Inhibitors of Angiotensin

INHIBITORS OF ANGIOTENSIN

Renin, angiotensin, and aldosterone play important roles in at least some people with essential hypertension. Approximately 20% of patients with essential hypertension have inappropriately low and 20% have inappropriately high plasma renin activity. Blood pres-sure of patients with high-renin hypertension responds well to drugs that interfere with the system, supporting a role for excess renin and angiotensin in this population.

Mechanism & Sites of Action

Renin release from the kidney cortex is stimulated by reduced renal arterial pressure, sympathetic neural stimulation, and reduced sodium delivery or increased sodium concentration at the distal renal tubule . Renin acts upon angio-tensinogen to split off the inactive precursor decapeptide angio-tensin I. Angiotensin I is then converted, primarily by endothelial ACE, to the arterial vasoconstrictor octapeptide angiotensin II (Figure 11–5), which is in turn converted in the adrenal gland to angiotensin III. Angiotensin II has vasoconstrictor and sodium-retaining activity. Angiotensin II and III both stimulate aldoster-one release. Angiotensin may contribute to maintaining high vascular resistance in hypertensive states associated with high plasma renin activity, such as renal arterial stenosis, some types of intrinsic renal disease, and malignant hypertension, as well as in essential hypertension after treatment with sodium restriction, diuretics, or vasodilators. However, even in low-renin hypertensive states, these drugs can lower blood pressure .

A parallel system for angiotensin generation exists in several other tissues (eg, heart) and may be responsible for trophic changes such as cardiac hypertrophy. The converting enzyme involved in tissue angiotensin II synthesis is also inhibited by ACE inhibitors.

Three classes of drugs act specifically on the renin-angiotensin system: ACE inhibitors; the competitive inhibitors of angiotensin at its receptors, including losartan and other nonpeptide antago-nists; and aliskiren, an orally active renin antagonist . A fourth group of drugs, the aldosterone receptor inhibitors (eg, spironolactone, eplerenone) are discussed with the diuretics. In addition, β blockers, as noted earlier, can reduce renin secretion.