While acute activation of the novel endocannabinoid receptor GPR18 causes
hypotension, there are no reports on GPR18 expression in the heart or its
chronic modulation of cardiovascular function. In this study, after
demonstrating GPR18 expression in the heart, we show that chronic (2 weeks)
GPR18 activation with its agonist abnormal cannabidiol (abn-cbd; 100
µg/kg/day; i.p) produced hypotension, suppressed the cardiac sympathetic
dominance, and improved left ventricular (LV) function (increased the
contractility index dp/dtmax, and reduced LV end diastolic pressure,
LVEDP) in conscious rats. Ex vivo studies revealed increased: (i) cardiac and
plasma adiponectin (ADN) levels; (ii) vascular (aortic) endothelial nitric oxide
synthase (eNOS) expression, (iii) vascular and serum nitric oxide (NO) levels;
(iv) myocardial and plasma cyclic guanosine monophosphate (cGMP) levels; (v)
phosphorylation of myocardial protein kinase B (Akt) and extracellular signal
regulated kinase 1/2 (ERK1/2) along with reduced myocardial reactive oxygen
species (ROS) in abn-cbd treated rats. These biochemical responses contributed
to the hemodynamic responses and were GPR18-mediated because concurrent
treatment with the competitive GPR18 antagonist (O-1918) abrogated the abn-cbd
evoked hemodynamic and biochemical responses. The current findings present new
evidence for a salutary cardiovascular role for GPR18, mediated, at least
partly, via elevation in the levels of ADN.
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