Angiotensin-Converting Enzyme Inhibitors

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

The relative ease of administration and superior effi-cacy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARB) have largely relegated hydralazine and nitrate therapy to second-line therapies for CHF. The demonstration of the sur-vival benefit conferred by vasodilator therapy resulted in a paradigm shift in the approach to CHF. It was rec-ognized that the way to improve survival in heart failure was not by directly addressing the weakened heart pump but rather by reversing the inappropriate periph-eral vasoconstriction that results from neurohumoral activation.

Captopril (Capoten) was the original prototype product, and it was administered three times a day. A once-a-day preparation was subsequently patented and marketed. Prospective multicenter double-blind placebo-controlled clinical trials have repeatedly demonstrated an early and persistent survival benefit with ACE inhibitors in CHF patients. ACE inhibitors were found superior to hydralazine and nitrates in a di-rect comparison. ACE inhibitors are now clearly the agents of first choice in the pharmacological manage-ment of CHF. There are also a number of additional rea-sons to use ACE inhibitors. The HOPE trial and other studies demonstrated additional survival and renal pro-tective benefits of ACE inhibition in diabetic and/or hy-pertensive patients long before they develop CHF.

Our understanding of the mechanism of action of ACE inhibitors has evolved along with our growing ap-preciation of the physiological and pathophysiological role of angiotensin II. Initially, angiotensin II was shown to be elaborated in response to low blood flow to the kidney in animal models of hypertension. Low flow to the kidney occurs when damage to the heart results in a low cardiac output. The low EF criterion for CHF noted previously is a noninvasively determined surrogate marker for a low cardiac output. The low flow to the kid-ney is perceived as bleeding. The appropriate response by the kidney to low flow is to elaborate renin. Renin cir-culates to the liver. Renin in the liver converts an-giotensinogen to angiotensin I. Angiotensin I travels to the lung, where it is converted to angiotensin II by ACE.

Angiotensin II binds to its receptor and increases in-tracellular ionized free calcium. This increase in intra-cellular ionized free calcium causes vasoconstriction by vascular smooth muscle cells, aldosterone secretion by adrenal glomerulosa cells, increased central sympa-thetic outflow, and enhanced thirst. This system is acti-vated as part of the normal host response to stressful injury, such as bleeding or trauma. The systemic an-giotensin II levels rise acutely to retain fluid and im-prove short-term survival following injury. Unfor-tunately, these short-term adaptive mechanisms are not designed to protect against the long-term consequences of chronic low blood flow from CHF. The extraordinary success of ACE inhibitors in CHF clearly demonstrates the harmful effects of chronic angiotensin II activation.

Further refinement of this basic understanding fol-lowed. First of all, ACE inhibitors not only block the conversion of angiotensin I to angiotensin II; they also block the breakdown of bradykinin. Kinins are va-sodilators and serve as part of the yin–yang of the vas- cular system (i.e., vasoconstrictors vs. vasodilators). The use of an ACE inhibitor results in the elaboration of more kinins and less angiotensin II. Thus, the benefits of ACE inhibitors may derive from their elaboration of more kinins in addition to their inhibition of an-giotensin II formation.

Efforts to elucidate the mechanisms responsible for the pharmacological efficacy of ACE inhibitors have been further complicated by the discovery of alterna-tive pathways for forming angiotensin II independent of the conversion of angiotensin I to angiotensin II. Other cellular enzymes, such as chymases and trypsin, can also elaborate angiotensin II. And finally, at least two dis-tinct angiotensin II receptors have been cloned and se-quenced; they are confusingly named the type 1 and type 2 angiotensin II (AT-1;AT-2) receptors.

Elaboration of angiotensin II can result in either of two effects on an individual cell, depending on the rela-tive numbers of AT-1 and AT-2 receptors. Relatively se-lective AT-1 receptor blockers have been developed in an effort to achieve superior efficacy with enhanced se-lectivity. Thus far, clinical studies indicate that ARBs may be as effective as ACE inhibitors and have fewer side effects. The consensus in their use is to try an ACE inhibitor as the first-line therapy before using an ARB, such as valsartan or losartan. However, ACE inhibitors can induce a very troubling cough in susceptible indi-viduals as a result of the increase in kinins. ARBs serve as a very good substitute for such patients.