Renal autacoids are involved in the stimulation of renin gene expression by low perfusion pressure. This study aimed to examine the role of local autacoids for the regulation of renin secretion and renin gene expression by the renal perfusion pressure. To this end the effects of unilateral reduction of renal perfusion by 0.2 mm clips on plasma renin activity and on renal renin mRNA levels were examined in rats treated with the cyclooxygenase inhibitor meclofenamate (8 mg/kg body wt, twice a day), with the NO-synthase inhibitor nitro-L-arginine-methylester (L-NAME, 40 mg/kg body wt, twice a day) or with a combination of both. L-NAME alone decreased basal PRA values from 9.9 to 5.4 ng Ang I/hr times ml, while meclofenamate alone and the combination meclofenamate/L-NAME had no consistent effect on basal PRA. Unilateral renal artery clipping increased PRA values from 9.9 ng Ang I/hr times ml to 34, 27, and 16 ng Ang I/hr times ml in vehicle, meclofenamate, and L-NAME treated animals, respectively, but did not increase PRA in meclofenamate/L-NAME treated rats (9.5 ng Ang I/hr times ml). Renal renin mRNA levels in the clipped kidneys increased 4.8-, 2.6-, 2.5- and 1.8-fold in the clipped kidneys in vehicle, meclofenamate, L-NAME and meclofenamate/L-NAME injected animals, respectively. These findings indicate that both the inhibition of prostaglandin synthesis and of the formation of endothelium-derived relaxing factor (EDRF) attenuate the increase of renin gene expression and of renin secretion in response to acute unilateral renal hypoperfusion and that the effects of both maneuvers are additive. The data suggest that the stimulations of renin gene expression in response to low renal perfusion pressure require both intact prostaglandin and EDRF formation.