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This study assessed the effects of selective inhibitors of 3 ,5 -cyclic nucleotide phosphodiesterases (PDEs) on adipocyte lipolysis. IC224, a selective inhibitor of type 1 phosphodiesterase (PDE1), suppressed lipolysis in murine 3T3-L1 adipocytes (69.6 ؎ 5.4% of vehicle control) but had no effect in human adipocytes. IC933, a selective inhibitor of PDE2, had no effect on lipolysis in either cultured murine 3T3-L1 adipocytes or human adipocytes. Inhibition of PDE3 with cilostamide moderately stimulated lipolysis in murine 3T3-L1 and rat adipocytes (397 ؎ 25% and 235 ؎ 26% of control, respectively) and markedly stimulated lipolysis in human adipocytes (932 ؎ 7.6% of control). Inhibition of PDE4 with rolipram moderately stimulated lipolysis in murine 3T3-L1 adipocytes (291 ؎ 13% of control) and weakly stimulated lipolysis in rat adipocytes (149 ؎ 7.0% of control) but had no effect on lipolysis in human adipocytes. Cultured adipocytes also responded differently to a combination of PDE3 and PDE4 inhibitors. Simultaneous exposure to cilostamide and rolipram had a synergistic effect on lipolysis in murine 3T3-L1 and rat adipocytes but not in human adipocytes. Hence, the relative importance of PDE3 and PDE4 in regulating lipolysis differed in cultured murine, rat, and human adipocytes. Adipose tissue functions as an energy storage organ in which excess calories are sequestered in the form of triglyceride (TG). TG contained in circulating chylomicrons and VLDL particles is hydrolyzed by extracellular lipoprotein lipase to yield glycerol and FFA. FFA is then taken up by adipocytes, converted to fatty acyl-CoA, and reesterified with glycerol-3-phosphate to form intracellular TG. The size of adipose TG stores is dynamically regulated by endocrine signals in response to energy intake and metabolic demands. Thus, anabolic hormones, such as insulin, stimulate adipocyte TG synthesis (lipogenesis), whereas catabolic hormones, such as epinephrine, glucagon, and corticotropin, stimulate hydrolysis of adipocyte TG to glycerol and FFA (lipolysis).Cyclic AMP is an important second messenger in the signaling pathways that mobilize fat stores (1). Catecholamines (epinephrine and norepinephrine) stimulate adipocyte lipolysis by binding to ␤ -adrenoceptors, which activate adenylyl cyclase (AC) via the stimulatory guanine nucleotide binding protein (G s ), leading to an increase in intracellular cAMP and activation of cAMP-dependent protein kinase (PKA). Initially, cAMP-mediated stimulation of lipolysis was thought to be attributable exclusively to PKA-dependent phosphorylation and activation of hormone-sensitive lipase (HSL), the primary neutral lipase in adipose tissue (2). However, adipocytes from HSL knockout mice retain considerable TG lipase activity, and lipolysis in these cells is partially responsive to the ␤ -adrenoceptor agonist isoproterenol (ISO), suggesting that other lipases besides HSL play a role in lipolysis (3-5). Another layer of regulation of lipolysis is revealed by the observation that lipolytic stimuli cau...

RESULTSIn unobstructed rats, IC486051 (0.1 mg/kg intravenously) produced no significant changes in cystometric variables, while at a dose of 0.5 mg/kg maximum voiding pressure was reduced by 34%. At both doses, there was a small, transient increase in blood pressure. In both 4-and 6-week BOO rats IC486051 dose-dependently decreased the number and amplitude of non-voiding bladder contractions by up to 80%, relative to pretreatment values. At doses of 0.1 and 0.5 mg/ kg IC486051 had no significant effect on voiding variables. In the 4-week BOO rats, a dose of 1.0 mg/kg decreased bladder capacity, voided volume and residual volume by 21%, 32% and 18%, respectively. In 6-week BOO rats, a dose of 1.0 mg/kg decreased maximal voiding pressure by 17% and pressure threshold for voiding by 28%. In both groups of rats with BOO, voiding efficiency was unchanged. CONCLUSIONSA selective PDE4 inhibitor can effectively suppress detrusor overactivity in rats with BOO, at doses that have no effect on voiding bladder contractions. Thus, selective PDE4 inhibitors should be considered for the treatment of overactive bladder in patients with BOO. KEYWORDStype 4 phosphodiesterase, PDE4, bladder outlet obstruction, non-voiding contractions, detrusor overactivity, rat OBJECTIVETo investigate the effects of a selective type 4 cyclic nucleotide phosphodiesterase (PDE4) inhibitor, IC486051, on bladder activity in normal rats and those with and bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle. MATERIALS AND METHODSBOO was induced in female Sprague-Dawley rats by tying a silk ligature around the urethra. At 4 or 6 weeks after inducing BOO, conscious rats were assessed by cystometry with the urethral ligature intact. In unobstructed rats, blood pressure was also measured.

conscious rats were assessed by cystometry with the urethral ligature intact. The effects of IC485 (5, 10 and 50 mg/kg intravenous, i.v.) were examined and compared with those of tolterodine (0.01, 0.1 and 1 mg/kg i.v.). RESULTS IC485(5-50 mg/kg i.v.) decreased the number and amplitude of non-voiding contractions during the storage phase by 63-88% and 49-83%, respectively; IC485 also increased bladder capacity by 28-37%. There was no change in blood pressure after applying IC485. Tolterodine tartrate (0.1 and 1.0 mg/kg) significantly decreased the number and amplitude of non-voiding contractions by 38-74% and 29-44%, respectively, and increased bladder capacity by 19-51%.Whereas voiding efficiency and maximum voiding pressure were not altered by IC485 at any dose, tolterodine significantly reduced both, by 35-67% and 19-34%, respectively. CONCLUSIONBoth IC485 and tolterodine tartrate reduced detrusor overactivity in rats with BOO. In addition, doses of IC485 that suppressed nonvoiding contractions had no effect on voiding function. Therefore, selective PDE4 inhibitors deserve further study as potential agents for treating detrusor overactivity in patients with BOO. KEYWORDSbladder outlet obstruction, detrusor overactivity, rat, type 4 phosphodiesterase Study Type -Aetiology (case control) Level of Evidence 3b OBJECTIVETo investigate the effects of the selective phosphodiesterase (PDE) type 4 inhibitor IC485 and the widely used antimuscarinic drug tolterodine tartrate on bladder activity in rats with bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle. MATERIALS AND METHODSBOO was induced in female Sprague-Dawley rats by tying a silk ligature around the urethra. Six weeks after inducing BOO,

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