Platelet activating factor: A potent constrictor of cerebral arterioles in newborn pigs

Abstract

This study characterized the nature of the response to platelet activating factor (PAF) in the cerebral microcirculation of the newborn pig. Pial arterioles were observed directly using a closed cranial window in chloralose-anesthetized piglets. Topical application of 10-100 ng/ml PAF produced dose-dependent decreases in pial arteriolar diameter; diameters were 193 ± 27 μm for control, 167 ± 25 μm at 10 ng/ml, and 129 ± 21 μm at 100 ng/ml. Topical application of 30-300 ng/ml norepinephrine and 3-30 ng/ml U46619, a purported thromboxane A2 receptor agonist, also produced dose-dependent decreases in pial arteriolar diameter. After topical administration of U66985 (1 μg/ml), a putative PAF antagonist, responses to PAF were attenuated significantly, but responses to norepinephrine and U46619 were unchanged. Moreover, intravenously administered U66985 (0.1 mg/kg) antagonized PAF responses as well. Responses to PAF were unchanged after cyclooxygenase and leukotriene receptor inhibition. Further, PAF did not increase cortical subarachnoid cerebrospinal fluid prostaglandin or leukotriene levels. These data indicate that PAF is a potent constrictor of cerebral arterioles in newborn pigs and that its mechanism of action is independent of formation of cyclooxygenase and lipoxygenase products of arachidonic acid metabolism. These data suggest that U66985 may be a selective PAF antagonist that crosses the blood-brain barrier. Since PAF is an endogenous lipid released from a variety of tissues and may be an important mediator of inflammation and allergic reaction, PAF could be involved in the pathophysiology of the cerebral circulation in the perinatal period.