G protein-coupled receptor 81 (GPR81) is abundant in adipocytes and activation by the endogenous ligand lactate or by the specific agonist AZ’5538 inhibits lipolysis1,2. GPR81 is also found in non-adipose tissue1and AZ’5538 infusion has been shown to increase blood pressure (BP)2. Here, we localised Gpr81 mRNA in mouse arteries and kidney and examined the in vivo effects of AZ’5538 on renal haemodynamics. The expression of Gpr81 in tissues from WT and Gpr81-KO mice was assessed by PCR and in situ hybridisation. Separately, WT and Gpr81-KO mice were anaesthetised (Inactin; 120mg/kg, IP), the carotid artery cannulated for BP measurement and renal blood flow (RBF) measured by a Doppler ultrasound probe on the right renal artery. Doppler probes were also inserted into the cortex and medulla for measurement of intrarenal perfusion during IV infusion of either AZ’5538 or 5% mannitol vehicle. Plasma endothelin-1 (ET-1) was assessed by ELISA at baseline and post AZ’5538 or vehicle infusion. In a final group of mice, we examined the effect of ET receptor antagonism on the cardiorenal actions of AZ’5538. All animal work was performed under UK Home Office licences after ethical review by The University. Data are mean±SD. Gpr81 was expressed in the renal arteries, aorta and mesenteric arteries of wildtype mice (n=4). In situ hybridization showed Gpr81 expression in the vascular smooth muscle, glomeruli and perivascular cells in the medullary rays. In wildtype mice, AZ’5538 increased systolic BP by 14.9±6.5mmHg; vehicle had no significant effect (0.7±3.1mmHg, n=10). AZ’5538 also decreased RBF (-0.33±0.23mL/min vs vehicle 0.04±0.02mL/min, P=0.027, n=5). AZ’5538 had no effect in Gpr81-KO mice. In separate studies, AZ’5538 decreased cortical flux in wildtype animals only (-312.6±113.7PU vs 12.0±42.3PU for WT and KO respectively, P<0.0001, n=6); the reduction in medullary flux did not reach statistical significance (P=0.07). In C57 mice, plasma ET-1 was increased by AZ’5538 from baseline compared to vehicle (0.44±0.28pg/mL vs 0.12±0.28pg/mL respectively, n=8, P=0.04) but there were no differences in kidney or aorta levels. Prior infusion of endothelin-A receptor (ETRA) inhibitor BQ-123 prevented the AZ’5538 mediated BP increase (n=4, P=0.04), whereas BQ-788, an endothelin-B receptor antagonist, did not (n=5, P=0.18). We show Gpr81 expression in vascular smooth muscle, glomerulus and perivascular cells of the mouse kidney. In vivo, GPR81 activation influences cardiorenal haemodynamics in an ETRA mediated manner by stimulating circulating ET-1. The sensitivity of the renal circulation to GPR81 activation may become physiologically significant when circulating lactate, the endogenous ligand of GPR81, concentration rises, as can occur in ischemic renal disease.