Specific antagonists of platelet activating factor-mediated vasoconstriction and glycogenolysis in the perfused rat liver

Abstract

Stimulation of hepatic glycogenolysis and vasoconstriction of the hepatic vasculature in response to acetyl glyceryl ether phosphocholine (AGEPC; platelet activating factor) was inhibited by two structural analogues of AGEPC, U66985 (1-O-octadecyl-2-O-acetyl-sn-glycero-3-phosphoric acid-6'-trimethyl ammonium hexyl ester) and CV3988 [rac-3-(N-n-octadecylcarbamoyloxy)-2-methoxy-propyl-2-thiazolioethyl+ ++ phosphate]. Infusion of CV3988, 10(-7) M, increased the AGEPC dose needed for half-maximal hemodynamic response by approximately 5-fold, while U66985 at 10(-7) M increased by twenty times the dose of AGEPC required to give the half-maximal response. Glucose output responses were similarly inhibited. U66985, 10(-6) M, completely abolished both hemodynamic and glycogenolytic responses to AGEPC, 2 X 10(-10) M, while in the presence of CV3988, 10(-6) M, approximately 15% of the uninhibited responses remained. Perfusion of livers for 20 min after termination of inhibitor infusion, in the absence or presence of bovine serum albumin, resulted in only a slightly smaller extent of inhibition than simultaneous infusion of agonist and antagonist. Specificity of the inhibitors was demonstrated by only a minimal inhibition of glycogenolytic response to the alpha-adrenergic agonist phenylephrine at a sub-maximal dose.