S-nitrosocaptopril: A novel nitrovasodilator resistant to nitrate tolerance
We recently synthesized the molecule, S-nitrosocaptopril, and demonstrated that this molecule combines the properties of a nitrovasodilator and angiotensin-converting enzyme inhibitor. Similarly to other nitrovasodilators, it inhibits platelet aggregation and vascular contraction in association with significant increases in cyclic guanosine monophosphate. The replacement of the sulfhydryl moiety by a thionitrite group does not alter the inhibitory action of this molecule on angiotensin-converting enzyme. Since this molecule is a nitrosothiol we reasoned that it may be resistant to nitroglycerin tolerance. To test this hypothesis in vitro, vascular rings of rabbit thoracic aorta were suspended in organ chambers for continuous recording of isometric force. They were contracted by norepinephrine and relaxed with cumulative doses of S-nitrosocaptopril, nitroglycerin, or sodium-nitroprusside before and after prolonged exposure to S-nitrosocaptopril (10-4 M), nitroglycerin (10-4 M) or vehicle control. To theoretically prevent tolerance, some experiments were performed in normoxic-conditions or in the presence of free thiol. Nitroglycerin, sodium nitroprusside, and S-nitrosocaptopril, but not captopril, directly induced concentration-dependent relaxation of vascular rings with EC
