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Novel organic nitrates are potent dilators of large coronary arteries with reduced development of tolerance during long-term infusion in dogs: role of the sulfhydryl moiety

Zanzinger, Johannes, Feelisch, Martin and Bassenge, Eberhard (1994) Novel organic nitrates are potent dilators of large coronary arteries with reduced development of tolerance during long-term infusion in dogs: role of the sulfhydryl moiety Journal of Cardiovascular Pharmacology, 23, (5), pp. 772-778. (PMID:7521460).

Record type: Article

Abstract

The vasodilator action of organic nitrates can be severely impaired by induction of drug tolerance. A critical depletion of sulfhydryl groups has been proposed to play a key role in impairment of the biotransformation of organic nitrates to nitric oxide (NO). We studied the effects of the new cysteine-containing nitrate SPM-5185 and the corresponding cysteine-free compound SPM-4744 on hemodynamics and large coronary artery dilation in chronically instrumented conscious dogs. Both nitrates caused dose-dependent increases of the diameter of the left circumflex artery (LCX); the cysteine-containing compound SPM-5185 however, caused such increases at < or = 30-fold lower doses as compared with SPM-4744. Coinfusion of the cysteine-containing analogue of SPM-5185 lacking the nitrate group (SPM-5267) did not alter the dose-response relationship to SPM-4744. Continuous infusion of SPM-5185 (4 micrograms/kg/min, n = 6) and SPM-4744 (2.7 micrograms/kg/min, n = 5) elicited LCX diameter increases of 0.24 +/- 0.06 and 0.17 +/- 0.07 mm, respectively, representing 60-70% of maximal dilator capacity. In contrast to classic organic nitrates, both SPM-5185 and SPM-4744 caused LCX diameter to decrease only slightly during 5-day infusions. Both compounds elicited sustained dilation even at day 5 (p < or = 0.05). SPM-5185 caused an initial decrease in mean arterial pressure (MAP) and evoked sustained increases in heart rate (HR), whereas SPM-4744 had no significant peripheral effects. On withdrawal of SPM-5185, LCX diameter was decreased below pretreatment values for several hours.

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More information

Published date: May 1994
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337905
URI: http://eprints.soton.ac.uk/id/eprint/337905
ISSN: 0160-2446
PURE UUID: 46a5c6a5-9f4e-4ffd-8344-79d3ca097be1
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 15 Jun 2012 10:19
Last modified: 18 Jul 2017 06:00

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Contributors

Author: Johannes Zanzinger
Author: Martin Feelisch ORCID iD
Author: Eberhard Bassenge

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