Prevention of nitrate tolerance with angiotension converting enzyme inhibitors

Activation of neurohumoral hormones or sulfhydryl group depletion may contribute to the development of nitroglycerin tolerance. In an attempt to prevent nitrate tolerance, this study evaluated the interaction of nitroglycerin with angiotensin converting enzyme (ACE) inhibitors with and without a sulfhydryl group. Thirty-four subjects were randomized to a 7-day regimen of enalapril 10 mg b.i.d., captopril 25 mg t.i.d., or placebo. Venodilator response to nitroglycerin was assessed with forearm plethysmography by measuring the change in venous volume after administration of 0.4 mg sublingual nitroglycerin. Plethysmographic measurements were obtained serially 1) at baseline, 2) after 4 days of ACE inhibitor or placebo, 3) 2 hours after application of a 10 mg/24 hr nitroglycerin patch, and 4) 74 hours after continuous nitropatch application. ACE inhibition alone caused no significant change in the response to sublingual nitroglycerin. Nitrate response remained unchanged after 2 hours ("acute") of nitropatch exposure in all three groups. After 74 hours ("chronic") of continuous nitropatch application, the venodilator response to sublingual nitroglycerin was reduced by 40% in the placebo group, 10% in the enalapril group, and 2% in the captopril group. This attenuation was significant only in the placebo group (p less than 0.01). Pairwise comparison of nitrate response between groups was significantly different between the captopril and placebo groups (p less than 0.01) and between the placebo and enalapril groups (p less than 0.05). Plasma renin levels increased equally in the enalapril and captopril groups. Body weight increased only in the placebo group, suggesting prevention of nitrate-induced volume expansion in the ACE inhibitor groups. This study demonstrates that ACE inhibitors may prevent nitrate tolerance to long-term nitrate therapy.