Outline the pathophysiological basis for the use of angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) in congestive cardiac failure.

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College Answer

The renin-angiotensin system plays a central role in the pathophysiology of heart failure.
Thus this question required integration of knowledge of the renin-angiotensin system and
how pharmacological agents affect it in the treatment of cardiac failure. Candidates were
expected to describe the pathway and the influence of these drug groups on cardiac failure
and to recognise underlying basic physiological principles such as the interaction between
AT1 and AT2 receptors along with awareness of production of Ang II by ACE-independent
enzymes.
A good answer was expected to contain the following points: Angiotensinogen is cleaved by
kidney-derived renin to form the decapeptide angiotensin I (Ang I); ACE converts Ang I to
Ang II; Ang II is a potent arterial vasoconstrictor and an important mediator of Na+ and water
retention through its effects on glomerular filtration pressure and aldosterone secretion; Ang
II potentiates neural catecholamine release, is a secretagogue for catecholamine release from
the adrenal medulla, promotes vascular hyperplasia and pathologic myocardial hypertrophy.
ACE inhibitors suppress Ang II and aldosterone production, decrease sympathetic nervous
system activity, and potentiate the effects of diuretics in heart failure. ACE is identical to
kininase II, which degrades bradykinin and other kinins that stimulate production of NO,
cyclic GMP, and vasoactive eicosanoids; these vasodilator substances seem to oppose the
effects of Ang II on the growth of vascular smooth muscle and cardiac fibroblasts and on
production of extracellular matrix. Thus, the increased levels of bradykinin that result from
ACE inhibition may play a role in the hemodynamic and anti-remodeling effects of ACE
inhibitors.
An alternative means of attenuating the haemodynamic and vascular impact of the reninangiotensin
system is through inhibition of angiotensin receptors. Most of the known clinical
actions of angiotensin II are mediated through the AT1 angiotensin receptor. AT1 receptor
antagonists may provide more potent reduction of the effects of angiotensin II than do ACE
inhibitors.
Syllabus C2d 1 and part C2b 2f
Reference Goodman and Gilman 561-7, Guyton Chp 22