Mechanism of actions of sumatriptan on coronary flow before and after endothelial dysfunction in guinea-pig isolated heart.
1. The mechanism of action of sumatriptan on coronary flow was examined before and after two different forms of endothelial ablation in guinea-pig isolated hearts. The mechanism was assessed in terms of the influence of the integrity of the coronary endothelium, the role of release of nitric oxide (NO) from the endothelium, and the receptor subtypes mediating the effects. 2. Continuous perfusion with sumatriptan reduced coronary flow, but the concentration-response curve was v-shaped. Sumatriptan (0.001-0.1 microM) caused a concentration-dependent decrease in coronary flow with the maximum effect achieved at 0.23 +/- 0.04 microM. The pEC50 was 8.49 +/- 0.07. At higher concentrations (0.1-10 microM) there was a concentration-dependent diminution of the vasoconstrictor effect. Endothelial ablation by saponin removed the diminution in the vasoconstrictor effect. In contrast pretreatment with NG-nitro L-arginine methyl ester (L-NAME) (100 microM. 45 min perfusion) did not affect it. This was despite both saponin and L-NAME being effective in reducing basal release of NO into the coronary effluent (measured by chemiluminescence) to the same extent (71 +/- 3 and 73 +/- 2%, respectively). 3. GR127935, a selective 5-hydroxytryptamine1D (5-HT1D) receptor antagonist (3 and 10 nM), which by itself had no effect on coronary flow or NO release, antagonized the vasoconstrictor response to sumatriptan and unmasked a sumatriptan-induced concentration-dependent increase in coronary flow and NO release. These increases in coronary flow and NO release were abolished by pretreatment with either saponin or L-NAME. 4. Mesulergine, a 5-HT2 receptor antagonist which had no effect by itself on basal coronary flow or NO release, inhibited the vasodilator response to sumatriptan that occurred in the presence of GR127935, and actually enhanced the vasoconstrictor response, increasing the max mum fall in coronary flow from -3.9 +/- 0.4 to -5.2 +/- 0.4 ml min-1 g-1 (P < 0.05). The diminution of vasoconstrictor effect of sumatriptan was abolished by mesulergine and by pretreatment with saponin, but not by L-NAME. 5. In conclusion, guinea-pig coronary arteries constrict to low concentrations of sumatriptan, causing a reduction in coronary flow. This effect appears to be caused by 5-HT1D agonism with the receptors located on the coronary vascular smooth muscle. With higher concentrations of sumatriptan this is partially offset by a weaker vasodilator effect, which is caused by low affinity 5-HT2 agonism. Although this effect is endothelium-dependent. It is not caused by the release of NO. Interestingly, when the vasoconstrictor effect of sumatriptan was inhibited by the 5-HT1D antagonist GR127935, a high affinity vasodilator effect of sumatriptan was unmasked. This is 5-HT2 receptor mediated and is caused by release of NO from the coronary endothelium. 6. In man, sumatriptan, and 5-HT may both be capable of causing pathogenic coronary vasoconstriction. The implications of the present data are that the scope for this may depend greatly on (i) the extent of underlying endothelial dysfunction, (ii) the extent of endothelial 5-HT2 receptor-mediated release of vasodilator autacoids (which include NO) and (iii) the extent of smooth muscle 5-HT1D receptor-mediated vasoconstriction.
Ellwood
A J
AJ
Department of Pharmacology, King's College, University of London.
Curtis
M J
MJ
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004873:Ergolines / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D012503:Saponins / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D004873:Ergolines; D010069:Oxadiazoles; D010879:Piperazines; D012503:Saponins; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; C090701:GR 127935; D009569:Nitric Oxide; D018170:Sumatriptan; D019001:Nitric Oxide Synthase; C031649:mesulergine; D019331:NG-Nitroarginine Methyl Ester