Martin Laser

Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle.

Cannabinoids elicit hypotension mainly via activated CB1 receptors and show complex cardiovascular actions. Effects on human heart muscle have not been studied yet. Isolated human atrial heart muscle preparations were stimulated by electrical field with 1 Hz to contract isometrically at optimal length and were challenged with the endogenous cannabinoid arachidonyl ethanolamide (anandamide), the metabolically stable analogue R-methanandamide, and the potent synthetic CB1 receptor agonist HU-210. Anandamide dose-dependently decreased systolic force (82.2 ± 4.8% and 60.8 ± 6.8% of maximal systolic force for 0.1 and 1 &mgr;M, respectively, P < 0.05). The selective CB1 receptor antagonist AM-251 (1 &mgr;M, P < 0.05), but not the CB2 receptor antagonist, AM-630 (1 &mgr;M), the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) (500 &mgr;M), or the cyclooxygenase inhibitor indomethacin (100 &mgr;M), prevented the effect. Contrary to indomethacin, l-NAME alone showed negative inotropic effects (72.1 ± 3.54%, P < 0.001). The R-methanandamide (1 &mgr;M: 50.4 ± 3.5%, P < 0.001) and HU-210 (1 &mgr;M: 60.1 ± 3.8%, P < 0.001) had similar negative inotropic effects. The existence of CB1 receptors on heart muscle was verified using Western blot analysis and immunofluorescence staining. The conclusion is that anandamide, R-methanandamide, and HU-210 decrease contractile performance in human atrial muscle via CB1 receptors.

CB1 cannabinoid receptor antagonism promotes remodeling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infarction

To study the long‐term effects of altered cannabinoid receptor activity on myocardial and vascular function, Wistar rats were treated with the selective CB1 antagonist AM‐251 (0.5 mg kg−1 d−1), the potent synthetic cannabinoid HU‐210 (50 μg kg−1 d−1) or vehicle for 12 weeks after coronary artery ligation or sham operation. AM‐251 further reduced the pressure‐generating capacity, shifted the pressure volume curve to the right (P<0.05) and increased the left‐ventricular operating volume (AM‐251: 930±40 μl vs control: 820±40 μl vs HU‐210: 790±50 μl; P<0.05) in rats with large myocardial infarction (MI). Left‐ventricular CB1 immunoactivity in rats 12 weeks after large MI was unaltered as compared with noninfarcted hearts. Cannabinoid receptor activation through HU‐210, a cannabinoid that alters cardiovascular parameters via CB1 receptors, increased the left‐ventricular end‐diastolic pressure (LVEDP, P<0.05). However, it prevented the drop in left‐ventricular systolic pressure (HU‐210: 142±5 mm Hg; P<0.05 vs control: 124±3 mm Hg; and P<0.001 vs AM‐251: 114±3 mm Hg) and prevented endothelial dysfunction (ED) in aortic rings of rats with large MI (P<0.05). Compared with AM‐251, HU‐210 prevented the decline in the maximal rate of rise of left‐ventricular pressure and the maximum pressure‐generating ability (P<0.05). In rats with small MI, HU‐210 increased cardiac index (P<0.01) and lowered the total peripheral resistance (P<0.05). The study shows that during the development of congestive heart failure post‐large MI, cannabinoid treatment increases LVEDP and prevents hypotension and ED. Presumed CB1 antagonism promotes remodeling despite unchanged myocardial CB1 expression.

Coronary vasodilator effects of endogenous cannabinoids in vasopressin-preconstricted unpaced rat isolated hearts

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 μmol) caused no change in coronary flow (CF) or 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 mm Hg. The metabolically stable endocannabinoid derivatives, R-methanandamide and noladin ether, displayed similar effects. In contrast, Δ9-THC (10-100 nmol), the major psychoactive ingredient of cannabis, strongly decreased CF and LVSP. The CB2 receptor agonist JWH-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 “CB3 antagonist” O-1918 did not have an inhibitory effect. Immunohistochemistry revealed the presence of cardiac CB1 but no CB2 receptors. Anandamide and 2-arachidonoylglycerol were detected in heart tissue. However, combined application of fatty acid amidohydrolase inhibitors and the transport inhibitor AM-404 to augment tissue levels of endocannabinoids was without effect on CF or LVSP. We conclude that in the rat isolated heart with reestablished vasoconstrictor tone, cannabinoids including anandamide elicit coronary vasodilation and a secondary increase in contractility via CB1 receptors and potassium channels.