LONG-TERM INCREASES IN CORONARY ARTERIAL CONDUCTANCE DURING 5 DAY INFUSION OF LOW-DOSE NICORANDIL

Objective: The aim was to test the effects of nicorandil on coronary arterial conductance and on a possible development of tolerance or cross tolerance glyceryl trinitrate during a 5 d continuous intravenous infusion of this hybrid molecule (consisting of a combination of potassium channel activation and simultaneous nitro-ester induced soluble guanylyl-cyclase activation). Methods: Continuous intravenous infusions of nicorandil at 2.5 mu g.kg(-1).min(-1) and 10 mu g.kg(-1).min(-1) into conscious chronically instrumented dogs were carried out for 5 d using a special portable infusion system. Employing additional short term infusions, dose-response curves were obtained by giving nicorandil or glyceryl trinitrate at increasing dosages both in the preinfusion control state and 4 h after terminating the nicorandil infusion. Results: The 5 d of 2.5 or 10.0 mu g.kg(-1).min(-1) nicorandil resulted in a significant increase in large coronary artery diameter by 4.21(SEM 0.14)% or 9.20(0.28)%, respectively. At the lower dose no significant tolerance or cross tolerance with glyceryl trinitrate was observed. However, at the higher dose there was a shift of the dose-response curve of both nicorandil and glyceryl trinitrate to the right, indicating some tolerance. The smaller dose did not induce hypotension or reflex increase in heart rate, whereas the larger resulted in a 42(2.5)% increase in heart rate. Conclusions: A dose regimen of 2.5 mu g.kg(-1).min(-1) continuously administered for 5 d is capable of inducing a significant increase in coronary arterial conductance which was well maintained over the whole infusion period. Thus nicorandil can exert a selective large coronary artery dilatation and may bring about a well maintained increase in epicardial coronary conductance, especially when applied as a low dose slow release preparation which circumvents hypotension and increase in heart rate.