Calcium-entry blockers are widely used for the treatment of
coronary vasospasm. The mechanisms responsible for
coronary vasospasm are still uncertain, but ultimately involve contraction of the vascular smooth muscle of the large coronary artery. The direct constrictor responses of coronary smooth muscle can be reduced by the inhibitory effect of
endothelium-derived relaxing factor(s). The absence of endothelium can augment the response of vascular smooth muscle to
vasoconstrictor stimuli, but may also modify the potency of
calcium-entry blockers. The role of
calcium-entry blockers on the endothelial function is not known.
Nisoldipine is a new compound from a series of
calcium-antagonistic
dihydropyridines. The aim of the present experiments was: 1. to determine the effect of
nisoldipine on contractions of large coronary arteries evoked by possible mediators of
coronary vasospasm and 2. to determine whether or not the presence of endothelial cells affects the response to the
calcium-entry blockers. Rings of canine coronary arteries with and without endothelium were studied in organ chambers filled with modified Krebs-Ringer
bicarbonate solution. The rings were incubated for 45 min either in control
solution or in the presence of increasing concentrations of
nisoldipine (10(-10) to 10(-6) M). In the concentration range of 10(-9) to 10(-7) M
nisoldipine inhibited the contractile responses evoked by allagents: KCL (10 to 80 mM),
5-hydroxytryptamine (10(-9) to 10(-6) M),
ergonovine (10(-9) to 10(-6) M),
norepinephrine and
phenylephrine (10(-9) to 10(-4) M both in the presence of
propranolol 5 X 10(-6) M).
Nisoldipine was more potent in inhibiting contractions to
potassium chloride in the absence of the endothelium. By contrast, in case of
5-hydroxytryptamine or
phenylephrine,
nisoldipine was less potent in the absence of the endothelium. Similar results were obtained in the case of
ergonovine and
norepinephrine. The hypoxic contractions were reduced by
nisoldipine in a concentration dependent manner.
Nisoldipine inhibited the platelet-induced contractions both in the presence and the absence of endothelium. The present study demonstrates that the
dihydropyridine,
nisoldipine, is a potent inhibitor of contractions of the smooth muscle of large coronary arteries caused by a number of putative mediators of
coronary vasospasm including
catecholamines and products released by aggregating platelets. It also prevents hypoxic contractions of coronary vascular smooth muscle.