Plasma concentrations of natriuretic peptides ANP and BNP increase in states of volume expansion and after nephrectomy. The particulate guanylate cyclase (pGC) pathway, through ANP/BNP activation of natriuretic receptor type A (NPRA), as well as the soluble guanylate cyclase (sGC) pathway could cause renal vasorelaxation and improve GFR. We hypothesized that ANP and BNP cause concentration-dependent vasorelaxation in human intrarenal arteries comparable to soluble guanylate cyclase pathway-dependent vasodilatation. Human intrarenal arteries (n=31, 755.6 ± 86.8 µm 95% CI) were dissected from nephrectomy samples at 4 degrees celsius under a stereomicroscope and stored for up to 20 h at 4 degrees celsius in organ-buffer for drug washout. Segmental murine intrarenal arteries (n= 60, diameter 305.3 ± 15.5 µm 95% CI) were dissected from euthanized BL6J-mice. Development of isometric tension was recorded in a wire-myograph. Concentration-response curves for K+ and α1-adrenoceptor agonist phenylephrine (PE) were established. Rings were precontracted with EC50 of either PE or high K+ and subjected to cumulatively increasing concentrations of BNP, ANP, the phosphodiesterase (PDE)-5-inhibitor sildenafil, or the sGC activator BAY 60-2770 or stimulator BAY 41-2272. EC50-values were 30 mmol/L K+ for human arteries and 3×10-7 M phenylephrine for murine arteries. BNP (IC50 human/mouse = 10-7.1/10-7.3), ANP (IC50 mouse = 10-8.3), sildenafil (IC50 human/mouse =10-4.9/10-6.3), BAY 60-2770 (IC50 mouse = 10-7.5) and BAY 41-2272 (IC50 human/mouse = 10-5.1/106.6) caused concentration-dependent relaxation in human and murine intrarenal arteries. Pretreating vessels with sildenafil or BAY 41-2272 did not affect the BNP concentration response curve. PCR analysis showed consistent expression of PDE5, sGC and NPRC while NPRA was less consistently observed and NPRB was not present in human kidney vasculature. In conclusion, natriuretic peptides and sGC relax human and murine intrarenal arteries, in a concentration dependent fashion, suggesting that the renal vascular bed contains functional NPR, sGC and PDE-5. In perspective, drugs that interact with the pGC/sGC pathways may have renoprotective effects.