THE LIPOXYGENASE INHIBITOR PHENIDONE IS A POTENT HYPOTENSIVE AGENT IN THE SPONTANEOUSLY HYPERTENSIVE RAT

Previous studies from our laboratory indicated that the lipoxygenase inhibitor phenidone markedly attenuates angiotensin II (AII) induced vascular contractility. Phenidone was also shown to inhibit the formation of vascular lipoxygenase products and to reduce blood pressure in the AII-dependent renovascular hypertensive rat. We have now examined the effects of phenidone in the spontaneously hypertensive rat (SHR). A single dose of phenidone lowered intraarterial systolic pressure in a dose dependent manner in both SHR and Wistar-Kyoto (WKY) [(max 74 +/- 15 and 22 +/- 3 mm Hg, respectively; P < .001)], but the effect was substantially greater in SHR. Long-term oral phenidone administration arrested the evolution of hypertension in 6 week old SHR treated over a period of 4 weeks (control 190 +/- 2 mm Hg; phenidone treated rats 164 +/- 4 mm Hg; P < .01). To assess the role of AII related mechanisms in the hypotensive effect of phenidone, the acute effect was studied in SHR on high and low sodium intake. In addition, the effect of captopril was compared to that of phenidone alone or captopril and phenidone in salt restricted SHR. While a single dose of phenidone (30 mg/kg intraperitoneally) elicited similar maximal effects in SHR on high and low sodium intake (54 +/- 6 and 52 +/- 5 mm Hg compared to basal blood pressure, respectively), the hypotensive effect in sodium restricted rats was more sustained. Phenidone had no further hypotensive effect in captopril treated, salt restricted SHR. These results suggest that the hypotensive effects of the lipoxygenase blocker phenidone are mediated by both All dependent and AII independent mechanisms. This agent appears to have potent antihypertensive properties in several models of experimental hypertension.