CHARACTERIZATION OF ENDOTHELIN RECEPTORS IN THE CEREBRAL VASCULATURE AND THEIR LACK OF EFFECT ON SPREADING DEPRESSION

The changes in cerebral blood flow that accompany spreading depression are well-described, as are parallel changes in cellular activity, wit h a wave of hyperemia followed by a prolonged oligemic phase. In this study, a cat model of the CBF changes associated with spreading depres sion and in vitro pharmacology were used to determine if there is a ro le for the powerful peptide vasoconstrictor endothelin in this respons e. For the pharmacological studies, the middle cerebral artery was har vested from cats postmortem. For the physiological studies, cats were anesthetized with halothane induction and alpha-chloralose (60 mg/kg, intraperitoneal loading; 20 mg/kg i.v. 2-h maintenance). CBF was monit ored continuously in the parietal cortex using laser Doppler flowmetry (CBFLDF) after exposure of the dura mater. The in vitro work demonstr ated that endothelin-1 (ET-1) mediates a strong and potent contraction of cerebral vessels. Both the selective ET(A) receptor antagonist FR1 39317 and the combined ET(A) and ET(B) receptor antagonist Bosentan ca used a rightward shift of the concentration-response curve without att enuation of the maximum effect. The calculated pA(2) values were 6.28 and 6.90, respectively. The slope did not differ from unity, suggestin g that the ET-1-mediated contraction is evoked by a single population of ET(A) receptors, which were effectively antagonized by these compou nds. Spreading depression was induced with a needle stick injury to th e cortex. Local administration of the endothelin antagonists FR139317 (10 mu M) and Bosentan (10 mu M) did not affect resting blood flow in the cortex. Induction of spreading depression following local administ ration of FR139317 and Bosentan resulted in responses no different fro m those in control cortex. These data demonstrate that endothelin does not play a significant role in the vasoconstrictor portion of the CBF change seen in spreading depression, nor does it affect resting flow. Since it is widely held that spreading depression, or a very similar mechanism, underlies the aura phase of migraine, it may be suggested f rom these studies that endothelin antagonists are unlikely to be usefu l in migraine.