Abstract P322: Different Responses To Intrarenomedullary Infusion of Anandamidevs. PF-3845 Reveal Additional Mechanisms Of Pressure-lowering And Diuresis-stimulation By Renomedullary FAAH Inhibition

Abstract

The fatty acyl ethanolamides comprise a group of lipids having biological activities consistent with multiple mechanisms of blood pressure-lowering, including vasodepressor, diuretic and natriuretic, and sympatholytic activities. One of these, N-arachidonoylethanolamide (anandamide, AEA), is an agonist at cannabinoid type 1 receptors (CB1) and is enriched in the renal medulla together with two of its metabolizing enzymes, fatty acyl amide hydrolase (FAAH) and cyclooxygenase-2 (COX-2). The purpose of the present study was to characterize and compare the effects of AEA with those of a selective FAAH inhibitor, PF-3845, on blood pressure and urine excretion parameters after intramedullary infusion into the outer medulla of anesthetized C57BL/6 (WT) or FAAH knockout (KO) mice. Intramedullary infusion of PF-3845 into WT mice stimulated UV but had a delayed MAP-lowering effect. Homozygous FAAH KO mice were refractory to intramedullary PF-3845- induced changes in MAP but UV was still increased. Both the MAP and UV responses to intramedullary PF-3845 in C57BL/6J mice were diminished by pretreatment with the cannabinoid type 1 receptor (CB1)-selective antagonist but not COX2-selective inhibitor. In contrast, intramedullary AEA treatment stimulated UV to similar extents in WT and FAAH KO mice but had no effect on MAP. The increase in UV by AEA was blocked by pretreatment with CB1 antagonist and COX-2 inhibitor. These data indicate fundamental differences in mechanisms of blood pressure-lowering by a FAAH inhibitor vs. AEA.