Characterization of contractile responses to endothelin in human cerebral arteries: implications for cerebral vasospasm.

Cerebral vascular tone is modulated, at least in part, by the vascular endothelium. This probably results from a balance between the release of the endothelium-derived relaxing factor(s) and the endothelium-derived constricting factor(s) (e.g., endothelin). The time course of the induction and the decay of these mutually antagonizing substances differ considerably. Endothelium-derived relaxing factor is probably involved in rapid changes in vascular tone whereas endothelin may be more important in long-term modulation. We have studied the vasoconstrictor properties of endothelin in human cerebral artery strips. Endothelin typically produced an intense, sustained increae in tone over a dose range similar to that seen with other vasoconstrictor substances such as serotonin and prostaglandin F2 alpha (ED50 = 10(-8) M). The response was resistant to selective antagonists of norephinephrine, serotonin, isoproterenol, histamine, acetycholine, and angiotensin II. Only sodium nitroprusside, verapamil, and a disulfide bond reducing agent (dithiothreitol) inhibited the response. The physiological properties of this response are similar to those of a vasoconstrictor protein found in cerebrospinal fluid from patients with cerebral vasospasm after subarachnoid hemorrhage. The time course of the induction of endothelin production is consistent with the temporal sequence of vasospasm, further supporting the hypothesis that endothelin may be involved in this pathological process.