We have previously shown that increasing the renal perfusion pressure by using an extracorporeal circuit in anesthetized rabbits resulted in a progressive fall in systemic arterial pressure. Prior ablation of the renal medulla with 2-bromoethylamine abolished the hypotensive response. In the present study, we investigated whether vasodilator prostanoids or platelet activating factor (PAF), both known to be produced in the renal medulla, were responsible for the hypotensive response to increased renal perfusion pressure. Anesthetized animals were treated with indomethacin (5 mg/kg + 0.5 mg/kg per hour), the PAF antagonist WEB 2086 (0.5 mg/kg + 0.5 mg/kg per hour), enalaprilat (2 mg/kg + 10 micrograms/kg per hour), or all three agents. In response to acute elevation of renal artery pressure to 170 mm Hg, systemic mean arterial pressure fell at 0.76 +/- 0.17, 0.59 +/- 0.08, and 0.76 +/- 0.17 mm Hg/min in the indomethacin, WEB 2086, and enalapril groups, respectively. These responses were not significantly different from the rate of 1.00 +/- 0.21 mm Hg/min in a control group that received vehicle infusion alone. Renal blood flow and the diuretic and natriuretic responses were also similar in all groups. Thus, increased renal perfusion pressure resulted in a progressive fall in systemic arterial pressure that was not mediated by PAF, prostaglandins, or suppression of renin release and angiotensin II production.