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S-nitrosocaptopril: A novel nitrovasodilator resistant to nitrate tolerance

Publication ,  Journal Article
Cooke, JP; Wang, BY; Andon, N; Loscalzo, J; Dzau, VJ
Published in: Journal of Vascular Medicine and Biology
January 1, 1993

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 EC50 values of 2.9, 5.0 and 20 x 10-7 respectively. After prolonged exposure to nitroglycerin, there was a 30-fold shift in sensitivity to nitroglycerin (EC50 = 8.1 x 10-6 M), but no effect on the response to S-nitrosocaptopril (EC50 1.6 x 10-6 M). Conversely, after prolonged exposure to S-nitrosocaptopril, there was a 7-fold shift in the response to S-nitrosocaptopril, but no shift in the EC50 value for nitroglycerin or sodium nitroprusside. Alteration in ambient oxygen or the presence of free thiols had no effect on these responses. S-nitrosocaptopril is a unique molecule with combined actions as an angiotensin-converting enzyme inhibitor and nitrovasodilator; it demonstrates modest self-tolerance in vitro, but no cross-tolerance with nitroglycerin or sodium nitroprusside.

Duke Scholars

Published In

Journal of Vascular Medicine and Biology

ISSN

1042-5268

Publication Date

January 1, 1993

Volume

4

Issue

2-3

Start / End Page

115 / 121
 

Citation

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Cooke, J. P., Wang, B. Y., Andon, N., Loscalzo, J., & Dzau, V. J. (1993). S-nitrosocaptopril: A novel nitrovasodilator resistant to nitrate tolerance. Journal of Vascular Medicine and Biology, 4(2–3), 115–121.
Cooke, J. P., B. Y. Wang, N. Andon, J. Loscalzo, and V. J. Dzau. “S-nitrosocaptopril: A novel nitrovasodilator resistant to nitrate tolerance.” Journal of Vascular Medicine and Biology 4, no. 2–3 (January 1, 1993): 115–21.
Cooke JP, Wang BY, Andon N, Loscalzo J, Dzau VJ. S-nitrosocaptopril: A novel nitrovasodilator resistant to nitrate tolerance. Journal of Vascular Medicine and Biology. 1993 Jan 1;4(2–3):115–21.
Cooke, J. P., et al. “S-nitrosocaptopril: A novel nitrovasodilator resistant to nitrate tolerance.” Journal of Vascular Medicine and Biology, vol. 4, no. 2–3, Jan. 1993, pp. 115–21.
Cooke JP, Wang BY, Andon N, Loscalzo J, Dzau VJ. S-nitrosocaptopril: A novel nitrovasodilator resistant to nitrate tolerance. Journal of Vascular Medicine and Biology. 1993 Jan 1;4(2–3):115–121.

Published In

Journal of Vascular Medicine and Biology

ISSN

1042-5268

Publication Date

January 1, 1993

Volume

4

Issue

2-3

Start / End Page

115 / 121