Pharmacological evidence of a role for platelet activating factor as a modulator of vasomotor tone and blood pressure

Abstract The purpose of the present study was to investigate the role of platelet-activating factor (PAF, 1- O -hexadecyl-2-acetyl- sn -glyceryl-3-phosphorylcholine), a phospholipid mediator synthesized by endothelial and smooth muscle cells, in the modulation of vascular tone and blood pressure. In pentobarbitone-anaesthetised rabbits, unloading of the carotid sinus baroreceptors by a bilateral carotid artery occlusion elicited a reflex rise in arterial pressure which was markedly potentiated by pretreating the animals with the PAF receptor antagonists WEB 2086 [3-4-(2-chlorphenyl)-9-methyl-6 H -thieno-3,2 f -1,2,4-triazolo-4,3 a -1,4-diazepin-2-yl-(4-morpholinyl)- l -propanone; 2, 5 or 10 mg kg −1 , i.v.] or BN 52021 (ginkgolide B; 0.1, 0.3 or 1.0 mg kg −1 , i.v.). The increases in systemic vascular resistance induced by noradrenaline (30 μg 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 kg −1 , i.v.). In contrast, pretreatment with the cyclooxygenase inhibitor indomethacin (3 mg kg −1 , i.v.) did not affect the haemodynamic actions of noradrenaline, thus excluding the possibility that prostacyclin may modulate the potentiating effect. To further confirm that PAF is released during systemic vasoconstriction, the cardiovascular PAF receptors were desensitized by the daily administration of PAF (3 μg kg −1 , i.v.) for seven days. This procedure significantly reduced the intensity and duration of the hypotensive response to a subsequent PAF injection (3 μg kg −1 , i.v.). In desensitized animals, the hypertensive response to bilateral carotid artery occlusion was potentiated to the same extent as in the animals treated with PAF receptor antagonists. Inhibition of PAF biosynthesis by pretreatment of the animals with the phospholipase A 2 inhibitor mepacrine (5 mg kg −1 , i.v.) also enhanced the increase in blood pressure elicited by carotid artery occlusion. We conclude that PAF is involved in the acute but not basal modulation of vasomotor tone and, hence, arterial pressure, probably by a negative feedback mechanism triggered by important increases in the vascular tone.