Serelaxin is a novel recombinant human relaxin‐2 that is being investigated for the treatment of heart failure. However, the effects on renal function, especially on renal microcirculation remain uncertain. Immunofluorescence studies localized RXFP1,2 and 3 receptors on endothelial cells, vascular smooth muscle cells, mesangial and collecting duct cells. Therefore we investigated the effects of serelaxin on the renal microvasculature under normal conditions and in presence of exogenous angiotensin (Ang) II levels. Clearance experiments were performed in male pentobarbital anesthetized Sprague‐Dawley normotensive (n=5) and Ang II infused rats (3ng/min, n=5). In control rats, serelaxin (5ug/100g body weight/hr) significantly increased mean arterial pressure (119±1.7 vs. 135±1.1 mmHg; P<0.05), renal blood flow (7.5±0.2 vs. 9.5±0.2 ml/min/g; P<0.05), urine flow (5.1±0.1 vs. 9.9±0.9 μl/min/g; P<0.05) and sodium excretion rates (0.12±0.01 vs. 2.15±0.19 μmol/min/g; P<0.05) without significant changes in GFR (1.26±0.04 vs. 1.38±0.03 ml/min/g). During infusion with subthreshold Ang II infused rats, serelaxin did not alter mean arterial pressure (122±1.3 vs. 126±0.7 mmHg), renal blood flow (9.3±0.2 vs. 10.1±0.3 ml/min/g) or urine flow (4.7±0.2 vs. 4.9±0.3 μl/min/g). However, the increases in sodium excretion rate were sustained (0.4±0.05 vs. 1.18±0.16 μmol/min/g; P<0.05). Serelaxin did not significantly alter GFR in Ang II infused rats (1.27±0.12 vs. 1.4±0.09 ml/min/g). Heart rates were elevated by serelaxin infusion in both control rats (373±8.2 vs. 508±2.9 beat/min; P< 0.05) and in Ang II infused rats (460±7.4 vs. 512±5.1 beat/min; P<0.05). Using the in vitro isolated juxtamedullary nephron preparation, the effects of serelaxin on afferent and efferent arteriolar diameters from control rat kidneys and during Ang II superfusion were assessed with videomicroscopy. In control rat kidneys, serelaxin (20, 40 ng/ml infusion in blood) significantly dilated afferent arterioles (10.8±1.2 vs. 12.2±1.2 and 13.7±1.2 μm; n=5; P<0.05) and efferent arterioles (9.7±0.9 vs. 11.4±1.1 and 12.0±0.9 μm; n=5; P<0.5). During Ang II superfusion (0.5nM), serelaxin (20, 40 ng/ml infusion in blood) had no effects on afferent arteriolar diameters (11.5±0.1 vs. 11.7±0.1, 11.8±0.1 μm; n=4). These results demonstrate that serelaxin has direct dilating actions on both pre‐ and post‐glomerular arterioles. In the presence of exogenous Ang II levels, the effects of serelaxin were prevented. The responses of the renal microvasculature may be related to changes in NO bioavailability and oxidative stress. In conclusion, serelaxin increases overall renal blood flow, urine flow and sodium excretion by dilating both pre and post glomerular arterioles in control conditions, but these effects are attenuated in the presence of exogenous Ang II.Support or Funding InformationThis study was supported by Novartis Pharmaceuticals Corporation.