Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease

OBJECTIVES We sought to demonstrate non-angiotensin converting enzyme (ACE) dependent angiotensin II (AII) generating pathways in resistance arteries from patients with chronic heart Failure (CHF). BACKGROUND Non-ACE dependent AII generation occurs in resistance arteries f rom normal volunteers. Inhibition of non-ACE dependent AII generation may h ave therapeutic potential in CHF. METHODS Resistance arteries were dissected from gluteal biopsies from patie nts with coronary heart disease (CHD) and preserved left ventricular functi on and from patients with CHF. Using wire myography, concentration response curves to angiotensin I (AI) and AII were constructed in the presence of 1 ) vehicle, 2) chymostatin [an inhibitor of chymase], 3) enalaprilat, and 3) the combination of chymostatin and enalaprilat. RESULTS In resistance arteries from patients with CHD, the vasoconstrictor response to AI was not inhibited by either inhibitor alone (chymostatin [p greater than or equal to 0.05] or enalaprilat [p greater than or equal to 0 .05]) but was significantly inhibited by the combination (p < 0.001). In ar teries from patients with CHF, AI responses were inhibited by enalaprilat ( p < 0.05) but not by chymostatin alone (p > 0.05). The combination of chymo statin and enalaprilat markedly inhibited the response to AI (p < 0.001) to a greater degree than enalaprilat alone (p <less than or equal to> 0.01). CONCLUSIONS Non-ACE dependent AII generating pathways exist in resistance a rteries from patients with both CHF and CHD. In resistance arteries from pa tients with CI-ID, inhibition of either the ACE or chymase pathway alone ha s no effect on AII generation, and both pathways must be blocked before the vasoconstrictor action of AI is inhibited. In CHF, blockade of ACE results in marked inhibition of responses to hi, but this is enhanced by coinhibit ion of chymase. These studies suggest that full suppression of the renin-an giotensin system cannot be achieved by ACE inhibition alone and provide a r ationale for developing future therapeutic strategies. (J Am Coll Cardiol 2 001;37:1056-61) (C) 2001 by the American College of Cardiology.