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Renin-Angiotensin-Aldosterone System Blockade:A Foundation for Antihypertensive Therapy
George R. Aronoff, M.D., FACPProfessor of Medicine and Pharmacology
Chief, Division of NephrologyUniversity of Louisville School of Medicine
Renin-Angiotensin-Aldosterone System Blockade:A Foundation for Antihypertensive Therapy
Educational Objectives
– Review physiology of renin-angiotensin system
– Establish renin-angiotensin system as major regulator of blood pressure
– Review strategies for blocking renin-angiotensin system
The Kidneys and Circulation
Hypothesis– “A blood-pressure raising substance is formed
in the kidneys and passed into the blood”
Methods– Homogenized fresh rabbit kidney in saline– Centrifuged the material– Injected the supernatant fluid into other
rabbits
Tigerstedt R, Bergman PG: Niere und kreislauf. Scand Arch Physiol 8: 223, 1898
Tigerstedt R, Bergman PG: Niere und kreislauf. Scand Arch Physiol 8: 223, 1898
“For the sake of brevity we will call it Renin”
Goldblatt Hypothesis– Decreased blood flow to
the kidneys results in renal ischemia
– Causes increased blood pressure
Methods– Partial constriction of
renal arteries of dogs using adjustable silver clamp
Goldblatt H, Lynch J, Hanzal RF, Summerville WW: Studies on experimental hypertension. I. The production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 59: 347, 1934
Simultaneous Discoveries
– Purified renin extract limited effect on blood pressure
– Requires “renin substrate”– Results in formation of
“hypertensin” or “angiotonin”
Angiotensin
Page, I.H., and O.M. Helmer. 1939. Proc. Center Soc. Clin. Invest. 12:17.Braun-Menendez, E., and J.C. Fasciolo. 1939. Rev. Soc. Argent. Biol. 15:420–425.
Blood Pressure = C.O. X Peripheral Resistance
Vasoconstriction
ReninAngiotensinAldosterone
System
SympatheticNerve
Activity
ContractilityHeart Rate
Preload
RenalSodium
Retention
Control of Blood Pressure
Angiotensin AT1 Receptor
Extracellular
Intracellular
Murphy TJ, Alexander RW, Griendling KK, Runge MSand Bernstein KE (1991)Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature(Lond) 16:233–236.
Ca2+
ExtracellularAngiotensin II
AT1receptor
AT1receptor
Cell membrane
Intracellular
G protein Gq protein
Mitochondria
Aldosteroneproduction
SteroidSynthesis
Ca2+
Myofilaments
Vaso-constricton
Endoplasmic reticulumCa2+ storage
SecretoryGranules
Catecholaminerelease
PLA2 AA LysPC
PC
Prostaglandins
GeneTranscriptionTranslation
mRNA
AT1
A II
Cell growth
ProteinSynthesis
Growthfactor
Structural Proteins
Angiotensin II
PLC
PIP2
DAG
IP3
Renin secreted by kidney inResponse to decreased renal perfusion.
Renin cleaves angiotensinogenTo form Angiotensin I
Ang I converted toAng II by ACE and Non-ACE enzymes
Ang II
ACEAT1
Ang II inhibitsRenin release.
Renin
ACE-IACE-IARBARB
DRIDRI
Angiotensinogen452AA
Ang I
10AA
8AA
Renin secreted by kidney inResponse to decreased renal perfusion.
Renin cleaves angiotensinogenTo form Angiotensin I
Ang I converted toAng II by ACE and Non-ACE enzymes
Ang II
ACEAT1
Ang II inhibitsRenin release.
Renin
ACE-IACE-I
Angiotensinogen452AA
Ang I
10AA
98AA
Antihypertensive Effect of the Oral Angiotensin Converting-enzyme Inhibitor SQ
14225 in man.
– 12 hypertensive patients
– 400 to 1,000 mg daily
– 3 to 12 weeks
0
20
40
60
80
100
120
140
160
180
Control SQ14225
Systolic
Diastolic
Gavras H, Brunner HR, Turini GA et al. Antihypertensive effect of the oral angiotensin converting-enzyme inhibitor SQ 14225 in man. N Engl J Med. 1978 May 4;298(18):991-5.
The Effect of Angiotensin-Converting-Enzyme Inhibition on Diabetic Nephropathy
409 IDDM Patients Randomized– proteinuria more than 500 mg/day– creatinine less than 2.5 mg/dl– 3 - 4 years follow-up– Captopril 25 mg tid or Placebo– Blood Pressure Equally Controlled– Doubling of Serum Creatinine
Lewis, et al. NEJM 329:1456-62, 1993.
0 1 2 3 4 5
Years of Follow-up
0
10
20
30
40
50
60
70
80%
W
ith D
oubl
ing
of B
ase-
line
Cre
atin
ine
Placebo ≥ 1.5 mg/dl
Captopril ≥ 1.5 mg/dl
Placebo < 1.5 mg/dl
Captopril < 1.5 mg/dl
Lewis, et al. NEJM 329:1456-62, 1993.
Renin secreted by kidney inResponse to decreased renal perfusion.
Renin cleaves angiotensinogenTo form Angiotensin I
Ang I converted toAng II by ACE and Non-ACE enzymes
Ang II
ACEAT1
Ang II inhibitsRenin release.
