Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart
Introduction
Remote ischemic preconditioning or preconditioning at a distance is a cardioprotective phenomenon which was first described by Przyklenk et al. (1993) in the canine model of myocardial ischemia/reperfusion. In their report, brief episodes of ischemia in one vascular bed protected remote virgin myocardium from subsequent sustained coronary occlusion (intra-cardiac remote preconditioning). A similar adaptive phenomenon, inter-organ remote preconditioning, has also been reported which is triggered by ischemia/reperfusion of other organs such as kidneys (Takaoka et al., 1999), intestines (Wolfrum et al., 2002), and limbs (Kharbanda et al., 2002, Kristiansen et al., 2005, Weinbrenner et al., 2002, Weinbrenner et al., 2004) in a variety of other species. Despite the promising results of the preliminary explorations of the clinical application of this clinically feasible procedure (Gunaydin et al., 2000), the mechanisms responsible for this phenomenon and its signaling pathways are still remained elusive.
In addition to their well-known neurobehavioral effects (Howlett et al., 2004), endogenous cannabinoids exert important physiological roles in cardiovascular system, such as hypotension and bradycardia (Randall et al., 2002, Randall et al., 2004, Wagner et al., 1998). These effects are considered to be due to activation of specific G-protein-coupled, cannabinoid CB1 and CB2, receptors (Niederhoffer and Szabo, 1999). Although cannabinoid CB1 receptors are preferentially located on brain, the cardiovascular depressor effects of cannabinoids appear to mostly involve cannabinoid CB1 receptors expressed in peripheral tissues, including blood vessels, the heart, and sympathetic nerve terminals (Batkai et al., 2004). The possible contribution of cannabinoid CB2 receptors, which are mainly located on peripheral non-neuronal cells (Niederhoffer and Szabo, 1999) including cardiovascular system, to modulation of cardiovascular function is less well documented.
Recent investigations have proposed the involvement of endogenous cannabinoids in infarct size-reducing effects conferred by lipopolysaccharide (Lagneux and Lamontagne, 2001) and heat stress (Joyeux et al., 2002), as well as endothelial protection afforded by classic ischemic preconditioning (Bouchard et al., 2003) in isolated rat hearts. However, the roles of endogenous cannabinoids in infarct size-reducing and anti-arrhythmic effects of remote ischemic preconditioning have not yet been evaluated. Therefore, we examined the cardioprotective effects of endogenous cannabinoids in the well-known model of remote preconditioning induced by a brief episode of mesenteric artery occlusion and reperfusion in intact rats.
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Animals
Animals were handled in accordance with the criteria outlined in the “Guide for the Care and Use of Laboratory Animals” (NIH US publication 85-23 revised 1996). Male Sprague–Dawley rats weighing 200–250 g were used. Animals were housed in groups of 3–4 in a room controlled at 22 ± 1°C and maintained in an alternating 12-h light/12-h dark cycles, and were allowed free access to food and water.
Study groups and experimental protocols
Animals were randomly divided into 6 groups:
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Vehicle + sham operation: Vehicle was intravenously administered
Hemodynamic parameters
As presented in Table 1, there was no significant difference in basal hemodynamic parameters among the groups. Variations in mean arterial pressure, as the percentage of the basal mean arterial pressure, is summarized in Fig. 1. AM251, but not AM630, treatment resulted in significant mean arterial pressure elevation in both sham-operated and preconditioned groups compared to the basal levels (P < 0.05). Mean arterial pressure was significantly elevated by mesenteric artery occlusion (P < 0.01) and
Discussion
This study provides evidence that endogenous cannabinoids contribute to the cardioprotective effects of remote preconditioning, conferred by a brief episode of mesenteric artery occlusion and reperfusion. This cardioprotection, manifested as reduction in the infarct size and severity of arrhythmias, seems to be mediated through cannabinoid CB2 receptors.
In this study we used AM251 as a specific cannabinoid CB1 receptor antagonist. AM251 is structurally very close to SR 141716A (rimonabant)
Acknowledgment
The authors are grateful to Dr. Ali Reza Mani (The UCL Institute of Hepatology, Royal Free & University College Medical School, UCL) for his support to this study.
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Both authors contributed equally to this study.