Modulation of mean arterial pressure and diuresis by renomedullary infusion of a selective inhibitor of fatty acid amide hydrolase

Am J Physiol Renal Physiol. 2018 Oct 1;315(4):F967-F976. doi: 10.1152/ajprenal.00090.2018. Epub 2018 May 30.

Abstract

The kidneys contribute to the control of body fluid and electrolytes and the long-term regulation of blood pressure through various systems, including the endocannabinoid system. Previously, we showed that inhibition of the two major endocannabinoid-hydrolyzing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, in the renal medulla increased the rate of urine excretion (UV) and salt excretion without affecting mean arterial pressure (MAP). The present study evaluated the effects of a selective FAAH inhibitor, N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidine carboxamide (PF-3845) on MAP and renal functions. Infusion of PF-3845 into the renal medulla of C57BL/6J mice reduced MAP during the posttreatment phases and increased UV at 15 and 30 nmol/min per gram kidney weight (g kwt), relative to the pretreatment control phase. Intravenous PF-3845 administration reduced MAP at the 7.5, 15, and 30 doses and increased UV at the 15 and 30 nmol⋅min-1⋅g-1 kwt doses. PF-3845 treatment elevated sodium and potassium urinary excretion and medullary blood flow. Homozygous FAAH knockout mice were refractory to intramedullary PF-3845-induced changes in MAP, but UV was increased. Both MAP and UV responses to intramedullary PF-3845 in C57BL/6J mice were diminished by pretreatment with the cannabinoid type 1 receptor-selective antagonist, rimonabant (3 mg/kg, ip) but not the cyclooxygenase 2-selective inhibitor, celecoxib (15 mg/kg, iv). Liquid chromatography-tandem mass spectrometry analyses showed increased anandamide in kidney tissue and 2-arachidonoyl glycerol in plasma after intramedullary PF-3845. These data suggest that inhibition of FAAH in the renal medulla leads to both a diuretic and blood pressure-lowering response mediated by elevated anandamide in kidney tissue or 2-arachidonoyl glycerol in plasma.

Keywords: anandamide; cannabinoid receptor; diuresis; endocannabinoids; fatty acid amide hydrolase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amidohydrolases / metabolism
  • Amidohydrolases / pharmacology*
  • Animals
  • Arachidonic Acids / pharmacology
  • Arterial Pressure / drug effects*
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Diuresis / drug effects
  • Endocannabinoids / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Kidney Medulla / drug effects*
  • Male
  • Mice, Inbred C57BL
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Piperidines / pharmacology*
  • Polyunsaturated Alkamides / pharmacology
  • Pyridines / pharmacology*

Substances

  • Arachidonic Acids
  • Cyclooxygenase 2 Inhibitors
  • Endocannabinoids
  • Enzyme Inhibitors
  • PF 3845
  • Piperidines
  • Polyunsaturated Alkamides
  • Pyridines
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • anandamide