Background and Purpose-Elevated levels of endothelin-1 (ET-1) have been reported in cerebral ischemia. A role for ET may prove more important if the vascular receptors were changed. We addressed whether there is any change in ET receptor expression in cerebral ischemia. Methods-The right middle cerebral artery (MCA) was occluded in male Wistar rats for 2 hours with the intraluminal filament method. The basilar artery and both MCAs were removed after 46 hours of recirculation. The contractile responses to ET-1, a combined ET A and ET B receptor agonist, and sarafotoxin 6c (S6c), a selective ET B receptor agonist, were examined in vitro, and ET receptor mRNA was quantified by real-time polymerase chain reaction. Results-S6c, which had no contractile effect per se on fresh or sham-operated rat cerebral arteries, induced a marked contraction in the occluded MCA (E max [maximum contraction, calculated as percentage of the contractile capacity of 63.5 mmol/L K ϩ ]ϭ68Ϯ68%; PϽ0.0001), while there was no difference in the responses to ET-1 after cerebral ischemia. Real-time polymerase chain reaction revealed a significant upregulation of both the ET A and ET B receptors (both PϽ0.05) in the occluded MCA compared with the nonoccluded MCA from the same rats. Conclusions-Focal cerebral ischemia in rat induces increased transcription of both ET A and ET B receptors, which results in the appearance of a contractile response to the ET B receptor agonist S6c. These results suggest a role for ET receptors in the pathogenesis of a vascular component after cerebral ischemia.

Ž .Objective: The aim of this study was to investigate the appearance of contractile endothelin ET -B receptors following organ culture in different vascular regions. Method: The contractile responses of vascular smooth muscle induced by ET-1 and the selective ET B Ž . Ž receptor agonist sarafotoxin 6c S6c were investigated in circular segments representing eight vascular regions in the rat aorta, femoral . artery, mesenteric artery, branch of the mesenteric artery, proximal and distal parts of the caudal artery, femoral and mesenteric veins . To allow the ET receptor to be expressed, the segments were placed in organ culture for 1 to 5 days. Pharmacological characterisation of B the ET receptors was performed in mesenteric arterial segments. All contractile responses were measured in percentage of K q -induced Ž . contraction. Results: ET-1 induced strong concentration-dependent contractions of all fresh not cultured segments. S6c had negligible effects on all fresh vessels with the exception of the mesenteric vein, where a small contraction was seen. After 1 day of organ culture all tested segments, with the exception of aorta and the proximal part of the caudal artery, showed concentration-dependent contractile responses to S6c which were further augmented after 5 days of culture. The ET-1-induced responses were only slightly affected by organ culture. Contractions induced by S6c were more enhanced in small arteries and veins than in larger arteries. Furthermore, the S6c-induced response was more pronounced in the mesenteric region as compared to the hindlimb. In fresh mesenteric arterial segments FR139317 Ž . Ž . Ž . ET receptor antagonist and bosentan ET rET receptor antagonist but not IRL 2500 ET receptor antagonist shifted theET-1-induced concentration-response curve in parallel to the right. In contrast, after organ culture the S6c-induced concentration-response curves were shifted parallel to the right in the following potency order: IRL 2500) bosentan) FR139317. Conclusion: During normal conditions, the ET receptor is the dominating mediator of endothelin-induced contraction in eight different vascular regions.A Furthermore, this study indicates that most of the vessels have the ability to develop contractile ET receptors and that this plasticity B differs in vascular regions. q 1998 Elsevier Science B.V.

Triptans are agonists at 5-HT1B and 5-HT1D (where 5-HT is 5-hydroxytryptamine; serotonin) receptors and cause vasoconstriction of isolated blood vessels. The aim of the present study was to determine vasoconstrictor potency (EC50) of triptans in human coronary and cerebral arteries and to examine whether there was any relationship with the maximal plasma concentrations (Cmax; nM) of the drugs achieved following oral administration of clinically relevant doses to man using values reported in the literature. We also examined the expression of 5-HT1B receptors in atherosclerotic and normal coronary arteries. The vasocontractile responses to sumatriptan, rizatriptan or eletriptan were characterized by in vitro pharmacology. The ratio of Cmax/EC50 was calculated. 5-HT1B and 5-HT1D receptors were visualized by immunohistochemical techniques in coronary arteries. Sumatriptan, rizatriptan and eletriptan were powerful vasoconstrictors in cerebral artery. The rank order of agonist potency was eletriptan=rizatriptan=sumatriptan. In the coronary artery, the triptans were weaker vasoconstrictors. The rank order of potency was similar. In cerebral artery the ratio of Cmax/EC50 was not significantly different from unity, indicating a relationship between these two parameters. In general for the coronary artery, the ratios were significantly less than unity, indicating no direct relationship. Immunohistochemistry showed expression of 5-HT1B receptors in the medial layer, but did not reveal any obvious difference in 5-HT1B receptor expression between normal and atherosclerotic coronary arteries. The results support the notion that triptans are selective vasoconstrictors of cerebral arteries over coronary arteries and that there is a relationship between vasoconstrictor potency in cerebral arteries and clinically relevant plasma levels.

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