Drugs that block the sympathetic nervous system inhibit the release of renin. Examples are propranolol and other β-adrenoceptorblocking drugs, which act by blocking the renal β receptors involved in the sympathetic control of renin release.
Cleavage of angiotensinogen by renin (Figures 17–1 and 17–3) is the rate-limiting step in the formation of ANG II and thus represents a logical target for inhibition of the renin-angiotensin system. Several nonpeptide, low-molecular-weight, orally active inhibitors are available. Aliskiren was the first nonpeptide renin inhibitor to be approved for the treatment of hypertension. In healthy subjects, aliskiren produces dose-dependent reductions in plasma renin activity and plasma ANG I, ANG II, and aldosterone concentrations. In patients with hypertension, some of whom have elevated plasma renin levels, aliskiren suppresses plasma renin activity and causes dose-related reductions in blood pressure similar to those produced by ACE inhibitors and ARBs (see below). The safety and tolerability of aliskiren are comparable to ARBs. Thus, renin inhibition has become an established treatment for hypertension. Aliskiren is contraindicated in pregnancy.
Inhibition of the renin-angiotensin system with ACE inhibitors or ARBs may be incomplete because the drugs disrupt the negative feedback action of ANG II on renin release and thereby increase plasma renin activity. Other antihypertensive drugs, notably hydrochlorothiazide and other diuretics, also increase plasma renin activity. Aliskiren not only decreases baseline plasma renin activity in hypertensive subjects, but also eliminates the rise produced by ACE inhibitors, ARBs, and diuretics, thereby enhancing their antihypertensive effects. For this reason, aliskiren has been used in combination with an ACE inhibitor or ARB. However, such dual blockade may not produce significant clinical benefit and may be associated with adverse effects.
Orally active ACE inhibitors are directed against the active site of ACE and are now extensively used. Captopril and enalapril are examples of the many ACE inhibitors that are available. These drugs differ in their structure and pharmacokinetics, but they are interchangeable in clinical use. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. As described in Chapters 11 and 13, they are effective in the treatment of hypertension, decrease morbidity and mortality in heart failure and left ventricular dysfunction after myocardial infarction, and delay the progression of diabetic nephropathy.
ACE inhibitors not only block the conversion of ANG I to ANG II but also inhibit the degradation of other substances, including bradykinin, substance P, and enkephalins. The action of ACE inhibitors to inhibit bradykinin metabolism contributes significantly to their hypotensive action (see Figure 11–5); indeed, it has been proposed that increased bradykinin levels are more important than decreased ANG II levels. Bradykinin is apparently responsible for some adverse side effects, including cough and angioedema. These drugs are contraindicated in pregnancy because they cause fetal kidney damage.