The aim of the study was to investigate the mechanisms underlying the down regulation of renal blood flow (RBF) following a prolonged reduction in the renal perfusion pressure (RPP) in adult spontaneously hypertensive rats (SHR). We tested the effect on the RBF response of clamping plasma angiotensin II (ANG II) by infusion of the converting-enzyme inhibitor captopril and ANG II in sevoflurane-anaesthetized SHR. We also tested the effect of general cyclooxygenase (COX) inhibition by infusion of indomethacin and the effect of inhibiting the inducible COX-2 enzyme with a specific inhibitor NS-398. Furthermore, we assessed the effect of clamping the nitric oxide (NO) system by simultaneous infusion of the NO-synthase inhibitor N-nitro-L-arginine methyl-ester (L-NAME) and sodium nitroprusside. A prolonged period (15 min) of reduced RPP (100 mm Hg) induced a down regulation of RBF, and this was unchanged following both clamping of the plasma ANG II concentration, and general inhibition of COX and specific inhibition of COX-2. In contrast, clamping the NO system diminished the ability of the SHR to down regulate RBF to a lower level after a prolonged reduction of RPP. In the control group, the down regulation of RBF was not associated with a resetting of the lower limit of autoregulation. The same appeared to be the case in ANG II clamped and the NO clamped SHR. However, general COX and specific COX-2 inhibition enabled a downward resetting of the lower level of autoregulation. In conclusion, in SHR the renin-angiotensin system does not appear to play a major role in the down regulation of RBF following a prolonged (15 minutes) reduction of RPP. This response appears to be mediated, at least in part, by the NO system. We hypothesize that in SHR the lack of a downward resetting of the lower limit of autoregulation in response to a prolonged lowering of RPP could be due to an increased, COX-2 mediated production of vasoconstrictory prostaglandins.