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

1 MK-462 ,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine) is a novel selective 5-HT1D-receptor agonist which in clinical trials has been s hown to be an effective antimigraine agent. As angiographic studies ha ve shown that sumatriptan (an established 5-HT1D-receptor agonist) can cause coronary artery vasoconstriction in patients, we compared the e ffects of MK-462 with those of 5-HT and those of sumatriptan, on isola ted segments of human coronary artery in vitro. 2 Coronary arteries we re obtained from explanted hearts from patients (n = 22, 2 females, 20 males, aged 21-60 years) undergoing cardiac transplantation. Endothel ium-denuded ring segments of coronary artery, 2 mm long were mounted i n organ-baths for isometric tension recording. For each arterial ring segment, a cumulative concentration-effect curve to either 5-HT, sumat riptan or MK-462 was determined. After maximal response to each agonis t 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 w as determined. 3 Out of 22 coronary arteries studied, only 10 showed a ny 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 e fficacious than 5-HT (n = 10) in contracting human coronary artery (P < 0.03 and P < 0.001 respectively) and furthermore MK-462 was signific antly less effective than sumatriptan (P < 0.04). These E(max) values were similar to the E(max) values which were obtained from four vessel s which responded to all three agonists. Ketanserin partially reduced the response to each of the agonists, and the further addition of meth iotepin removed the remainder of the response indicating the involveme nt of 5-HT1D-receptors and possibly 5-HT2-receptors.