and T.M.

Mills, “Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent

pathway”. Nature Medicine, vol. 7, no. 1, pp. 119-122, 2001.

75. K. Chitaley, R.C. Webb, and T.M. Mills, “The ups and downs of Rho-kinase and penile

erection: upstream regulators and downstream substrates of rho-kinase and their potential role

in the erectile response”. International Journal of Impotence Research, vol. 15, pp. 105-109,

2003.

76. T.M. Mills, K. Chitaley, and R.W. Lewis, “Vasoconstrictors in erectile physiology”.

International Journal of Impotence Research, vol. 13, no. 5, pp. 29-34, 2001.

77. R.W. Rees, D.J. Ralph, M. Royle, S. Moncada, and S. Cellek S, “Y-27632, an inhibitor of

Rho-kinase, antagonizes noradrenergic contractions in the rabbit and human penile corpus

cavernosum”. British Journal of Pharmacology, vol. 133, no. 4, pp. 455-458, 2001.

78. F. Guagnini, M. Ferazzini, M. Grasso, S. Blanco, and T. Croci, “Erectile properties of the

Rho-kinase inhibitor SAR407899 in diabetic animals and human isolated corpora cavernosa”.

Journal of Translational Medicine, vol. 10, pp. 1-11, 2012.

79. M.B. Ganz, and A. Seftel, “Glucose induced changes in protein kinase C and nitric oxide are

prevented by Vit E”. American Journal of Preventive Medicine, vol. 278, pp. 146-152, 2000.

80. X.F. Ming, H. Viswambharan, C. Barandier, J. Ruffieux, K. Kaibuchi, S. Rusconi, and Z.

Yang, “Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase

phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells”.

Molecular and Cellular Biology, vol. 22, no. 24, pp. 8467-8477, 2002.

81. T.J Bivalacqua, M.F. Usta, K. Chitaley, H.C. Champion, R.C. Webb, R.W. Lewis, T.M. Mills,

and W. Hellstrom, “Adeno-associated viral gene transfer of dominant negative RhoA

improves erectile function in streptozotocin diabetic rats [abstract]”. Journal of Urology, vol.

169, pp. 1198, 2003.

82. P.A. Craven, R.K. Studer, and H. Negrete, “Protein kinase C in diabetic nephropathy”.

Journal of Diabetes and Its Complications, vol. 9, no. 4, pp. 241-245, 1995.

83. T. Bonke, S.R. Thorpe, M.T. Coughlan, K. Fukami, F.Y. Yap et al., “Inhibition of NADPH

oxidase prevents AGE product mediated damage in diabetic nephropathy through a protein

kinase C alpha dependent pathway”. Diabetes, vol. 57, no. 2, pp. 460-469, 2008.




84. T. Shiba, T. Ionguchi, J.R. Sportsman, W. Health, S. Bursella et al., “Correlation of

diacylglycerol and PKC activity in rat retina circulation”. American Journal of Physiology,

vol. 235, no. 5, pp. 783-793, 1993.

85. T. Inoguchi, R. Battan, E. Handler, J.R. Sportsman, W. Health et al., “Preferential elevation of

protein kinase C isoform and diacylglycerol levels in the aorta and heart of diabetic rats,

differential reversibility to glycemic control by islet cell transplantation”. Proceedings of

National Academy of Sciences United State of America, vol. 89, pp. 11059-11063, 1992.

86. M. Kunisaki, S.E. Bursell, F. Umeda, H. Nawata, and G.L. King, “Normalization of DAG-

Protein kinase C activation by Vit E in aorta of diabetic rats and cultured rat smooth muscle

cells exposed to elevated glucose levels”. Diabetes, vol. 43, no. 11, pp. 1372-1377, 1994.

87. D. Wallach, E.E. Varfolomeer, N.L. Malinin, Y.V. Goltser, A.V. Kovalenko et al., “Tumour

necrosis factor receptor and FAS signaling mechanisms”. Annual Review of Immunology,

vol. 17, pp. 331-367, 1999.

88. M. Grell, H. Wajant, G. Zimmermann, and P. Scheurich, “The type I receptor (CD120a) is the

high affinity receptor and FAS signaling mechanisms”. Annual Review of Immunology, vol.

17, pp. 331-367, 1999.

