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

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.