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Title: Effects of endogenous cannabinoids and related substances on electrical activity and contraction in cardiac ventricular muscle
Author: Bolton, Emma L.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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Stimulation of cardiac β-adrenoceptors is the primary mechanism by which cardiac output is increased to meet metabolic demands of the body. Recently, nicotinic acid adenine dinucleotide phosphate (NAADP), has been implicated as a novel component of the β-adrenoceptor signalling pathway. NAADP is thought to mobilise Ca2+ from acidic endolysosomal stores which then supplements sarcoplasmic reticulum Ca2+ load, leading to a positive inotropic effect. Recent progress in the field has been made with the identification of two-pore channel 2 (TPC2) as a candidate NAADP receptor. Isolated ventricular myocytes from mice lacking TPC2 proteins (Tpcn2-/-) displayed blunted maximal responses to the β-adrenoceptor agonist isoprenaline. This blunted response was also evident in Langendorff-perfused Tpcn2-/- hearts. Furthermore, a blunted response was observed in guinea pig ventricular myocytes which had been treated with bafilomycin A1, which disrupts the integrity of acidic endolysosomal stores. These data add to the body of evidence that NAADP signalling forms an important additional component of the β-adrenoceptor signalling pathway. Chronic activation of the β-adrenoceptor pathway is associated with certain disease states including heart failure and arrhythmias. Anandamide is an endogenous cannabinoid, ('endocannabinoid'), with similar properties to δ9-tetrahydrocannabinol (δ9-THC), the primary active constituent of Cannabis sativa. These compounds have widespread physiological effects through actions at cannabinoid CB1 and CB2 receptors, which are negatively coupled to adenylyl cyclases and are expressed in cardiac muscle. Exposure of guinea pig ventricular myocytes to anandamide resulted in a reduction in the amplitude of contractions and Ca2+ transients. This was associated with a reduction in action potential duration and amplitude of ICaL. These effects of anandamide could not be prevented by cannabinoid receptor antagonists, and could not be mimicked by cannabinoid receptor agonists. An inhibition of IKs was also observed. Given the reported Gi-protein coupling of cannabinoid receptors, it may be expected that additional negative inotropic actions of anandamide might be observed when adenylyl cyclases are stimulated. However, the effects of anandamide to reduce amplitude of contraction and ICaL were no greater in the presence of isoprenaline. Furthermore, the effects of anandamide were not prevented by pre-treatment of myocytes with pertussis toxin (PTX). This is in contrast to the actions of adenosine, which displayed clear PTX sensitive actions in the presence of isoprenaline. These data suggest that cannabinoid receptors are not involved in mediating the negative inotropic actions of anandamide. Another endocannabinoid, 2-arachidonoylglycerol, was without significant effect on action potentials or contractions in the absence or presence of isoprenaline. δ9-THC shared many of the actions of anandamide. It appears that anandamide and δ9-THC exert significant effects on cardiac muscle through direct modulation of ion channel function, although additional actions, for example, on the sarcoplasmic reticulum or myofilaments, cannot be ruled out.
Supervisor: Terrar, Derek A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology ; anandamide ; cardiac electrophysiology