[Role of cannabinoid receptors in regulation of cardiac tolerance to ischemia and reperfusion].

Coronary artery occlusion (45 min) and reperfusion (2 h) were modeled in vivo in anesthetized artificially ventilated Wistar rats. Total ischemia (45 min) and reperfusion (30 min) of the isolated rat heart were performed in vitro. The selective agonist of cannabinoid (CB) receptors HU-210 was injected intravenously at a dose of 0.1 mg/kg 15 min prior to the coronary artery ligation. The selective CB1 antagonist SR141716A and the selective CB2 antagonist SR144528 were injected intravenously 25 min prior to ischemia. In vitro, HU-210 and SR141716A were added to the perfusion solution at the final concentrations of 0.1 microM prior to total ischemia. Preliminary injection of HU-210 reduced the infarct size-to-area at risk (IS/AAR) ratio in vivo. This cardioprotective effect was completely abolished by SR141716A but remained after SR144528 injection. Both antagonists had no effect on the IS/AAR ratio. Preliminary injection of the K(ATP) channel blocker glibenclamide did not abolish the cardioprotective effect of HU-210. The addition of HU-210 prior to ischemia reduced the creatine phosphokinase (CPK) level in the coronary effluent and decreased left ventricular developed pressure. SR141716A alone had no effect on cardiac contractility and CPK levels. These results suggest that cardiac CB1 receptor activation increases cardiac tolerance to ischemia-reperfusion and has a negative effect on the cardiac pump function. Endogenous cannabinoids are not involved in the regulation of cardiac contractility and tolerance to ischemia and reperfusion. ATP-sensitive E+ channels are not involved in the mechanism of the cardioprotective effect of HU-210.

[Significance of cardiac cannabinoid receptors in regulation of cardiac rhythm, myocardial contractility, and electrophysiologic processes in heart].

Intravenous administration of cannabinoid (CB) receptor agonists (HU-210, 0.1 mg/kg; ACPA, 0.125 mg/kg; methanandamide, 2.5 mg/kg; and anandamide, 2.5 mg/kg) induced bradycardia in chloralose-anesthetized rats irrespective of the solubilization method. Methanandamide, HU-210, and ACPA had no effect on the electrophysiological activity in the heart, while anandamide increased the duration of the QRS complex. The negative chronotropic effect of HU-210 was due to CB1 receptor activation since is was not observed after CB1 receptor blockade by SR141716A (1 mg/kg intravenously) but was present after pretreatment with CB2 receptor antagonist SR144528 (1 mg/kg intravenously). CB receptor antagonists SR141716A and SR144528 had no effect on cardiac rhythm or ECG indices. Hence, in the intact heart, endogenous CB receptor agonists are not involved in the regulation of cardiac rhythm and electrophysiological processes. The chronotropic effect of CBs was independent of the autonomic nervous system because it remained significant after autonomic ganglion blockade by hexamethonium (1 mg/kg intravenously). CB receptor activation by HU-210 (0.1 and 1 microM) in vitro decreased the rate and force of isolated heart contractions, the rates of contraction and relaxation, and end diastolic pressure. The negative chronotropic effect of HU-210 was less pronounced in vitro than in vivo. The maximum inotropic effect of HU-210 was reached at the concentration of 0.1 microM.

[Paticipation of cannabinoid receptors in the regulation of cardiac rhythm and cardiac contractility].

It has been found that i. v. administration of cannabinoid receptor (CB) agonists (HU-210, ACPA, anandamide, methanandamide) induced a decrease in the heart rate (HR) in anesthetized rats. Pretreatment with CB1 receptor antagonist SR141716A completely abolished a negative chronotropic effect of CB receptor agonist HU-210. The CB2 receptor antagonist SRI 44528 did not prevent a HU-210-induced decrease in the HR. Pretreatment with the ganglion blocker hexamethonium had no effect on the negative chronotropic action of HU-210. Addition of HU-210 (100 nM) to perfusion solution induced a decrease in the HR, left ventricular development pressure, rate of contractility and relaxation of isolated perfused rate heart without change in end diastolic pressure. These data suggest that cardiac CBI receptor activation induces a decrease in the HR both in vivo and in vitro. An occupancy of the same receptors mediates a negative inotropic effects of cannabinoids.