FORSKOLIN INCREASES OSMOTIC WATER PERMEABILITY OF RABBIT CORTICAL COLLECTING TUBULE

Forskolin is a unique diterpene that may directly activate the catalytic subunit of adenylate cyclase. The effect of 50 .mu.M forskolin on osmotic water permeability was examined in rabbit cortical collecting tubules perfused in vitro. Forskolin increased net volume flux (Jv, from 0.30-1.22 nl/mm/min, P < 0.02) in all tubules. The hydro-osmotic effect of forskolin was similar with respect to magnitude and time course to that produced by a maximal dose (250 .mu.U/ml) of arginine vasopressin. An additive effect on Jv and Lp [hydrualic conductivity] was not observed when maximal concentrations of forskolin and arginine vasopressin were given simultaneously. The compound d(CH2)5Tyr(Et) VAVP [arginine vasopressin], which noncompetitively inhibits the vasopressin receptor, significantly reduced collecting tubular hydro-osmotic response to arginine vasopressin. The hydro-osmotic response to forskolin was maintained in the presence of d(CH2)5 Tyr(Et)VAVP. The hydro-osmotic response to forskolin could be inhibited by 1.0 .mu.M guanine 5''-(.beta.,.gamma.-imido)triphosphate (GppNHp) and by the calmodulin inhibitor N-(6-amenohexyl)-5-chloro-1-naphthalenesulfonamide (W-7). These results demonstrate that forskolin exerts an hydro-osmotic effect in the mammalian nephron which occurs independent of the vasopressin receptor. Guanine nucleotide regulatory proteins may modulate the osmotic water permeability effect of forskolin. Calmodulin is required for full expression of the effect of forskolin to increase osmotic water flux.