A COMPARISON OF THE CONTRACTILE EFFECTS OF 5-HYDROXYTRYPTAMINE, SUMATRIPTAN AND MK-462 ON HUMAN CORONARY-ARTERY IN-VITRO

1 MK-462 (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine) is a novel selective 5-HT1D-receptor agonist which in clinical trials has been shown to be an effective antimigraine agent. As angiographic studies have shown that sumatriptan (an established 5-HT1D-receptor agonist) can cause coronary artery vasoconstriction in patients, we compared the effects of MK-462 with those of 5-HT and those of sumatriptan, on isolated segments of human coronary artery in vitro. 2 Coronary arteries were obtained from explanted hearts from patients (n = 22, 2 females, 20 males, aged 21-60 years) undergoing cardiac transplantation. Endothelium-denuded ring segments of coronary artery, 2 mm long were mounted in organ-baths for isometric tension recording. For each arterial ring segment, a cumulative concentration-effect curve to either 5-HT, sumatriptan or MK-462 was determined. After maximal response to each agonist had been obtained, ketanserin (a 5-HT2 receptor antagonist) 0.6 mu M was added to the tissue bath, followed by methiotepin (0.6 mu M) and the reduction in tension produced by the addition of each antagonist was determined. 3 Out of 22 coronary arteries studied, only 10 showed any response (contraction) to 5-HT. Not all arteries which responded to 5-HT contracted in response to both sumatriptan and MK-462 (one ring from each artery being exposed to a single agonist in each case). Both sumatriptan and MK-462 (E(max) values of 57.6% (n = 6) and 32.5% (n = 8) with respect to 45 mM KCl, respectively) were significantly less efficacious than 5-HT (n = 10) in contracting human coronary artery (P < 0.03 and P < 0.001 respectively) and furthermore MK-462 was significantly less effective than sumatriptan (P < 0.04). These E(max) values were similar to the E(max) values which were obtained from four vessels which responded to all three agonists. Ketanserin partially reduced the response to each of the agonists, and the further addition of methiotepin removed the remainder of the response indicating the involvement of 5-HT1D-receptors and possibly 5-HT2-receptors.