Renin
ARBARB
Angiotensinogen452AA
Ang I
10AA
8AA
Antihypertensive Effect of a Non-peptide Angiotensin II receptor Antagonist, MK954, in
Patients with Essential Hypertension
– 8 hypertensive patients
– 12.5 mg to 100 mg per day
– 2 to 4 weeks
Hagino T, Abe K, Tsunoda K, Yoshinaga K. Nippon Jinzo Gakkai Shi. 1992 Feb;34(2):133-40.
0
20
40
60
80
100
120
140
160
180
Control MK 945
Systolic
Diastolic
RENAAL Reduction of Endpoints in Non-insulin Dependent Diabetes Mellitus With the
Angiotensin II Antagonist Losartan
– Multicenter
– Randomized
– Placebo controlled
– 1,513 type II diabetics
Brenner et al. NEJM Sept. 2001
RENAALRisk Reduction
-25
-35
-25
-35
-30
-25
-20
-15
-10
-5
0
Per
cen
t
Doubling ofCreatinine
Proteinuria ESRD
Brenner et al. NEJM Sept. 2001
AliskirenDirect Renin Inibitor
National Center for Biotechnology Information. PubChem.
Molecular Formula
C30 H53 N3 O6
Molecular Weight
551.758g/mol
(2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methyl-propyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-propan-2-yl-nonanamide
Alice HuxleyThe $880 Million Smile
Wood et al. BBRC 2003.
Aliskiren Binding to Renin
Renin
Aliskiren bound toActive site
Aliskiren
Direct renin inhibitor– 50 – 80 % decrease plasma renin activity
Pharmacokinetics– Accumulation Half-life of ~ 24 hours– 7 – 8 days to achieve steady state levels– Elimination Half-life of ~ 48 hours– 25 % excreted by kidneys– Metabolized by CYP 450-3A4– Does not induce or suppress CYP 450– No effect on QT interval
Aliskiren in Human Hypertension
– 652 hypertensive patients
– Randomized to:
Placebo
Aliskiren 150 mg, 300 mg, 600 mg
Irbesartan 150 mg
– Treated for 4 weeks
Gradman, AH, Schmieder, RE, Lins, RL, et al. Circulation, Volume 111(8).March 1, 2005.1012-1018
Effect of Aliskiren on Systolic Blood Pressure
Gradman, AH, Schmieder, RE, Lins, RL, et al. Circulation, Volume 111(8).March 1, 2005.1012-1018
Effect of Aliskiren on Diastolic Blood Pressure
Gradman, AH, Schmieder, RE, Lins, RL, et al. Circulation, Volume 111(8).March 1, 2005.1012-1018
Aliskiren Adverse Events6,460 patients
Discontinuation– 2.2% (3.5% placebo)
Cough– 1.1% (0.6% placebo)
Angioedema– Less than 0.06 % (2 cases reported with respiratory symptoms)
Hyperkalemia– 0.9% (0.6% placebo)– 5.5 % when in combination with ACE-I
GI side effects– Diarrhea (2.3 % with 1.2% placebo)
Do not use in pregnancy
Antiproteinuric Effects of Aliskiren
– 15 Patients
– Type 2 DM
– Elevated urinary albumin/creatinine ratio
– eGFR ≥ 40 mL/min
– 4 week washout
– Aliskiren 300 mg daily
– 28 days
Persson F, et al. Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int. 2008 Mar 12
Antiproteinuric Effects of Aliskiren
Persson F, et al. Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int. 2008 Mar 12
Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy
– 599 patients
– multinational, randomized, double-blind
– UACR > 300 ≤ 3,500
– All received 100 mg losartan
– Aliskiren 150 mg for 3 mo, then 300 mg for 3 mo or placebo
– Reduction in urine albumin/creatinine at 6 months
Parving H-H, Persson F, Lewis, JB; for the AVOID Study Investigators. NEJM 358(23), 5 June 2008, p 2433–2446.
Mean Blood Pressureat Baseline and End of Study
Parving H-H, Persson F, Lewis, JB; for the AVOID Study Investigators. NEJM 358(23), 5 June 2008, p 2433–2446.
Primary EndpointDifference UACR at 6 Months
20 %P < 0.001
Parving H-H, Persson F, Lewis, JB; for the AVOID Study Investigators. NEJM 358(23), 5 June 2008, p 2433–2446.
One in four aliskiren patients had > 50 % reduction UACR
Effect of Aliskiren in Patientswith Heart Failure
302 Patients– Stable heart failure– Hypertension– BNP > 100 pg/ml
Randomized– Placebo or 150 mg aliskiren for 12
weeks– Standard therapy for HF (ACEI or ARB)
McMurray JJV, et al. Circ Heart Fail 2008;1:17-24
Aliskiren DecreasedNT-proBNP and BNP
McMurray JJV, et al. Circ Heart Fail 2008;1:17-24
Conclusions– Over a century of research has led
elucidation of an important mechanism in the control of blood pressure in humans
– RAAS is a target for the control of human hypertension
– Downregulation of RAAS decreases the rate of sclerosing kidney disease
Renin-Angiotensin-Aldosterone System Blockade:A Foundation for Antihypertensive Therapy