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EXPERIMENTAL STUDY

Endogenous cannabinoids mediate hypotension after experimental myocardial infarction

^a Department of Medicine, University of Würzburg, Würzburg, Germany
^b National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA

Manuscript received April 24, 2001; revised manuscript received August 15, 2001, accepted August 29, 2001.

^* Reprint requests and correspondence: Dr. Jens A. Wagner, Department of Medicine, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.
j.wagner{at}medizin.uni-wuerzburg.de

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 cannabinoid₁ receptor (CB₁) antagonist SR141716A (herein referred to as SR, 6.45 µmol/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 [] 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 (MAP = –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. Cannabinoid₁ receptor blockade restores MAP but increases 2-h mortality, possibly by impairing endothelial function.

Abbreviations and Acronyms   2-AG   2-arachidonyl glycerol   CB1   cannabinoid1 receptor   HR   heart rate   IV   intravenous   LC/MS   liquid chromatography/mass spectrometry   MAP   mean arterial pressure   MI   myocardial infarction   SNP   sodium nitroprusside

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