5-HT1D receptor agonists and human coronary artery reactivity in vitro: crossover comparisons of 5-HT and sumatriptan with rizatriptan and L-741,519

Abstract

1. Rizatriptan (MK-462, (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine)) and its structurally related analogue L-741,519 (N-methyl-4-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]piperidine) are novel 5-HT1D-receptor agonists. Rizatriptan has shown efficacy as an anti-migraine agent in clinical trials. Since angiographic studies in patients have shown that sumatriptan (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 from explanted hearts from patients undergoing cardiac transplantation (n = 16 viable arteries from 13 males, 3 females, aged 38-68 years) and arterial segments (5-6 mm in length) were mounted in organ baths for isometric tension recording. Each segment was first exposed to 45mM KCl and then to 5-HT (1 nM-100 microM). Concentration-effect curves to rizatriptan 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 consecutive 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 responsiveness varied significantly between arteries from different patients; but not between arterial segments from the same patient. Desensitization was seen consistently across all agonists but did not significantly affect inter-agonist comparisons. 4. There was graded effectiveness in the ability of the agonists to cause contraction with the rank order of Emax values being 5-HT >> sumatriptan > L-741,519 > rizatriptan. In terms of EC50 values, L-741,519 was significantly more potent than sumatriptan. 5. The present study (using a 'cross-over' experimental protocol) confirms our previous observation that rizatriptan is less effective than sumatriptan in causing contraction of human isolated 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-receptor agonists between patients or between segments from the same artery.

5‐HT1B‐receptors and vascular reactivity in human isolated blood vessels: assessment of the potential craniovascular selectivity of sumatriptan

“…This concentration of KCl was selected since it causes membrane depolarization and the opening of voltage‐operated calcium channels, giving a substantial, submaximal contraction that is readily reversible on wash‐out. For detailed methodology of studies with cranial arteries see [8], for saphenous vein see [18] and for uterine arteries see [19].…”

Coronary Vasoconstrictor Potential of Triptans: A Review of In Vitro Pharmacologic Data

“…In studies conducted in separate laboratories, other triptans, including rizatriptan, frovatriptan, and eletriptan, have been shown to cause human isolated coronary artery contractions comparable to sumatriptan 18 , 23–26 . Based on their similar receptor affinity profiles, it is likely that contraction by these triptans is also mainly mediated via the 5‐HT 1B receptor.…”

Pharmacology and Potential Mechanisms of Action of Rizatriptan

“…Comparison of the contractile response of the middle meningeal artery with serotonin and with rizatriptan show that both compounds produce a very similar maximal response ( 6,7). Since rizatriptan has contractile activity only at 5‐HT 1B receptors, this indicates that predominant serotonergic contractile effect on this vessel is mediated by the 5‐HT 1B receptor ( Fig.…”

“…Craniovascularselectivity comes from a higher density of 5‐HT 1B receptors in target middle meningeal blood vessels than in coronary blood vessels, and because all triptans are devoid of activity at 5‐HT 2A receptors at clinically relevant doses. Arrows represent therapeuticconcentration range at which the compounds are virtually inactive in the coronary artery assay (modified from 6 and 7).…”