EFFECTS OF VARIOUS PHOSPHODIESTERASE-INHIBITORS, FORSKOLIN, AND SODIUM-NITROPRUSSIDE ON PORCINE DETRUSOR SMOOTH-MUSCLE TONIC RESPONSES TO MUSCARINERGIC STIMULATION AND CYCLIC-NUCLEOTIDE LEVELS IN-VITRO

The cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cycli c guanosine monophosphate (cGMP) are second messengers involved in the regulation of contractility in various smooth muscle organs including detrusor smooth muscle. They are synthesized by activation of adenyla te and guanylate cyclases, respectively, and inactivated by phosphodie sterases (PDEs). In order to delineate the intracellular regulation of porcine detrusor contractility by cyclic nucleotides and phosphodiest erases, functional organ bath studies and determinations of intracellu lar cyclic nucleotide contents were performed after incubation of porc ine detrusor strips with forskolin (adenylate cyclase activator), sodi um nitroprusside (guanylate cyclase activator), and various phosphodie sterase-inhibitors. Significant relaxant responses were achieved only by forskolin, the nonspecific phosphodiesterase-inhibitor papaverine, and the phosphodiesterase 1-inhibitor vinpocetine (62.4 +/- 5.6%, 73 /- 4.3%, and 53 +/- 7.9%, respectively). Sodium nitroprusside and the selective PDE-inhibitors milrinone, rolipram, zaprinast, and dipyridam ole were significantly less efficacious (26.9 +/- 3.9%, 15.5 +/- 3.8%, 15.3 +/- 3.0%, 13 +/- 4.0%, and 13.2 +/- 2.1%, respectively). Forskol in, papaverine, and vinpocetine elevated intracellular cAMP concentrat ions (7.3-, 1.9-, and 1.7-fold increase at 100 mu M, respectively), wh ereas the other substances failed to enhance cAMP levels. cGMP levels were only increased by sodium nitroprusside (7.8-fold). The adenylate cyclase-cAMP system seems to be the more important signal transduction system involved in the relaxation of carbachol induced smooth muscle tone of the porcine detrusor. The role of the guanylate cyclase-cGMP s ystem is less clear. In addition, the calcium/calmodulin-stimulated PD E I seems to be of major functional importance in regulating cAMP hydr olysis in the porcine detrusor smooth muscle in vitro. (C) 1996 Wiley- Liss, Inc.