We have shown that heparin lowers blood pressure significantly in hypertensive rats. This study was initiated to examine whether prostaglandin (PG) mediates the antihypertensive action of heparin. To this end, the effect of three different PG synthesis inhibitors (indomethacin, aspirin, meclofenamate) on the cardiovascular and renal actions of heparin was studied in spontaneously hypertensive rats (SHR). During 4 weeks of treatment, heparin reduced blood pressure significantly (P less than 0.01) in SHR. This was accompanied by significant decrements in hematocrit and total peripheral resistance but a significant increment in cardiac output. All of the PG inhibitors used significantly potentiated the antihypertensive effect of heparin and further reduced blood pressure by about 20%. Although heparin alone increased plasma renin activity, heparin and PG inhibitors together prevented this effect. When compared with heparin-treated rats, SHR treated with heparin and PG inhibitors combined had significantly (p less than 0.05 to 0.01) lower plasma aldosterone levels. These levels, however, were not different from SHR treated with PG inhibitors alone. Like blood pressures, the renal histopathologic lesions in SHR treated with heparin or heparin and PG inhibitors combined were significantly less severe than those in untreated SHR or SHR treated with PG inhibitors alone. Finally, captopril was shown to potentiate the effect of heparin. In conclusion, the antihypertensive effect of heparin does not appear to be PG mediated, but may be related to the structural changes in renal arterioles, inhibition of angiotensin-converting enzyme, or both.