After arterial denudation by external rubbing of the left main renal artery, we assessed renal plasma flow rate (RPF) and glomerular filtration rate (GFR) in left and right kidneys of Munich-Wistar rats before and after intravenous infusion of acetylcholine (ACH), atrial natriuretic peptide (ANP), or nitroprusside (NP). In the right kidney RPF and/or GFR increased in response to both endothelium-derived relaxing factor (EDRF)-dependent (i.e., ACH) and -independent vasodilators (i.e., ANP and NP); on average, RPF rose by 22±4% (P < 0.005), 19±10% (P < 0.005), and 37±12% (P > 0.05), respectively. By contrast, in the left kidney RPF failed to increase after ACH (falling by 23±10%, P < 0.001) and rose only in response to ANP and NP. To further evaluate the main renal artery's contribution to renal vasodilation, ACH and another EDFR-dependent agent, histamine, were infused through a micropipette into either renal artery. Proximal infusion of ACH led to increases in RPF and GFR, on average by 8±2% (P < 0.025) and 10±3% (P < 0.01), while bypassing the arterial endothelium by distal infusion failed to increase RPF and GFR, which fell by 24±6% (P < 0;025) and 22±6% (P < 0.005), respectively. Similarly, proximal infusion of histamine increased RPF by 12±3% (P < 0.05), while distal infusion was virtually without effects on plasma flow. Micropuncture study during intravenous ACH infusion revealed significantly higher afferent and efferent arteriolar resisrances and lower ultrafiltration coefficients in denuded versus nondenuded kidneys. These data indicate that the main renal artery is a major regulator of renal blood flow and vascular resistances. Similar to other endothelium-derived substances, EDRF may be elaborated mainly by large vessels and may act on the downstream microcirculatory systems, which determine organ blood flow and transcapillary fluid transfer.