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GPR55 EXERTS DIFFERENTIAL EFFECTS ON CARDIAC ADRENOCEPTOR SUBTYPES IN MICE
  1. SK Walsh,
  2. CL Wainwright
  1. Institute for Health & Wellbeing Research, Robert Gordon University, Aberdeen, UK

Abstract

Studies have suggested that G protein coupled receptor 55 (GPR55) may mediate the haemodynamic effects of several atypical cannabinoid ligands; however this data is conflicting and the cardiovascular role of this receptor is unknown. Our previous work demonstrated that GPR55 knockout (GPR55−/−) mice were characterised by a reduced contractile reserve in response to the non-selective adrenoceptor agonist, dobutamine. The present study was carried out to identify the adrenoceptor subtype(s) affected by GPR55 gene deletion and determine their role in the cardiac decompensation observed in these mice. Cardiac function was assessed via pressure volume loop analysis in male wild-type (WT) and GPR55−/− mice. Anaesthetised mice received increasing doses of either A-61603 (α1-adrenoceptor agonist), dobutamine in the presence of prazosin and ICI 118,551 (to antagonise α- and β2-adrenoceptors), or procaterol (β2-adrenoceptor agonist). β2-adrenoceptor activation had minimal effects on cardiac function that did not differ between genotypes. However, GPR55−/− mice exhibited reduced inotropy (dP/dtmax) and lusitropy (dP/dtmin) compared to WT mice following β1-adrenoceptor stimulation. In contrast, GPR55−/− mice were characterised by enhanced inotropy and lusitropy in response to α1-adrenoceptor stimulation. Our findings demonstrate that GPR55 influences adrenoceptor function in the heart, exerting opposing effects on adrenoceptor subtypes. Unlike β1-adrenoceptors, α1-adrenoceptors are not downregulated in heart failure and thus may make a substantial contribution to the remaining positive inotropy in failing hearts. With this in mind, our findings may suggest a pivotal role for GPR55 in the progression of heart failure and thus suggest this receptor as a potential therapeutic target for this condition.

  • CARDIAC PROCEDURES AND THERAPY

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