Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system.

Abstract

The renin–angiotensin system (RAS) plays a major role in regulating the cardiovascular system, and disorders of the RAS contribute largely to the pathophysiology of hypertension, renal diseases, and chronic heart failure. Two subtypes of angiotensin II (Ang II) receptors have been defined on the basis of their differential pharmacological and biochemical properties: Ang II type 1 receptors (AT1), which are involved in most of the well-known physiological effects of Ang II, and Ang II type 2 receptors (AT2), which have a less well-defined role but appear capable of counterbalancing some of the effects of AT1 stimulation. The 2 receptors, both of which belong to the superfamily of G-protein–coupled receptors, are believed to have different signaling pathways and different functions.1 AT1 transactivates growth pathways and mediates major Ang II effects such as vasoconstriction, increased cardiac contractility, renal tubular sodium reabsorption, cell proliferation, vascular and cardiac hypertrophy, inflammatory responses, and oxidative stress. AT2 is believed to induce essentially opposite effects, including vasodilation and antigrowth and antihypertrophic effects,1–3 and to play a significant role in blood pressure (BP) regulation.4 The 2 major pharmacological inhibitors of the RAS, which are now important elements in the treatment of hypertension and cardiovascular disease, are ACE inhibitors and angiotensin receptor blockers (ARBs). These 2 classes of drugs have different effects on the RAS: suppression of Ang II production by ACE inhibitors reduces activation of both Ang II receptor subtypes, whereas ARBs preferentially block AT1 and leave AT2 unopposed. Long-term administration of ARBs results in a several-fold increase in plasma Ang and thus a possible overstimulation of AT2. It is generally accepted that the effects of stimulation of AT2 on the cardiovascular system are beneficial and that no harm would result from increased activation of …