1. Wellcome Surgical Institute and Hugh Fraser Neuroscience Laboratories, University of Glasgow, Glasgow, U.K.
2. ^*Merck Research Laboratories, Department of Pharmacology, West Point, Pennsylvania, U.S.A.

Correspondence: Omar Touzani, Wellcome Surgical Institute and Hugh Fraser, Neuroscience Laboratories, University of Glasgow, Garscube Estate, Bearsden Road, Glasgow, G61 1QH, Scotland, United Kingdom.

Received 10 April 1997; Revised 2 July 1997; Accepted 2 July 1997.

Abstract

In the cerebral circulation, endothelin-A receptor activation mediates marked prolonged vasoconstriction whereas endothelin-B (ETB) receptor activation effects dilation. In contrast to some peripheral vascular beds, ET_B receptor-induced vasoconstriction has not yet been demonstrated in brain vessels. In this study in chloralose-anesthetized cats, with perivascular microapplications of ET_B selective agonist (BQ-3020) and antagonist (BQ-788), we investigated whether ET_B receptor-mediated constriction could be uncovered in cortical arterioles in vivo. In addition, we examined whether normal dilator response to ET_B receptor activation is preserved in post-ischemic cerebral arterioles. The first microapplication of the selective ET_B receptor agonist BQ-3020 (1 mol/L) onto a pial cortical arteriole elicited marked dilation (caliber increased by 26.3 15.1% from preinjection baseline). A second application of BQ-3020 (10-minute interval) onto the same vessel failed to evoke any significant vasomotor response. Subsequent (third and fourth) adventitial microapplication of the ET_B receptor agonist on the same arteriolar site effected a significant constriction of cerebral arterioles (-15.3 12.7% and -9.7 6.3% from preinjection baseline, respectively, at 20 and 30 minutes after the first application). The pial arterioles did not display tachyphylaxis to repeated applications of potassium (10 mmol/L). The perivascular application of the ET_B receptor antagonist BQ-788 (0.001 to 1 mol/L) had no effect on arteriolar caliber per se but blocked both BQ-3020-induced dilation (inhibitory concentration 5 nmol/L) and vasoconstriction elicited by repeated activation of ET_B receptors. After middle cerebral artery occlusion, most of the arterioles examined displayed a sustained dilation. The microapplication of BQ-3020 into the perivascular space surrounding postischemic dilated arterioles elicited a constriction of a similar magnitude to that induced by application of CSF (-17 7% and -17 7% from preinjection baseline, respectively). The adventitial microapplication of the ET_B receptor antagonist (BQ-788, 0.1 mol/L) on postocclusion dilated pial arterioles effected no change in the arteriolar caliber when compared with preinjection baseline. This BQ-788-induced response was significantly different from that induced by perivascular microinjection of CSF (P < 0.001, analysis of variance). These investigations indicate that (1) repeated activation of ET_B receptors displays tachyphylaxis of the vasodilator response but also uncovers significant constriction of cerebral arterioles in vivo; (2) the ability of BQ-3020 to elicit dilation is lost within 30 minutes of induced focal ischemia; and (3) ET_B-mediated contractile tone contributes in a small but significant manner in limiting postischemia dilation of cortical pial arterioles.