89. R. Lucas, I. Garica, Y.R. Donati, M. Hribar, S.J. Mandriota et al., “Uromodulin (Tamm-

Horsfall glycoprotein): a renal ligand for lymphokines”. Science, vol. 237, pp. 1479-1484,

1987.

90. K.L Mac Naul, and N.I. Hutchinson, “Differential expression of iNOS and cNOS mRNA in

human vascular smooth muscle cells and endothelial cells under normal and inflammatory

conditions”. Biochemical and Biophysical Research Communications, vol. 196, no. 3, pp.

1330-1334, 1993.

91. D. Sorescu, and K.K. Griendling, “ROS, mitochondria, amd NADPH oxidases in the

development and progression of heart failure”. Congestive Heart Failure, vol. 8, no. 3, pp.

132-140, 2002.

92. J.M. Downey, B. Omar, and H. Ooiwa, “SOD therapy for myocardial ischemia”. Free Radical

Research Communications, vol. 12, pp. 703-720, 1991.

93. K.A. Pritchard, L. Groszek, D.M. Smalley, W.C. Sessa, M. Wu et al., “Native LDL increases

endothelial cell NO synthase generation of superoxide anion”. Circulation Research, vol. 77,

no. 3, pp. 510-518, 1995.




94. T. Ferro, P. Neumann, N. Gertzberg, R. Clements, and A. Johnson, “Protein kinase C alpha

mediates endothelial barrier dysfunction induced by TNF alpha”. American Journal of

Physiology Lung Cellular and Molecular Physiology, vol. 278, pp. 1107-1117, 2000.

95. K. Daisuke, and K. George, “Protein kinase C activation and development of diabetic

complications”. Diabetes, vol. 47, pp. 121-125, 1998.

96. D.B. Jiaan, A.D. Seftel, J. Forarty, N. Hampel, W. Cruz et al., “Age related increase in AGE

in penile tissue”. World Journal of Urology, vol. 13, pp. 369-375, 1995.

97. C.R. Moore, and R. Wang, “Pathophysiology and treatment of diabetic erectile dysfunction”.

Asian Journal of Andrology, vol. 8, no. 6, pp. 675-684, 2006.

98. M.E. Sullivan, M.R. Dashwood, C.S. Thompson, J.R. Muddle, D.P. Mikhailidis et al.,

“Alterations in endothelin B receptor sites in cavernosal tissue of diabetic rabbits: potential

relevance to the pathogenesis of erectile dysfunction”. Journal of Urology, vol. 158, no. 5, pp.

1966-1972, 1997.

99. V.S. Thore, A.D. Kshirsagar, N.S. Vyawahare, V.S. Joshi, K.G. Ingale et al., “Diabetes

induced Erectile dysfunction: epidemiology, pathophysiology and management”. Journal of

Diabetes and Its Complications, vol. 25, pp. 129-136, 2011.

100. L.C. Maillard LC, “Action des acides amines sur les sacres, formation des melanoidines par

voie methodique”. Proceedings of the Academy of Sciences, vol. 154, no. 2, pp. 66-68, 1912.

101. R. Nagai, T. Mori, Y. Yamamoto, Y. Kaji, and Y. Yonei, “Significance of advanced

glycated end products in aging-related disease”. Japanese Society of Anti-aging Medicine,

vol. 7, no. 10, pp. 112-119, 2010.

102. M. Brownlee, A. Cerami, and H. Vlassara, “Advanced glycosylation end products in tissue

and the biochemical basis of diabetic complications”. The New England Journal of Medicine,

vol. 318, no. 20, pp. 1315-1321, 1988.

103. C. Vlachopoulos, K. Aznaouridis, N. Ioakeimidis, K. Rokkas, C. Vasiliadou, N.

Alexopoulos, E. Stefanadi, A. Askitis, and C. Stefanadis, “Unfavourable endothelial and

inflammatory state in erectile dysfunction patients with or without coronary artery disease”.

European Heart Journal, vol. 27, pp. 2640-2648, 2006.

104. C. Vlachopoulos, K. Rokkas, N. Ioakeimidis, and C. Stefanadis, “Inflammation, metabolic

syndrome, erectile dysfunction, and coronary artery disease: Common links”. European

Urology, vol. 52, pp. 1590-1600, 2007.




