Differential mechanisms mediating depressor and diuretic effects of anandamide.
BACKGROUND
Anandamide (AEA), one of the endocannabinoid compounds, has an important regulatory function by serving as an autocrine/paracrine or endocrine factor throughout the body via activation of the cannabinoid receptor 1 (CB1) and/or the transient receptor potential vanilloid type 1 (TRPV1) channels. However, the role of AEA in the regulation of renal excretory function is largely unknown. The present study was designed to test the hypothesis that intrarenal administration of AEA enhances renal excretory function leading to a decrease in blood pressure.


METHODS
A metabolically stable analog of AEA, methanandamide (MethA, 300 nmol/kg per min), was infused into the left renal medulla of anesthetized Wistar rats with or without a selective TRPV1 antagonist, capsazepine (Capz, 150 nmol/kg per min) or a selective cannabinoid receptor 1 (CB1) antagonist, AM251 (Am, 150 nmol/kg per min). Ureters were cannulated for collection of urine. A laser-Doppler flowmeter was used to determine the changes of blood flow in the cortex and medulla of the infused kidney.


RESULTS
In the absence of the changes in cortical and medullary blood flow, unilateral intramedullary infusion of MethA significantly increased urine flow rate by 64% ipsilaterally and 62% contralaterally without changing sodium excretion when compared to vehicle controls (P < 0.01). Neither Capz nor Am blocked the MethA-induced increases in urine flow rate bilaterally. Intramedullary infusion of MethA significantly decreased mean arterial pressure (MAP) (P < 0.01), which was blocked by Am but not Capz. Denervation of the infused kidney blocked the MethA-induced increases in urine flow rate bilaterally without altering MethA-induced decreases in MAP.


CONCLUSIONS
Therefore, our data show that intramedullary infusion of AEA increases urine volume excretion and decreases blood pressure via distinct operational mechanisms. While activation of the CB1 receptor may underlie AEA-induced depressor effects, the diuretic effect of AEA appears to be mediated by neuronal reflex of the kidney, which is not sensitive to blockade of the TRPV1 or CB1 receptor.
Li
Jianping
J
Department of Medicine and Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA.
Wang
Donna H
DH
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D007668:Kidney / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D007679:Kidney Medulla / Q000187:drug effects; D008297:Male; D053284:Polyunsaturated Alkamides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000502:physiology
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; C088155:methanandamide; C071423:capsazepine; D002211:Capsaicin; C078814:anandamide