Endothelin-B Receptors in Cerebral Resistance Arterioles and their Functional Significance after Focal Cerebral Ischemia in Cats

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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, ETB receptor–induced vasoconstriction has not yet been demonstrated in brain vessels. In this study in chloralose-anesthetized cats, with perivascular microapplications of ETB selective agonist (BQ-3020) and antagonist (BQ-788), we investigated whether ETB receptor–mediated constriction could be uncovered in cortical arterioles in vivo. In addition, we examined whether normal dilator response to ETB receptor activation is preserved in postishemic cerebral arterioles. The first microapplication of the selective ETB receptor agonist BQ-3020 (1 μmol/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 ETB 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 ETB receptor antagonist BQ-788 (0.001 to 1 μmol/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 ETB 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 ETB receptor antagonist (BQ-788, 0.1 μmol/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 ETB 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) ETB-mediated contractile tone contributes in a small but significant manner in limiting postischemia dilation of cortical pial arterioles.