Pharmacological reactivity of human epicardial coronary arteries: phasic and tonic responses to vasoconstrictor agents differentiated by nifedipine.

1. Human epicardial coronary artery rings, freshly obtained from cardiac transplantation patients, commonly exhibited phasic contractile activity in vitro. This activity occurred either spontaneously or in response to vasoconstrictor stimulation. 2. Nifedipine pretreatment (1 nM-0.1 microM) reduced both types of phasic contractions in a concentration-dependent manner. At 0.1 microM nifedipine, spontaneous contractions were completely abolished, as were phasic contractions induced by U46619, endothelin-1 or 5-hydroxytryptamine (5-HT). 3. For U46619 (0.1-100 nM), the largest phasic contractions (amplitude peak to trough) occurred over the mid-range of concentrations used (1-10 nM). At higher concentrations (30-100 nM), phasic activity was reduced as the response reached a maximum. Estimated pEC50 values for the upper phasic and lower phasic curves were significantly different (8.71 +/- 0.13 versus 7.90 +/- 0.11; P < 0.05; n = 10). In the presence of nifidepine (0.1 microM), the purely tonic contraction curve to U46619 was similar to the lower phasic curve in the absence of nifedipine (pEC50 = 8.14 +/- 0.06, n = 10). Similar results were obtained for endothelin-1 (0.1-100 nM). 4. Responses to 5-HT (1 nM-3 microM) were more variable. The largest phasic contractions were spread unevenly throughout the concentration-response curve. In the presence of nifedipine (0.1 microM), the curve to 5-HT was significantly depressed in range but not sensitivity (pEC50) when compared with the phasic curves. 5. In conclusion, activation of dihydropyridine-sensitive voltage-operated Ca2+ channels mediated the phasic contractions commonly observed in human epicardial coronary arteries. These contractions amplified the contractile responses to low concentrations of vasoconstrictors. Inhibition of phasic activity by the Ca2+ channel antagonist, nifedipine, allowed the tonic vasoconstrictor profile of human isolated coronary artery to be determined which is important information for the accurate quantitative assessment of vasodilator responses in this tissue in vitro.