Jens A. Wagner

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.

Endogenous cannabinoids mediate hypotension after experimental myocardial infarction.

OBJECTIVES We sought to determine whether endocannabinoids influence hemodynamic variables in experimental models of acute myocardial infarction (MI). BACKGROUND Hypotension and cardiogenic shock are common complications in acute MI. Cannabinoids are strong vasodilators, and endocannabinoids are involved in hypotension in hemorrhagic and septic shock. METHODS The early effect of left coronary artery ligation on hemodynamic variables was measured in rats pretreated with the selective cannabinoid(1) receptor (CB(1)) antagonist SR141716A (herein referred to as SR, 6.45 micromol/kg body weight intravenously) or vehicle. Endocannabinoids produced in monocytes and platelets were quantified by liquid chromatography/mass spectrometry (LC/MS), and their effects on blood pressure and vascular reactivity were determined. RESULTS After MI, mean arterial pressure (MAP) dropped from 126 +/- 2 mm Hg to 76 +/- 3 mm Hg in control rats, whereas the decline in blood pressure was smaller (from 121 +/- 3 mm Hg to 108 +/- 7 mm Hg, p < 0.01) in rats pretreated with SR. SR increased the tachycardia that follows MI (change [Delta] in heart rate [HR] = 107 +/- 21 beats/min vs. 49 +/- 9 beats/min in control rats, p < 0.05). The MI sizes were the same in control rats and SR-treated rats. Circulating monocytes and platelets isolated 30 min after MI only decreased MAP when injected into untreated rats (DeltaMAP = -20 +/- 5 mm Hg), but not in SR-pretreated rats. The endocannabinoids anandamide and 2-arachidonyl glycerol were detected in monocytes and platelets isolated after MI, but not in cells from sham rats. Survival rates at 2 h after MI were 70% for control rats and 36% for SR-treated rats (p < 0.05). Endothelium-dependent arterial relaxation was attenuated in SR-treated rats (maximal relaxation: 44 +/- 3% [p < 0.01] vs. 70 +/- 3% in control rats) and further depressed by SR treatment (24 +/- 5%, p < 0.01 vs. MI placebo). CONCLUSIONS Cannabinoids generated in monocytes and platelets contribute to hypotension in acute MI. Cannabinoid(1) receptor blockade restores MAP but increases 2-h mortality, possibly by impairing endothelial function.

Cardiovascular Effects of 2-Arachidonoyl Glycerol in Anesthetized Mice

Cannabinoids, including the endogenous ligand anandamide, elicit pronounced hypotension and bradycardia through the activation of CB1 cannabinoid receptors. A second endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), has been proposed to be the natural ligand of CB1 receptors. In the present study, we examined the effects of 2-AG on mean arterial pressure and heart rate in anesthetized mice and assessed the role of CB1 receptors through the use of selective cannabinoid receptor antagonists and CB1 receptor knockout (CB1(-/-)) mice. In control ICR mice, intravenous injections of 2-AG or its isomer 1-AG elicit dose-dependent hypotension and moderate tachycardia that are unaffected by the CB1 receptor antagonist SR141716A. The same dose of SR141716A (6 nmol/g IV) completely blocks the hypotensive effect and attenuates the bradycardic effect of anandamide. 2-AG elicits a similar hypotensive effect, resistant to blockade by either SR141716A or the CB2 antagonist SR144528, in both CB1(-/-) mice and their homozygous (CB1(+/+)) control littermates. In ICR mice, arachidonic acid (AA, 15 nmol/g IV) elicits hypotension and tachycardia, and indomethacin (14 nmol/g IV) inhibits the hypotensive effect of both AA and 2-AG. Synthetic 2-AG incubated with mouse blood is rapidly (<2 minutes) and completely degraded with the parallel appearance of AA, whereas anandamide is stable under the same conditions. A metabolically stable ether analogue of 2-AG causes prolonged hypotension and bradycardia in ICR mice, and both effects are completely blocked by SR141716A, whereas the same dose of 2-AG-ether does not influence blood pressure and heart rate in CB1(-/-) mice. These findings are interpreted to indicate that exogenous 2-AG is rapidly degraded in mouse blood, probably by a lipase, which masks its ability to interact with CB1 receptors. Although the observed cardiovascular effects of 2-AG probably are produced by an arachidonate metabolite through a noncannabinoid mechanism, the CB1 receptor-mediated cardiovascular effects of a stable analogue of 2-AG leaves open the possibility that endogenous 2-AG may elicit cardiovascular effects through 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.

Natriuretic peptides and myocardial oxygen supply-to-demand ratio in patients with aortic stenosis

Background  In severe aortic stenosis (AS), brain natriuretic peptide (BNP) and its precursor, the amino‐terminal pro‐hormone (NT‐proBNP) are independent predictors of outcome. Deterioration of cardiac function in AS is currently assessed by symptomatology and echocardiography to determine the optimal time point for surgery. We investigated whether BNP or NT‐proBNP may help to estimate the individual risk of patients for subendocardial ischaemia in patients with moderate and severe AS.

Schrittmacherschaden durch Bestrahlung

As the number of implanted pacemakers and the incidence of malignant tumors increases, the probability of radiation-mediated pacemaker dysfunction increases. Radiation can substantially damage pacemaker electronics. We report here a case, with loss of communication after radiation therapy. Mit steigender Zahl eingebauter Schrittmacheraggregate und zunehmender Inzidenz von Tumorerkrankungen steigt die Wahrscheinlichkeit strahlungsbedingter Schrittmacherstörungen. Die Funktionalität des Schrittmachers kann durch eine Bestrahlung stark beeinträchtigt werden. Wir berichten über einen Fall, bei dem es nach Radiatio zum Verlust der Kommunikation mittels Telemetrie gekommen war.