Angiotensin II Receptors in the Human Coronary Circulation and in Heart Failure

Abstract: Angiotensin II (Ang II) is a potent vasoconstrictor that is implicated in the pathogenesis of hypertension, heart failure and atherosclerosis. In this thesis, the efficacy and safety of Ang II receptor blockers (ARB) were evaluated. The vasomotor effects of Ang II in endothelium-denuded human coronary arteries were characterized by in vitro pharmacology and the Ang II receptor mRNA levels were quantified by real-time PCR in human coronary arteries. The ARB, valsartan, and the angiotensin converting enzyme (ACE) inhibitor, enalapril, had similar effects on exercise capacity, symptoms of heart failure, quality of life, and left ventricular function and size. Moreover, it could be concluded that a shift from an ACE inhibitor to valsartan is safe. The contractile effect of Ang II in human coronary arteries is mediated by Ang II type 1 (AT1) and type 2 (AT2) receptors. AT1 receptors are of major importance, since the Ang II response could be inhibited by candesartan and AT1 receptor mRNA showed to be expressed in high amounts. The ARBs inhibited the Ang II induced vasoconstriction with the following order of potency: EXP 3174>candesartan=valsartan>losartan. The AT2 receptors also played a role since the contractile effect to Ang II was antagonised by PD 123319 and AT2 receptor mRNA expression could be demonstrated. AT1 and AT2 receptor mRNA levels were reduced in coronary arteries from heart failure patients as compared to controls. Furthermore, the Ang II effect diminished with increasing age, which may be a result of longstanding heart failure. These results indicate plasticity in Ang II receptor expression and functional responses in humans that may be of importance when tailoring the treatment for heart failure.