Haemodynamic profile and responsiveness to anandamide of TRPV1 receptor knock-out mice

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 TRPV(1) 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 TRPV(1) receptors to the in vivo hypotensive effect of anandamide is equivocal. We compared the cardiac performance of anaesthetized TRPV(1) knockout (TRPV(1)(-/-)) mice and their wild-type (TRPV(1)(+/+)) 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 TRPV(1)(-/-) and TRPV(1)(+/+) 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 TRPV(1)(+/+) and TRPV(1)(-/-) mice, as was the ability of the CB(1) receptor antagonist SR141716 to completely block these effects. In TRPV(1)(+/+) 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 TRPV(1)(-/-) mice. These results indicate that mice lacking TRPV(1) receptors have a normal cardiovascular profile and their predominant cardiovascular depressor response to anandamide is mediated through CB(1) receptors. The role of TRPV(1) receptors is limited to the transient activation of the Bezold-Jarisch reflex by very high initial plasma concentrations of anandamide.