105. C.B. Johannes, A.B. Araujo, H.A. Feldman, C.A. Derby, K.P. Kleinman, and J.B.

McKinlay, “Incidence of erectile dysfunction in men 40–69 years old: Longitudinal results

from the Massachusetts male aging study”. Journal of Urology, vol. 163, no. 2, pp. 460-463,

2000.

106. F.S. Carneiro, L.C. Sturgis, F.R. Giachini, Z.N. Carneiro, V.V Lima, B.M. Wynne, S. San

Martin, M.W. Brands, R.C. Tostes, and R.C. Webb, “TNF-alpha knockout mice have

increased corpora cavernosa relaxation”. The Journal of Sexual Medicine, vol. 6, no. 1, pp.

115-125, 2009.

107. I. Kifor, G.H. Williams, M.A. Vickers, M.P. Sullivan, P. Jodbert, and R.G. Dluhy, “Tissue

angiotensin II as a modulator of erectile function, Angiotensin peptide content, secretion and

effects in the corpus cavernosum”. Journal of Urology, vol. 157, pp. 1920-1925, 1997.

108. E.L. Schiffrin, and R.M. Touyz, “From bedside to bench to bedside: Role of renin-

angiotensin-aldosterone system in remodeling of resistance arteries in hypertension”.

American Journal of Physiology- Heart and Circulatory Physiology, vol. 287, pp. 435-446,

2004.

109. S. Granchi, G.B. Vannelli, L. Vignozzi, C. Crescioli, P. Ferruzzi, R. Mancina, M.C. Vinci, G.

Forti, S. Filippi, M. Luconi, F. Ledda, and M. Maggi, “Expression and regulation of

endothelin-1 and its receptors in human penile smooth muscle cells”. Molecular Human

Reproduction, vol. 8, no. 12, pp. 1053-1064, 2002.

110. E.L. Schiffrin, “Vascular endothelin in hypertension”. Vascular Pharmacology, vol. 43, pp.

19-29, 2005.

111. R.C. Tostes, and M.N. Muscara, “Endothelin receptor antagonists: Another potential

alternative for cardiovascular diseases”. Current Drug Targets- Cardiovascular and

Hematological Disorders, vol. 5, pp. 287-301, 2005.

112. P.A. Marsden, and B.M Brenner, “Transcriptional regulation of the endothelin-1 gene by

TNF-alpha”. American Journal of Physiology, vol. 262, pp. 854-861, 1992.

113. N.R. Ferreri, Y. Zhao, H. Takizawa, J.C. McGiff, “Tumor necrosis factor-alpha-angiotensin

interactions and regulation of blood pressure”. Journal of Hypertension, vol. 15, no. 12, pp.

1481-1484, 1997.

114. B. Luo, L. Liu, L. Tang, J. Zhang, Y. Ling, and M.B. Fallon, “ET-1 and TNF-alpha in HPS:

Analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats”.




American Journal of Physiology- Gastrointestinal and Liver Physiology, vol. 286, no. 2, pp.

294-303, 2004.

115. T. Kagawa, T. Takao, T. Horino, R. Matsumoto, K. Inoue, T. Morita, and K. Hashimoto,

“Angiotensin II receptor blocker inhibits tumour necrosis factor-alpha-induced cell damage in

human renal proximal tubular epithelial cells”. Nephrology (Carlton), vol. 13, no. 4, pp. 309-

315, 2008.

116. M. Cardenas-Leon, E. Diaz-Diaz, R. Arguelles-Medina, P. Sanchez-Canales, V. Diaz-

Sanchez et al., “Glycation and protein crosslinking in the diabetes and ageing pathogenesis”.

Revista de Investigacion Clinica, vol. 61, pp. 505-520, 2009.

117. J.J Cartledge, I. Eardley, and J.F. Morrison, “Nitric oxide mediated corpus cavernosal

smooth muscle relaxation is impaired in ageing and diabetes”. British Journal of Urology

International, vol. 87, pp. 394-401, 2001.

118. G. Basta, A.M. Schimidt, C. De, “Advanced glycation end products and vascular

inflammation: implications for accelerated atherosclerosis in diabetes”. Cardiovascular

Research, vol. 63, no. 4, pp. 582-592, 2004.

