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 < .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 < .0001). The type IV-specific phosphodiesterase inhibitors warrant further study as selective therapeutic agents in the treatment of endotoxin-induced renal failure.