ENDOTHELIN-MEDIATED VASCULAR TONE FOLLOWING FOCAL CEREBRAL-ISCHEMIA IN THE CAT

The actions of Bosentan and PD155080, non-peptide endothelin receptor antagonists, were examined in feline pial arterioles in situ following middle cerebral artery (MCA) occlusion to gain insight into the cereb rovascular influence of endogenous endothelins in focal cerebral ischa emia. Immediately following permanent MCA occlusion, all pial arteriol es overlying the suprasylvian and ectosylvian gyri displayed marked di latations, which were maintained in a population of vessels but differ entiated into sustained constrictions in others, Perivascular subarach noid microinjections of Bosentan (30 mu M), PD155080 (30 mu M), and ar tificial CSF (pH 7.2) were performed between 30 and 210 min following MCA occlusion. The perivascular microapplication of Bosentan (30 mu M) and PD155080 (30 mu M) around pial vessels overlying the suprasylvian and ectosylvian gyri, which are within the territory of the occluded MCA, elicited an increase in the calibre of postocclusion dilated and constricted pial arterioles. The perivascular microapplication of PD15 5080 (30 mu M) around postocclusion constricted arterioles overlying t he ectosylvian and suprasylvian gyri elicited an increase in the calib re of arterioles (69 +/- 49% from preinjection baseline; n = 8). The p erivascular microapplication of Bosentan (30 mu M) around postocclusio n constricted arterioles overlying the ectosylvian and suprasylvian gy ri also elicited an increase in the calibre of arterioles (68 +/- 60% from preinjection baseline; n = 13). In contrast, the microapplication of CSF (pH 7.2) elicited small reductions in pial arteriolar calibre of postocclusion constricted arterioles (-8 +/- 13% from preinjection baseline; n = 8). The perivascular microapplication of PD155080 (30 mu M) around postocclusion dilated pial arterioles overlying the ectosyl vian and suprasylvian gyri elicited an increase in the calibre of arte rioles (11 +/- 10% from preinjection baseline; n = 38). The perivascul ar microapplication of Bosentan (30 mu M) around postocclusion dilated arterioles elicited an increase in the calibre of arterioles (16 +/- 15% from preinjection baseline; n = 36). In contrast, the microapplica tion of CSF (pH 7.2) elicited small reductions in pial arteriolar cali bre of postocclusion dilated arterioles (-9 +/- 6% from preinjection b aseline; n = 44). Perivascular microapplication of Bosentan or PD15508 0 had minimal effect on the calibre of pial arterioles on the parasagi ttal gyrus (anterior cerebral artery territory), although these arteri oles had also displayed sustained dilatation following MCA occlusion. These results indicate that contractile factors (whose effects can be reversed with endothelin receptor antagonists) constrict or impair dil atation of cortical resistance arterioles in an acute cerebral ischaem ic episode.