The endocannabinoid anandamide exerts neurobehavioral, cardiovascular and immune-regulatory effects through cannabinoid receptors (CB). Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the in vivo degradation of anandamide. Recent experimental studies have suggested that targeting the endocannabinergic system by FAAH inhibitors is a promising novel approach for the treatment of anxiety, inflammation and hypertension. In this study we compared the cardiac performance of FAAH knockout (FAAH-/-) mice and their wild-type (FAAH+/+) littermates, and analyzed the hemodynamic effects of anandamide using the Millar pressure-volume conductance catheter system. Baseline cardiovascular parameters, systolic and diastolic function at different preloads and baroreflex sensitivity were similar in FAAH-/- and FAAH+/+ mice. FAAH-/- mice displayed increased sensitivity to anandamide-induced, CB1-mediated, hypotension and decreased cardiac contractility compared to FAAH+/+ littermates. In contrast, the hypotensive potency of synthetic CB1 agonist HU210, and the level of expression of myocardial CB1 were similar in the two strains. The myocardial levels of anandamide and oleoylethanolamide, but not 2-arachidonylglycerol, were increased in FAAH-/- compared to FAAH+/+ mice. These results indicate that mice lacking FAAH have a normal hemodynamic profile, and their increased responsiveness to anandamide-induced hypotension and cardiodepression is due to the decreased degradation of anandamide rather than an increase in target organ sensitivity to CB1 receptor agonists. The mechanisms by which cannabinoids alter coronary vascular tone and cardiac performance are controversial. We investigated the effects of various cannabinoids in spontaneously beating Langendorff-perfused rat hearts. Bolus injections of anandamide (0.1-1 ?Ymol) caused no change in coronary flow (CF) and left ventricular systolic pressure (LVSP). In hearts preperfused with vasopressin to induce vasoconstrictor tone, anandamide or the selective CB1 receptor agonist ACEA (1-100 nmol) dose-dependently increased CF by up to 267 % and LVSP by 20 mmHg. The metabolically stable endocannabinoid derivatives, R-methanandamide (0.1-1 ?Ymol) and noladin-ether (10-100 nmol), displayed similar effects. Abnormal cannabidiol (abn-cbd, 10-100 nmol), a selective agonist at putative endothelial cannabinoid receptors also increased CF. In contrast,?n?'9-THC (10-100 nmol), the major psychoactive ingredient of cannabis, strongly decreased CF and LVSP. The CB2 receptor agonist JW-133 (10-100 nmol) elicited vasodilator and positive inotropic effects only at higher doses. The CB1 antagonists SR141716A and AM-251 as well as the potassium channel inhibitors tetraethylammonium and iberiotoxin blocked the anandamide- induced increases in CF and LVSP, whereas the CB2 antagonist SR144528 and the putative endothelial cannabinoid receptor antagonist O-1918 did not have an inhibitory effect. Immunohistochemistry revealed the presence of cardiac CB1 but no CB2 receptors. The increases in CF caused by abn-cbd were attenuated by SR141716, but not by AM-251 or O-1918. Anandamide and 2-arachidonoyl-glycerol were detected in heart tissue. However, combined application of fatty acid amidohydrolase inhibitors and the transport inhibitor AM-404 in order to augment tissue levels of endocannabinoids was without effect on CF or LVSP. We conclude that in the rat isolated heart with re-established vasoconstrictor tone, cannabinoids including anandamide elicit coronary vasodilation and a secondary increase in contractility via CB1 receptors and potassium channels.
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