Novel Cardiorenal Effects of the Lactate Receptor GPR81 Activation

G protein-coupled receptor 81 (GPR81) is highly expressed in adipocytes and activation of the receptor by the endogenous ligand lactate inhibits lipolysis. The receptor is also expressed in non-adipose tissue but the function of GPR81 at these sites is not known. In the present study we first used end point PCR to screen for GPR81 expression in the kidney and vasculature isolated from male Sprague-Dawley rats (n=4). GPR81 was expressed in the whole kidney, aorta, mesenteric, renal and interlobar arteries. We next used a specific GPR81 agonist, AZ13415538, to assess the function of the receptor on renal haemodynamics in vivo. Male Sprague Dawley rats (n=14) were anesthetised with Inactin (120mg/kg) and a Doppler ultrasound probe placed round the left renal artery. Mean arterial blood pressure was measured via a cannula inserted into the femoral artery. Data are expressed as mean±sem. The agonist was injected into the jugular vein as a bolus in a 5 point cumulative dose response curve from 0.5μmol to 5μmol. Injection of AZ13415538 caused a rapid, dose-dependent rise in blood pressure and a reduction in renal blood flow. At the highest dose of 5μmol, the increase in mean arterial blood pressure over the pre-injection baseline was 20.4±1.6 mmHg; the nadir of renal blood flow was 3.0±0.5 mL/min. Both effects were transient and recovered after 75 seconds. The 5% mannitol vehicle (0.5ml) also caused an increase in blood pressure (11.4±0.8 mmHg) and a reduction of renal blood flow (1.8±0.2 mL/min) but these effects were not sustained. The effect of AZ13415528 was therefore expressed as area over and under the curve for blood pressure and renal blood flow, respectively. A significant dose-dependent effect for both blood pressure and blood flow was identified by One-Way Anova (P<0.0001). Post hoc comparisons against the effect of vehicle showed significant increases in blood pressure at 2–4μmol (P<0.05) and 5μmol (P<0.01). Renal blood flow was significantly reduced at 4μmol AZ13415528 (P<0.05) and 5μmol (P<0.01). The increase in renal vascular resistance observed after GPR81 activation shows novel cardiovascular effects of this receptor. The mechanisms underlying these actions have not been investigated.