Sildenafil corrects the increased contractility of rat detrusor muscle induced by alprostadil in vitro

Background: Sildenafil (PDE5-inhibitor) and alprostadil (PGE(1)) are used in combination clinically for the management of some cases of erectile dysfunction. Despite the roles of prostaglandins (PG) and nitric oxide (NO) pathways in contractility of bladder smooth muscle are frequently studied, the effect of sildenafil/alprostadil combination and the crosstalk between NO/cGMP and PG pathways on bladder activity is not documented. Methods: Organ-bath experiments were performed using isolated rat detrusor muscle. Direct and neurogenic contractions were induced using ACh and electric stimulation (EFS, 4 Hz, 80 V, 1 ms), respectively. The contractile responses in absence and presence of the tested drugs at different concentrations were compared. Results are expressed as mean +/- SEM (n = 5-7). Results: Alprostadil (0.01-10 mu M) concentration-dependently potentiated ACh (100 mu M)- and EFS (4 Hz)-induced contraction. Maximum potentiation of ACh-contraction in presence of alprostadil was 40 +/- 5%. Sildenafil potentiated ACh-induced contraction at low concentrations (0.01-1 mM), but inhibited it at higher ones (10-100 mu M). IBMX (non-selective PDE-inhibitor, 0.01-100 mu M) and SNP (NO-donor, 1nM-1 mM) produced the same biphasic pattern. The potentiatory phase of sildenafil was inhibited by atropine (0.1 mu M), L-NAME (non-selective NOS-inhibitor, 100 mu M), N-PLA (nNOS-inhibitor, 30 mu M) or MB (nonselective GC-inhibitor, 10 mu M). In presence of sildenafil (0.1 mu M), the concentration-response curve of alprostadil (0.01-10 mu M) on both ACh and EFS-induced contraction was clearly shifted downward. Conclusions: A crosstalk between PGE(1) and NO/cGMP pathways may exist. At low concentrations only, the effect of sildenafil on bladder contractility is dependent on NO/cGMP. cGMP intracellularly-elevated by sildenafil, may inhibit the activity of PLC and hence the cascade of EP1-receptors, thus masking the hyperactivity of bladder caused by alprostadil, which adds to the advantages of this combination. (C) 2019 Maj Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.