5-HT1D RECEPTOR AGONISTS AND HUMAN CORONARY-ARTERY REACTIVITY IN-VITRO - CROSSOVER COMPARISONS OF 5-HT AND SUMATRIPTAN WITH RIZATRIPTAN ANDL-741,519

1 Rizatriptan (MK-462, 2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamin e)) and its structurally related analogue L-741,519 -[5-(1,2,4-triazol -4-yl)-1H-indol-3-yl]piperidine) are novel 5-HT1D-receptor agonists. R izatriptan has shown efficacy as an anti-migraine agent in clinical tr ials. Since angiographic studies in patients have shown that sumatript an (an established 5-HT1D-receptor agonist) can cause coronary artery vasoconstriction, we compared the effects of rizatriptan and L-741,519 with those of 5-HT and sumatriptan on endothelium-denuded segments of human coronary artery in vitro. 2 Coronary arteries were obtained fro m explanted hearts from patients undergoing cardiac transplantation (n =16 viable arteries from 13 males, 3 females, aged 38-68 years) and ar terial segments (5-6 mm in length) were mounted in organ baths for iso metric tension recording. Each segment was first exposed to 45 mM KCl and then to 5-HT (1 nM-100 mu M). Concentration-effect curves to rizat riptan and sumatriptan (Study 1, n=6 or 7 arteries) or sumatriptan and L-741,519 (Study 2, n=8 arteries) were then performed in a consecutiv e and random manner. The response to repeated application of 5-HT was obtained in separate segments. 3 One artery showed severe atheroma and was not included in the analysis. ANOVA showed that 5-HT responsivene ss varied significantly between arteries from different patients, but not between arterial segments from the same patient. Desensitization w as seen consistently across all agonists but did not significantly aff ect inter-agonist comparisons. 4 There was graded effectiveness in the ability of the agonists to cause contraction with the rank order of E (max) values being 5-HT much greater than sumatriptan > L-741,519 > ri zatriptan. In terms of EC(50) values, L-741,519 was significantly more potent than sumatriptan. 5 The present study (using a 'cross-over' ex perimental protocol) confirms our previous observation that rizatripta n is less effective than sumatriptan in causing contraction of human i solated coronary artery. Furthermore, it shows that the lower maximum contractile response to rizatriptan, compared with that of sumatriptan , is not merely the consequence of variability in response to 5-HT1D-r eceptor agonists between patients or between segments from the same ar tery.