The direct effect of anandamide on heart rate is unclear. Previously reported mechanisms that may mediate responses to cannabinoids include activation of cannabinoid CB₁, CB₂ or vanilloid VR₁ receptors as well as uptake via a specific transporter and conversion into products of the arachidonic acid cascade (Howlett et al., 2002). The aim of this study was to examine if cannabinoids affect heart rate in rat isolated, spontaneously contracting right atria and identify a mechanism of action.

Right atria were removed from male Wister rats (250-350g) which were killed by an overdose of sodium pentabarbital followed by cerebral dislocation, and arranged in 20ml organ baths containing Krebs bicarbonate solution warmed to 37^oC and gassed with 5% CO₂ in oxygen. A resting tension of 1g was applied to the tissue, which was allowed to beat spontaneously and isometric tension recorded. Cumulative dose response curves were conducted using anandamide (AEA) or equivalent volumes of its vehicle (Tocrisolve^TM 100, Tocris Cookson, UK). Where used (all at 1 µM), antagonists selective for CB₁ receptors (SR141716A and AM281), CB₂ receptors (SR144528), vanilloid VR₁ receptors (capsazepine), or the anandamide transporter (AM404), were dissolved in DMSO (final concentration 0.5% vol/vol). The cyclo-oxygenase inhibitor, indomethacin (1 µM), where used, was dissolved in ethanol (0.5% vol/vol).

Statistical comparisons were made using ANOVA supported by Dunnett's multiple comparisons test, P<0.05 was taken as significant. Data are presented as means of % change in baseline ± S.E.M.

AEA caused a concentration-dependent increase in chronotropy. Maximal responses were not attained in the concentration range used (0.01 to 30 µM). At the highest concentration, AEA significantly increased chronotropy by 11±2% above baseline (n=11) whereas Tocrisolve^TM 100 had no significant effect (1%±1, n=6). DMSO and ethanol themselves, had no significant effect on AEA responses (7±2%, n=5 and 13±2%, n=4, respectively). Compared to their vehicle control (DMSO), SR141716A (11%±4, n=4), AM281 (4%±3, n=4), SR144528 (11%±6, n=6) or capsazepine (7%±3, n=3) had no significant effect on the AEA response. However, AM404 (0%±1, n=7) or indomethacin (2%±1, n=7) significantly inhibited AEA-induced positive chronotropy compared to their respective vehicle controls (DMSO and ethanol, respectively).

AEA is a positive chronotrope in rat isolated right atria. The response appears to be mediated by uptake and conversion into products of the arachidonic acid cascade. Cannabinoid CB₁, CB₂ or vanilloid VR₁ receptors do not appear to be involved in the mechanism of AEA-induced positive chronotropy.

Howlett, A.C., et al. (2002). Pharmacol Rev, 54, 161-202.

Supported by a grant from the British Heart Foundation(BHF). NJU is supported by a BHF studentship.