ENDOTHELIAL DYSFUNCTION IN CEREBRAL VESSELS FOLLOWING CAROTID-ARTERY INFUSION OF PHORBOL ESTER IN RABBITS - THE ROLE OF POLYMORPHONUCLEAR LEUKOCYTES

The effect of 4 beta-phorbol-12 beta-myristate- 13 alpha-acetate (PMA) on endothelium-dependent and endothelium-independent vasoconstriction and vasodilation was studied in isolated segments of rabbit middle ce rebral artery (MCA). Concentration-dependent responses of the left and right MCA to the constrictors KCl, noradrenaline, uridine 5'-triphosp hate, serotonin, and histamine, as well as to the dilators acetylcholi ne, bradykinin, sodium nitroprusside, and calcium ionophore (A23187), were compared in control animals and after PMA injection into the left common carotid artery. In the control animals there was no significan t difference in the responses of the left and right MCA to either the constrictors or the dilators studied. After PMA injection the endothel ium-dependent relaxation in response to acetylcholine, bradykinin, and A23187 was reduced in the left MCA (PMA-injected side), whereas the e ffect of the endothelium-independent dilator sodium nitroprusside rema ined unchanged. Simultaneously greater contractile responses of the le ft MCA to serotonin and histamine were obtained. Neither infusion of L -arginine in vivo before the PMA injection nor incubation of the isola ted MCA segments with L-arginine affected this difference in MCA react ivity. Platelet depletion did not change the PMA-induced reduction in the endothelium-dependent relaxation, whereas after leukocyte depletio n this reduction practically disappeared. These results suggest that t he PMA-induced brain microembolia causes acute endothelial dysfunction , which is possibly mediated by intravascular activation of leukocytes and is independent of nitric oxide synthesis from L-arginine. This ph enomenon might play an important role in cerebral angiospastic disorde rs after intravascular activation of leukocytes in cerebral ischemia a nd reperfusion.