PHARMACOLOGICAL EVIDENCE OF A ROLE FOR PLATELET-ACTIVATING-FACTOR AS A MODULATOR OF VASOMOTOR TONE AND BLOOD-PRESSURE

The purpose of the present study was to investigate the role of platel et-activating factor (PAF, xadecyl-2-acetyl-sn-glyceryl-3-phosphorylch oline), a phospholipid mediator synthesized by endothelial and smooth muscle cells, in the modulation of vascular tone and blood pressure. I n pentobarbitone-anaesthetised rabbits, unloading of the carotid sinus baroreceptors by a bilateral carotid artery occlusion elicited a refl ex rise in arterial pressure which was markedly potentiated by pretrea ting the animals with the PAF receptor antagonists WEB 2086 ,3a-1,4-di azepin-2-yl-(4-morpholinyl)-l-propanone; 2, 5 or 10 mg kg(-1), i.v.] o r BN 52021 (ginkgolide B; 0.1, 0.3 or 1.0 mg kg(-1), i.v.). The increa ses in systemic vascular resistance induced by noradrenaline (30 mu g kg(-1), i.v.) or by the central activation of the sympathetic nervous system with glutamate (1 mg kg(-1), intracerebroventricular) were also significantly potentiated in animals pretreated with WEB 2086 (5 mg k g(-1) i.v.). In contrast, pretreatment with the cyclooxygenase inhibit or indomethacin (3 mg kg(-1), i.v.) did not affect the haemodynamic ac tions of noradrenaline, thus excluding the possibility that prostacycl in may modulate the potentiating effect. To further confirm that PAF i s released during systemic vasoconstriction, the cardiovascular PAF re ceptors were desensitized by the daily administration of PAF (3 mu g k g(-1), i.v.) for seven days. This procedure significantly reduced the intensity and duration of the hypotensive response to a subsequent PAF injection (3 mu g kg(-1), i.v.). In desensitized animals, the hyperte nsive response to bilateral carotid artery occlusion was potentiated t o the same extent as in the animals treated with PAF receptor antagoni sts. Inhibition of PAF biosynthesis by pretreatment of the animals wit h the phospholipase A(2) inhibitor mepacrine (5 mg kg(-1), i.v.) also enhanced the increase in blood pressure elicited by carotid artery occ lusion. We conclude that PAF is involved in the acute but not basal mo dulation of vasomotor tone and, hence, arterial pressure, probably by a negative feedback mechanism triggered by important increases in the vascular tone.