INVESTIGATIVE UROLOGY

Effects of various nitric oxide donating agents on the contractility and cyclic nucleotide turnover of human seminal vesicles in vitro
Heuer O, Uckert S, Machtens SA, Stief CG, Tsikas D, Frolich JC, Jonas U
Department of Urology, Hannover Medical School, Hannover, Germany
Urology 2002; 59:958-62

• Objectives: To evaluate the effects of the nitric oxide (NO)-donating drugs sodium nitroprusside, S-nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteineetylester (SNACET), and linsidomine (SIN-1), as well as the adenylyl cyclase-stimulating agent forskolin, on electrically induced contractions and on tissue levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) of isolated human seminal vesicle strip preparations. The significance of the L-arginine-NO-cGMP pathway in the regulation of smooth muscle tone in the human genitourinary tract has been well established; however, information on the relevance of NO-mediated signal transduction in the functional control of mammalian seminal vesicles is still sparse.
• Methods: Seminal vesicle strip preparations were applied to an organ bath system under standard conditions. Phasic contractions were induced by electrical field stimulation (frequency 80 Hz, amplitude 10 V, single pulse 1 ms, total pulse duration 1 second, pause 90 seconds). After stable contraction amplitudes had been reached, the drugs were added in a cumulative manner (0.001 to 10 microM), and the isometric responses were registered. After drug exposure, freezing, tissue homogenization, and extraction of cyclic nucleotides, cAMP and cGMP were measured by means of enzyme-linked immunosorbent assays.
• Results: Electrical field stimulation-induced amplitudes were attenuated by the drugs in a dose-dependent manner. The rank order of potency was GSNO > sodium nitroprusside > forskolin > SNACET > or = SIN-1. The relaxing effect of GSNO was antagonized in the presence of 10 microM of guanylyl cyclase inhibitor methylene blue. The inhibitory effects of GSNO, sodium nitroprusside, and forskolin on the contractile activity were paralleled by an increase in tissue cGMP (2 to 100-fold) and cAMP (7 to 9-fold).
• Conclusions: Our results strongly support the hypothesis that the contractility of human seminal vesicles is in part regulated by the NO-cGMP-cascade. This may give a rationale for the use of S-nitrosothiols, such as GSNO, in the pharmacotherapy of hyperexcitatory disturbances of ejaculation.
  
  
• Editorial Comment
  Ejaculation is a multifunctional process involving sympathetic neuronal input, release of the ductus ejaculatory closure resistance and coordinated contraction of seminal vesicle and ductus deferens smooth muscle. In this context, normal regulation of seminal vesicle smooth muscle tension contributes to the facilitation of seminal emission, and defects at the level of neuromuscular control may result in impaired ejaculatory function (i.e., anejaculation or premature ejaculation).
  The authors provide interesting data regarding the role of NO-cGMP pathway in the regulation of seminal vesicle smooth muscle tone. In their results, neurogenic contractions of isolated seminal vesicle strips were most effectively reversed by the NO-donating drugs sodium nitroprusside (NNP) and S-nitroso-glutathione (GSNO). These attenuating effects were paralleled by an increase in tissue cGMP, but not cAMP. However, evidence that forskolin was not as effective as GSNO and NNP in the organ bath studies may highlight the fact that cAMP-mediated mechanisms of smooth muscle control are of inferior significance in the seminal vesicles. The increase in tissue cAMP mediated by linsidomine might be explained the as the increase in cGMP exerted by the activation of guanylyl cyclase may result in an inhibitory effect on phosphodiesterase (PDE) type 3 (cGMP-binding, cGMP-inhibited PDE), which in turn would induce an elevation of cellular cAMP. Although the expression of PDE3 has been demonstrated in human genitourinary tract tissues, such as the urinary bladder and corpus cavernosum penis, data on the presence of PDE isoenzymes in the human seminal vesicle are not yet available.
  This is a potentially important paper because presents additional evidence for the hypothesis that the contractility of human seminal vesicle is regulated by the balance between the generation and degradation of NO and cGMP. These findings open new avenues for the clinical management of premature ejaculation.

Dr. E. Alexsandro da Silva
Urogenital Research Unit
State University of Rio de Janeiro
Rio de Janeiro, Brazil