Renin-Angiotensin-Aldosterone System Blockade: A Foundation for Antihypertensive Therapy George R....

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