Investigation of cannabinoid-mediated cardioprotection.
Underdown, Nicola Joy.
mesheuropmc: lipids (amino acids, peptides, and proteins)
This thesis describes work carried out to characterise cardiac responses to cannabinoids. A particular focus of the work was to study the mechanism by which cannabinoids protect hearts from ischaemia-reperfusion injury. Studied in rat isolated right atria, anandamide (an endocannabinoid) induced a limited positive chronotropy. As this response was blocked by indomethacin and not mimicked by methanandamide (a non-hydrolysable analogue), the mechanism of action appears to involve conversion and release of products of cyclooxygenase-2. Conversely, negative chronotropy was observed when baseline rate was elevated by a b-adrenoceptor agonist. The pharmacological profile of this anti-adrenergic response indicated the involvement of CB2 receptors. Potential protection afforded by cannabinoids against rat isolated hearts subjected to ischaemia-reperfusion was studied in two different models. In the first, hearts were subjected to global, no-flow ischaemia-reperfusion with agonists introduced 5 min before ischaemia. The second method subjected hearts to regional ischaemia-reperfusion with agonists introduced 35 min into ischaemia. Antagonists, where used, were present throughout the protocol. In the global, no-flow ischaemia-reperfusion model both anandamide and methanandamide significantly reduced infarction but in the regional ischaemia-reperfusion model only methanandamide significantly reduced infarction. In both models the infarct limiting action was lost in the presence of both the CB1 receptor antagonist SR141716A and the CB2 receptor antagonist SR144528. However, CB1- or CB2-receptor agonists, used alone or in combination, were ineffective at reducing infarct size. These results suggest that neither CB1 nor CB2 receptors, alone or in synergy mediate cardioprotection. These results suggest that one or more novel sites of action, possibly a new cannabinoid receptor subtype, might mediate cardio-protection in rat hearts. These findings demonstrate the potential for cannabinoids to be used as adjuncts to thrombolytics. However, the in vivo effects of cannabinoids in situations of compromised cardiac function needs to be assessed as they could potentially cause excessive hypotension due to peripheral vasodilatation.
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