Inhibition of type IV phosphodiesterase by Ro 20-1724 attenuates endotoxin-induced acute renal failure.

We recently found that the type IV-specific phosphodiesterase inhibitor Ro 20-1724 increases isoproterenol-induced cAMP secretion in the isolated rat kidney, whereas type I- and type III-specific phosphodiesterase inhibitors do not. Because cAMP is a known vasodilator of renal microvessels, we examined whether Ro 20-1724 is protective against endotoxin-induced acute renal failure. Fifteen rats were anesthetized, instrumented and administered a constant rate intravenous infusion of either Ro 20-1724 (10 micrograms/kg/min; n = 6) or vehicle (n = 9). After 1 hr, a base-line renal clearance period was conducted. All rats then received intravenous endotoxin (20 mg/kg), and six additional renal clearance periods were performed. Urinary cAMP excretion in the Ro 20-1724 group was elevated 2- to 3-fold (P \u3c .01) compared with the control group throughout the protocol. In the control group, endotoxin decreased renal blood flow, increased renal vascular resistance and decreased glomerular filtration rate. Ro 20-1724 markedly attenuated endotoxin-induced changes in renal blood flow (P = .0004), renal vascular resistance (P = .0001) and glomerular filtration rate (P \u3c .0001). The type IV-specific phosphodiesterase inhibitors warrant further study as selective therapeutic agents in the treatment of endotoxin-induced renal failure