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.
Chronic GPR18 activation by its agonist abnormal cannabidiol (trans-4-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; abn-cbd) improves myocardial redox status and function in healthy rats. Here, we investigated the ability of abn-cbd to alleviate diabetes-evoked cardiovascular pathology and the contribution of GPR18 to this effect. Four weeks after diabetes induction by streptozotocin (STZ, 55mg/kg; i.p), male Wistar rats received abn-cbd, the GPR18 antagonist (1,3-dimethoxy-5-methyl-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-,cyclohexen-1-yl]benzene;O-1918), their combination (100µg/kg/day, i.p, each) or their vehicle for 2 weeks. Abn-cbd had no effect on diabetes-evoked cardiac hypertrophy or impaired glycemic control (hyperglycemia and hypoinsulinemia), but alleviated the associated reductions in left ventricular (LV) contractility (dP/dt) and relaxation (dP/dt) indices, and the increases in LV end diastolic pressure (LVEDP) and cardiac vagal dominance. Abn-cbd also reversed myocardial oxidative stress by restoring circulating and cardiac nitric oxide (NO) and adiponectin (ADN) levels and enhancing GPR18 expression and phosphorylation of Akt, ERK1/2 and eNOS in diabetic rats' hearts. Concurrent GPR18 blockade (O-1918) abrogated all favorable effects of abn-cbd in diabetic rats. Collectively, the current findings present evidence for abn-cbd alleviation of diabetes-evoked cardiovascular anomalies likely via GPR18 dependent restoration of cardiac adiponectin-Akt-eNOS signaling and the diminution of myocardial oxidative stress.
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