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First published online on April 30, 2004.
 Copyright © 2004 by The Physiological Society
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Received March 17, 2004
Revised April 7, 2004
Accepted after revision April 29, 2004

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

Pal Pacher1*, Sandor Batkai1, and George Kunos1

1 NIH, NIAAA

* To whom correspondence should be addressed. E-mail: pacher{at}mail.nih.gov.

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 that 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 anaesthetised 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 as well as 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 increase in TPR, followed by a brief pressor response, 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.


Key words: Cannabinoids • Cardiac function • Vanilloid receptor




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