Inhibition of vasoconstriction by AJ-2615, a novel calcium antagonist with alpha(1)-adrenergic receptor blocking activity in human conduit arteries used as bypass grafts.

Abstract

Graft spasm may develop during coronary artery bypass grafting and reversal of spasm is still challenging. The purpose of this study was to investigate the in vitro vascular relaxant properties of AJ-2615 in human internal mammary artery (IMA). We studied 264 IMA rings taken from 65 patients undergoing coronary artery bypass grafting surgery with organ bath technique. The interaction between AJ-2615 and various vasoconstrictors was investigated in two ways. AJ-2615 caused complete relaxation in methoxamine-contracted IMA rings (100.0+/-0.0%; n = 8) and nearly full relaxation in potassium chloride-contracted IMA rings (91.4+/-5.7%; n = 8) or noradrenaline-contracted IMA rings (89.3+/-2.8%; n = 8). AJ-2615 also induced remarkable relaxation in IMA rings contracted by other vasoconstrictors. In comparison with the alpha1-adrenoceptor antagonist prazosin, AJ 2615 showed similar maximal relaxation in IMA rings contracted by methoxamine or norepinephrine. On the other hand, incubation with AJ-2615 (0.1-1 microM) significantly inhibited all the vasoconstrictor-mediated vasoconstriction except endothelin-1 in a concentration-dependent manner. The results suggested that in human IMA, AJ-2615 has an inhibitory effect on vasoconstriction mediated by a variety of vasoconstrictors and the mechanism of relaxation may be related to its calcium antagonism and alpha1-adrenergic receptor blocking activity. AJ-2615 may have important clinical implications for patients undergoing coronary artery bypass surgery for reversing and preventing graft spasm.