119. R. Bucala, K.J. Tracey, and A. Cerami, “Advanced glycosylation products quench nitric

oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes”.

Journal of Clinical Investigation, vol. 87, no. 2, pp. 432-438, 1991.

120. M. Brownlee, “Biochemistry and molecular cell biology of diabetic complications”. Nature,

vol. 414, no. 6865, pp. 813-820, 2001.

121. D.B. Jiaan, A.D. Seftel, J. Fogarty, N. Hampel, W. Cruz, J. Pomerantz, and M. Zuik, and

V.M. Monnier, “Age-related increase in an advanced glycation end product in penile tissue”.

World Journal of Urology, vol. 13, no. 6, pp. 369-375, 1995.

122. A.D. Seftel, N.D. Vaziri, Z. Ni et al., “Advanced glycation end products in human penis:

elevation in diabetic tissue, site of deposition, and possible effect through iNOS or eNOS”.

Urology, vol. 50, pp. 1016-1026, 1997.

123. R. Lehmann, and E.D. Schleicher, “Evaluation of glutathione S-transferase P1 genetic

variants affecting type-2 diabetes susceptibility and glycemic control”. Clinica Chimica Acta,

vol. 297, pp. 135-144, 2000.

124. A. Heidland, K. Sebekova, and R. Schinzel, “Advanced glycation end products and the

progresive course of renal disease”. American Journal of Kidney Diseases, vol. 38, no. 4, pp.

100-106, 2001.




125. H. Vlassara, J. Cai, T. Crandal, R. Goldberg, and V. Oberstein, “Inflammatory markers are

induced by dietary glycotoxins: A pathway for accelerated atherosclerosis in diabetes”.

Proceedings of National Academic Sciences, vol. 99, no. 24, pp. 15596-15601, 2002.

126. R. Singh, A. Barden, T. Mori, and L. Beilin, “Advanced glycated end products: a review”.

Diabetologia, vol. 44, pp. 129-145, 2001.

127. T.J. Bivalacqua, M.F. Usta, M. Kendirci, L. Pradhan, and X. Alvarez, “Superoxide anion

production in rat penis impairs erectile function in diabetes: influence of in vivo extracellular

superoxide dismutase gene therapy”. The Journal of Sexual Medicine, vol.2, pp. 187-197,

2005.

128. J.J. Cartledge, I. Eardley, and J.F. Morrison, “Advanced glycation end-products are

responsible for the impairment of corpus cavernosal smooth muscle relaxation seen in

diabetes”. British Journal of Urology International, vol. 87, no.4, pp. 402-407, 2001.

129. R.A. Costabile, “Optimizing treatment for diabetes mellitus induced erectile dysfunction”.

Journal of Urology, vol. 170, pp. 35-39, 2003.

130. S. Morano, “Pathophysiology of diabetic sexual dysfunction”. Journal of Endocrinological

Investigation, vol. 26, pp. 65-69, 2003.

131. D. Chen, Y.X. Shan, and Y.T. Dai, “Advanced glycation end products and their receptors

elevate the activity of endothelin-1 in rat cavernosum”. Zhonghua Nan Ke Xue, vol. 14, pp.

110-115, 2008.

132. S. Cellek, J. Rodrigo, E. Lobos, P. Fernandez, J. Serrano et al., “Selective nitrergic

neurodegeneration in diabetes mellitus- a nitric oxide-dependent phenomenon”. British

Journal of Pharmacology, vol. 128, no. 8, pp. 1804-1812, 1999.

133. H. Vlassara, “The AGE-receptor in the pathogenesis of diabetic complications”. Diabetes/

Metabolism Research and Reviews, vol. 17, pp. 436-443, 2001.

134. M.F. Usta, M. Kendirci, S. Gur, N.A. Foxwell, T.J. Bivalacqua et al., “The breakdown of

preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-

induced diabetic rats: preventive versus curative treatment”. The Journal of Sexual Medicine,

vol. 3, pp. 242-250, 2006.

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International Journal of Innovative Pharmaceutical ...ijipsr.com/sites/default/files/articles/IJIPSRMN-80 (1).pdf · 2Department of Pharmacy, SBS PG Institute of Biomedical Sciences,