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Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA

The endocannabinoid anandamide and cannabinoid (CB) receptors have been implicated in the hypotension in various forms of shock and in advanced liver cirrhosis. Anandamide also activates vanilloid TRPV₁ receptors on sensory nerve terminals, triggering the release of calcitonin gene-related peptide which elicits vasorelaxation in isolated blood vessels in vitro. However, the contribution of TRPV₁ receptors to the in vivo hypotensive effect of anandamide is equivocal. We compared the cardiac performance of anaesthetized TRPV₁ knockout (TRPV₁^–/–) mice and their wild-type (TRPV₁^+/+) littermates and analysed in detail the haemodynamic effects of anandamide using the Millar pressure–volume conductance catheter system. Baseline cardiovascular parameters and systolic and diastolic function at different preloads were similar in TRPV₁^–/– and TRPV₁^+/+ mice. The predominant hypotensive response to bolus intravenous injections of anandamide and the associated decrease in cardiac contractility and total peripheral resistance (TPR) were similar in TRPV₁^+/+ and TRPV₁^–/– mice, as was the ability of the CB₁ receptor antagonist SR141716 to completely block these effects. In TRPV₁^+/+ mice, this hypotensive response was preceded by a transient, profound drop in cardiac contractility and heart rate and an increase in TPR, followed by a brief pressor response, effects which were unaffected by SR141716 and were absent in TRPV₁^–/– mice. These results indicate that mice lacking TRPV₁ receptors have a normal cardiovascular profile and their predominant cardiovascular depressor response to anandamide is mediated through CB₁ receptors. The role of TRPV₁ receptors is limited to the transient activation of the Bezold-Jarisch reflex by very high initial plasma concentrations of anandamide.

(Received 17 March 2004; accepted after revision 29 April 2004; first published online 30 April 2004)
Corresponding author P. Pacher: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA. Email: pacher{at}mail.nih.gov

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