Role of endocannabinoid system in pressure natriuresis, in mice with and without fatty acid amide hydrolase
Authors: Ahmad Ashfaq , Dempsey Sara K. , Daneva Zdravka , Li Ningjun , Li Pin‐Lan , Ritter Joseph K. 
Published: June 2021

Kidney is the major organ responsible for long term regulation of blood pressure. Impaired renal sodium excretion and perfusion pressure is main driver of hypertension. This perfusion pressure and renal sodium excretion is called as acute pressure natriuresis (PN). It was surprising to know that none of the study explained the role of endocannabinoids (ECs) in PN and importance of EC hydrolyzing enzymes in the modulation of PN mechanism. This study set out with the primary objective that after acute increase in mean arterial pressure (MAP) either anandamide (AEA) or 2‐arachidonoyl glycerol (2‐AG) is released in the kidney which modulate PN by lowering MAP, natriuretic and diuretic activities. Secondly, effect of genetic and pharmacological ablation of fatty acid amide hydrolase (FAAH) genes in mice modulate the PN relationship. Mice were anesthetized and cannulation was done in trachea, jugular vein, carotid artery and bladder. PN model was established in animals by ligations of celiac and superior mesenteric arteries (CML) and abdominal aorta (AL) while MAP and UV were observed at 10 minutes intervals in FAAH wild type and its knock out littermate. Ligation of celiac and mesenteric arteries resulted in increase in MAP (from baseline to CML‐1 phase) 91 to 121 (mmHg) with corresponding increase in UV from 9 to 17 (ul/min/g kwt) and urinary sodium (UNa) from 1.3 to 3.0 (umol/min/g kwt). MAP and UV reported at CML‐2 ligation was 113 mmHg and 17 ul/min/g kwt. MAP at AL‐1 and AL‐2 was noted as 119 and 104 (mmHg) with corresponding increase in UV 21 and 26 (ul/min/g kwt) while UNa was noted as 3.4 umol/min/g kwt. Pretreatment with selective FAAH inhibitor in the medulla of the kidney resulted in increase in MAP from baseline 88 to 131 and 109 mmHg at CML‐1, CML‐2 respectively while MAP was also observed 119 and 123 mmHg at AL‐1 and AL‐2 phase. There was significant increase (p<0.05) in UV after pretreatment with FAAH inhibitor which was noted 26 and 28 (ul/min/g kwt) at CML‐1 and CML‐2 while 49 and 48 (ul/min/g kwt) at AL‐1 and AL‐2 respectively. FAAH KO animals shifted MAP and UV curves of PN study towards right when compared to FAAH WT group. Analytical data showed significant increase (P<0.05) in 2‐AG levels in the kidney and plasma samples of FAAH WT animals underwent through PN when compared to control FAAH WT while AEA levels was significantly higher (p<0.05) in the kidney of FAAH KO animals with PN as compared to respective control group. It can be concluded that endocannabinoids are released in response to acute increase in MAP and results in diuretic and natriuretic activities which lowers the MAP and keep PN relationship intact. Lastly, regional blocking of FAAH in the kidney shift the MAP and UV curves of the PN models towards left and positively modulate the PN relationship.Support or Funding InformationThis work was supported by National Institute of Diabetes and Digestive and Kidney Disorders grant, DK102539This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.