ANG II receptor blockers are now widely used. Losartan, valsartan, and several others are orally active, potent, and specific competitive antagonists at angiotensin AT1 receptors. The efficacy of these drugs in hypertension is similar to that of ACE inhibitors, but they are associated with a lower incidence of cough. Like ACE inhibitors, ARBs slow the progression of diabetic nephropathy and valsartan has been reported to decrease the incidence of diabetes in patients with impaired glucose tolerance. The antagonists are also effective in the treatment of heart failure and provide a useful alternative when ACE inhibitors are not well tolerated. ARBs are generally well tolerated but should not be used by patients with nondiabetic renal disease or in pregnancy. In addition, some ARBs may cause a syndrome known as sprue-like enteropathy.
Marfan’s syndrome is a connective tissue disorder associated with aortic disease and other abnormalities involving increased transforming growth factor-β (TGF-β) signaling. Since ANG II increases TGF-β levels, it was reasoned that blockade of the reninangiotensin system might be beneficial in Marfan’s syndrome. Clinical studies indicate that the ARB losartan may be as effective as atenolol, the standard treatment for this syndrome.
The currently available ARBs are selective for the AT1 receptor. Since prolonged treatment with the drugs disinhibits renin release and increases circulating ANG II levels, there may be increased stimulation of AT2 receptors. This may be significant in view of the evidence noted above that activation of the AT2 receptor causes vasodilation and other beneficial effects. Indeed, a selective, orally active AT2 agonist, Compound 21 (C21), has been shown to produce several beneficial effects in animal models of cardiovascular disease. The drug is under clinical development and may represent the first of a new class of cardiovascular drugs.
The clinical benefits of ARBs are similar to those of renin and ACE inhibitors, and it is not clear if any has significant advantages over the others.
Summary: Renin-Angiotensin System
The renin-angiotensin system is an important control system involved in the regulation of blood pressure, fluid and electrolyte balance, and other functions. Overactivity of this system has been implicated in hypertension, heart failure, and other diseases. Drugs that block the formation or actions of ANG II are used extensively in the treatment of these diseases.
More recent observations suggest that the system is even more complex than originally envisioned. Specifically, there is evidence for roles of ANG 1-7, possibly acting via the Mas receptor, and the (pro)renin receptor, which may act via angiotensin-independent pathways. However, the significance of these findings remains to be defined.
Kinins are potent vasodilator peptides formed enzymatically by the action of enzymes known as kallikreins acting on protein substrates called kininogens. The kallikrein-kinin system has several features in common with the renin-angiotensin system.
Kallikreins are serine proteases present in plasma (plasma kallikrein) and in several organs (tissue kallikrein), including the kidneys, pancreas, intestine, sweat glands, and salivary glands. The two groups are secreted as zymogens and are activated by proteolytic cleavage. Plasma prekallikrein is activated by activated blood coagulation factor XII (FXIIa). The two groups differ in their gene structure, molecular weight, substrate specificity, and kinin produced. Kallikreins can convert prorenin to active renin, but the physiologic significance of this action is not known.