Role of renin angiotensin aldosterone system activation

Angiotensin II is formed from the substrate angiotensinogen through a series of steps. Renin catalyzes the conversion of angiotensinogen to angiotensin I, which is subsequently hydrolyzed by ACE to form angiotensin II. Alternate pathways, such as tissue plasminogen activator, cathepsin G, and tonin, also convert angio-tensinogen directly to angiotensin II, whereas angiotensin I is also catalyzed to angiotensin II by chymase and cathepsin G [46,47]. Angiotensin II mediates deleterious effects by binding specific receptors located on the cell membrane. Angio-tensin II receptor type I mediates the biologic activities that are harmful to the tissues. The expression of angiotensin II receptor type II is

Table 4

Angiotensin receptor blockers in clinical trials

Table 4

Angiotensin receptor blockers in clinical trials

Condition

Trial

Drugs

N

Duration

Outcome

Result

LVH and

LIFE [33]

losartan, 50-100 mg, versus

9193

5 yr

composite CV mortality,

13% RR (P = 0.021)

hypertension

atenolol, 50-100 mg

MI, stroke

hypertension

VALUE [34]

valsartan, up to 160 mg, versus

15,245

4.2 yr

composite endpoint of

no difference between valsartan and

amlodipine, up to 10 mg

mortality and morbidity

amlodipine

diabetic

IDNT [35]

irbesartan, up to 300 mg, versus

1715

2.6 yr

doubling of SCR, ESRD

20% lower than placebo (P = 0.02)

nephropathy

amlodipine, up to 10 mg,

or death

23% lower than amlodipine

versus placebo

(P = 0.006)

diabetic

IRMA [36]

irbesartan, 150 mg or 300 mg,

590

3 mo

albuminuria, overt proteinuria

24% lower albumin excretion with

nephropathy

versus placebo

150 mg irbesartan (P < 0.001),

38% lower albumin excretion with

300 mg irbasartan (P < 0.001),

70% reduction of overt

proteinuria (P < 0.001)

diabetic

RENAAL [37]

Losartan, 50-100 mg, versus

1513

3.4 yr

doubling of SCR, ESRD

16% reduction of composite

nephropathy

placebo

or death

(P = 0.02), 25% reduction in

doubling of SCR, 28% reduction

in ESRD, no change in deaths

acute MI

OPTIMAAL [38]

Losartan, 50 mg/d, or captopril,

5477

6 mo

all-cause mortality, SCD and

no difference between captopril and

50 mg tid

total and NFMI

losartan, 13.3% death with

captopril versus 15.3% death with

losartan (P = 0.03)

acute MI

VALIANT [39]

Valsartan, 160 mg bid, captopril

14,703

2.1 yr

all-cause mortality, CV death,

no difference between groups

50 mg tid, or combinations of

MI, hospitalization to CHF

valsartan, 80mg bid, and

captopril, 50 mg tid

CHF

ELITE II [40]

losartan 50 mg/d, captopril,

3152

555 d

all-cause mortality

no difference

50 mg tid

CHF

ValHeft [41]

valsartan 160 mg, placebo

5010

mortality and composite

no difference in mortality,

endpoint of mortality

improvement in hospitalization

and morbidity

with valsartan

CHF

CHARM, overall [42]

cansesartan 32 mg/d, placebo

7601

2 yr

all-cause mortality

17% reduction, statistically significant

CHF

CHARM, alternate [43]

cansesartan 32 mg/d, placebo

2028

33.7 mo

composite of CV death at

23% reduction, statistically significant

hospital

CHF

CHARM, added [44]

cansesartan 32 mg/d, placebo

2548

41 mo

composite

15% reduction, statistically significant

CHF

CHARM, preserved [45]

cansesartan 32 mg/d, placebo

3023

36.6 mo

CV death or hospitalization

11% reduction, statistically significant

Definitions: infarction.

CHF, congestive heart failure; CV, cardiovascular; LVH, left ventricular hypertension; IDNT, Irbesartan Diabetic Nephropathy Trial; MI, myocardial

Definitions: infarction.

CHF, congestive heart failure; CV, cardiovascular; LVH, left ventricular hypertension; IDNT, Irbesartan Diabetic Nephropathy Trial; MI, myocardial less well studied but seems to mediate beneficial effects that include vasodilation, inhibition of cell growth, and proliferation as well as cell differentiation [48,49]. The differential effects are shown in Fig. 1. The sequential progression of cardiovascular disease begins with the risk factors of hypertension, diabetes, smoking, metabolic syndrome, and dyslipidemia. These risk factors are independently associated with levels of angioten-sin II that in turn trigger the cascade of events. Progression to atherosclerotic disease and left ventricular hypertrophy leads to plaque destabili-zation in the face of uncontrolled risk factors, with acute coronary syndrome and myocardial infarction as the sequelae [50]. Loss of cardiac muscle eventually leads to remodeling of the left ventricle progressing relentlessly to heart failure and end-stage cardiomyopathy (Fig. 2).

Reducing Blood Pressure Naturally

Reducing Blood Pressure Naturally

Do You Suffer From High Blood Pressure? Do You Feel Like This Silent Killer Might Be Stalking You? Have you been diagnosed or pre-hypertension and hypertension? Then JOIN THE CROWD Nearly 1 in 3 adults in the United States suffer from High Blood Pressure and only 1 in 3 adults are actually aware that they have it.

Get My Free Ebook


Post a comment