Long-term angiotensin-converting enzyme inhibition with high-dose enalapril retards nitrate tolerance in large epicardial arteries and prevents rebound coronary vasoconstriction in vivo

Background Rebound myocardial ischemia develops in patients with unstable or stable angina pectoris after sudden cessation of nitroglycerin therapy. Long-term nitroglycerin infusion is associated with increases in plasma renin activity and catecholamine release rates, both of which may lead to excess angiotensin II and alpha-adrenergic-mediated vasoconstriction, particularly on withdrawal of nitroglycerin. Methods and Results Chronically instrumented dogs were treated for 5 days with nitroglycerin (1.5 mu g . k(-1). min(-1) IV) alone or in combination with the angiotensin-converting enzyme (ACE) inhibitor enalapril (0.1 mg/kg two times daily or 1 mg/kg). With long-term nitroglycerin therapy, the left anterior circumflex artery was maximally dilated 4 hours after the start of nitroglycerin infusion (9.5+/-0.6%) and returned to baseline levels within the third day of treatment (baseline, 2.52+/-0.07 mm; day 3,2.55+/-0.07 mm; P=NS), indicating a complete loss of nitroglycerin-induced coronary vasodilatation. Nitroglycerin infusion also was accompanied by a transient increase in plasma renin activity. Sudden withdrawal of nitroglycerin infusion caused a progressive constriction of the left anterior circumflex artery, which peaked 4 hours after nitroglycerin infusion cessation (-7.8+/-0.2%). This occurred in the absence of elevated plasma renin activity. Concommitant treatment with high-dose enalapril (1 mg . kg(-1). d(-1)) markedly reduced the degree of tolerance and prevented the rebound constriction on cessation of nitroglycerin therapy. Conclusions Long-term ACE inhibition with high-dose enalapril reduces nitroglycerin tolerance and prevents rebound vasoconstriction in coronary arteries. These phenomena were not associated with an activated circulating renin-angiotensin system. This observation suggests that during long-term nitroglycerin treatment, intrinsic abnormalities of the vascular smooth muscle may have developed that are suppressed by concomitant ACE inhibitor therapy. The present study also favors a combination of nitroglycerin and ACE inhibitors to maintain nitrate sensitivity of the vasculature during long-term nitroglycerin treatment.