A - Human Necessities – 61 – K
Patent
A - Human Necessities
61
K
A61K 31/23 (2006.01) A61K 31/00 (2006.01) A61K 31/164 (2006.01) A61K 31/25 (2006.01) A61K 31/352 (2006.01) A61K 31/404 (2006.01) A61K 31/415 (2006.01) A61K 31/5377 (2006.01)
Patent
CA 2286442
The potent anti-ischaemic effects of cannabis-like drugs in the brain and the presence of CB1 and CB2-type cannabinoid receptors in heart indicate that endogenous cannabinoids such as 2-arachidonylglycerol and palmitoylethanolamide may contribute to protect the heart against the deleterious effects of ischaemia and reperfusion. 2-arachidonylglycerol and palmitoylethanolamide abolished the deleterious effects produced by ischaemia and reperfusion by interacting with CB2 cannabinoid receptors located in heart. In agreement with these results, the CB2 antagonist SR144528, but not the CB1 antagonist SR141716A, enhances the effect of ischaemia and blocks the protective effect 2-arachidonylglycerol (2-AG) and palmitoylethanolamide (PEA) perfused exogenously. These results indicate that peripheral CB2 receptors participate in the intrinsic defense of the heart against ischaemic insult and their endogenously and locally produced agonists such as 2-arachidonylglycerol and palmitoylethanolamide may mediate this protective effect. We have previously shown that endogenously produced mediators such as adenosine, des-Arg9-bradykinin, and prostaglandin E2 are involved in the protective effect of ischemic preconditioning (IPC) on the coronary endothelial function. We assess that the protective effect of IPC on endothelial function in coronary arteries of the rat also involves endogenously produced cannabinoids. Isolated rat hearts were exposed to a 30-min low flow ischemia followed by 20-min reperfusion, after which the response to the endothelium-dependent vasodilator, serotonin (5-HT), was compared with that of the endothelium-independent vasodilator, sodium nitroprusside (SNP). In untreated hearts, ischemia-reperfusion diminished selectively 5-HT-induced vasodilatation, compared with time-matched sham hearts, the vasodilatation to SNP being unaffected. IPC in untreated hearts preserved the vasodilatation produced by 5-HT. Blockade of CB1 or CB2 receptors with either (CB1 or CB2 antagonists) abolished the protective effect of IPC on the 5-HT vasodilatation. Perfusion with either PEA or 2-AG, but not anandamide, 15 min before and lasting throughout the ischemia protected the endothelium. This protection was blocked by SR144528 in both cases, whereas SR141716A only blocked the effect of PEA. Ischemic preconditioning affords protection to the endothelial function in resistance coronary arteries of the rat partially by activation of CB1 and CB2 receptors. Exogenous cannabinoid perfusion protected the endothelium via CB1 and/or CB2 receptors.
Bouchard Jean-Francois
Lamontagne Daniel
Goudreau Gage Dubuc
Universite de Montreal
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