Vasodilator therapy: interaction of nitrates with angiotensin-converting enzyme inhibitors

Nitrates and other nitrosovasodilators are locally acting agents. Their efficacy is reported to depend upon the availability of sulfhydryl groups in vascular smooth muscle. Long term nitrosovasodilator therapy has limited effectiveness, and development of nitrate tolerance has been recognized to be due to exhaustion of the tissue sulfhydryl pool, in addition to vasodilation-induced reflex activation of the neurohumoral system. Under both experimental and clinical conditions it has been demonstrated that N-acetylcysteine and other exogenously introduced sulfhydryl donors potentiate hemodynamic responses to nitrates and reverse nitrate tolerance. The newer group of angiotensin-converting enzyme (ACE) inhibitor drugs has been reported to be effective in reducing afterload and preload in a variety of experimental and clinical trials. Captopril, the first developed ACE inhibitor, and its analogs contain sulfhydryl groups. Although the sulfhydryl group of captopril is not thought to be responsible for its vasodilator action, it can act as a sulfhydryl donor to promote nitrate effectiveness and prevent development of tolerance. Limited experimental and clinical trials on combined therapy with nitrates and captopril have produced promising results. An ingenious prototype compound, S-nitrosocaptopril, has recently been synthesized. This is an exciting new development in vasodilator therapy, but clinical application must await full experimental characterization of this and other identical compounds.