Effect of endothelin on cortical microvascular perfusion in rats.
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 (greater than or equal to 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, PaCO2, PaO2, 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 postischemic hypoperfusion.
Department of Pharmacology, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406-0939.
R N
RN
Willette
C
C
Sauermelch
M
M
Ezekiel
G
G
Feuerstein
E H
EH
Ohlstein
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002540:Cerebral Cortex / Q000098:blood supply*; D016232:Endothelins; D004730:Endothelium, Vascular; D006339:Heart Rate / Q000187:drug effects; D007834:Lasers; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D010974:Platelet Aggregation; D051381:Rats; D011919:Rats, Inbred Strains; D014655:Vascular Resistance
D016232:Endothelins; D010455:Peptides