We used laser-Doppler flowmetry to study the effects of endothelin-1 on local cortical microvascular perfusion and resistance in 29 pentobarbital-anesthetized rats. Intravenous administration of 10-300 pmol endothelin-1 reduced arterial blood pressure and microvascular resistance and increased microvascular perfusion. However, intracarotid administration of low doses of endothelin-1 increased microvascular perfusion and reduced microvascular resistance and arterial blood pressure, whereas high doses (^300 pmol) reduced microvascular perfusion and increased microvascular resistance and arterial blood pressure. Only the high dose/low flow response was associated with attenuation of the electrocorticogram. The low dose/high flow and high dose/low flow responses to endothelin-1 were not altered by blockade of muscarinic and adrenergic receptors. In addition, systemic metabolic changes (arterial pH, PacO}, PaO], and plasma glucose concentration) did not account for the cerebrovascular effects of endothelin-1. Platelet hyperaggregability also did not appear to be a causative factor in the high dose/low flow response to endothelin-1. In fact, ex vivo rat platelet aggregation was inhibited by intracarotid administration of 300 pmol endothelin-1. In conclusion, the cerebral vasculature exhibits extreme sensitivity to the vasodilator properties of endothelin-1 at low doses. The ischemic vasoconstrictor effects observed at high doses implicate endothelin-1 as an important mediator of cerebral vasospasm and/or postlschemic hypoperfusion. (Stroke 1990^1:451-458) E ndothelin (ET-1), a 21-amino acid peptide originally characterized from cultures of porcine aortic endothelial cells, is one in a family of recently described vasoactive isopeptides (ET-1, ET-2, and ET-3).1 -3 The most extensively studied member of this family, ET-1 is an extremely potent vasoconstrictor in a variety of in vitro vascular preparations, with veins being more sensitive than arteries. 4 In pithed or chemically denervated rats, the systemic administration of ET-1 elicits a slowly developing, prolonged pressor response. 1 -4 In contrast, in conscious and anesthetized rats the systemic administration of ET-1 produces an immediate hypotensive response, 4 which is associated, to varying degrees, with reductions in carotid, hind limb, renal, and mesenteric vascular resistance but little or no effect on heart rate (HR). 5 The decrease in vascular resistance may be related to the release of endotheliumderived relaxing factor (EDRF) and prostacyclin (PGI 2 ). Received June 27, 1989; accepted October 18, 1989. pmol/kg i.v.) to conscious or anesthetized rats often results in a biphasic arterial blood pressure response, that is, hypotension followed by hypertension.
4Little is known about the cerebrovascular effects of ET-1. However, the localization of specific, highaffinity ET-1 binding sites in small arteries and paravascular nerves, 7 together with the recent demonstration of prolonged basilar artery vasospasm following intracisternal administration of [8][...