Effects of Phosphodiesterase Inhibitors on Tension Induced by Norepinephrine and Accumulation of Cyclic Nucleotides in Isolated Human Prostatic Tissue

Abstract

To further evaluate the mechanism of action of phosphodiesterase (PDE) inhibitors on the human prostate, the effects of PDE4 and PDE5 inhibitors on the tension induced by norepinephrine (NE) and on the intracellular levels of cyclic nucleotides in isolated human prostatic tissue were investigated. Using the organ bath technique, the effects of increasing concentrations (1 nM to 10 microM) of the PDE5 inhibitors sildenafil, tadalafil, and vardenafil and the PDE4 inhibitors rolipram and RP 73401 on the tension induced by NE (40 microM) of prostate strip preparations were investigated. The accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate in response to drug exposure was determined by radioimmunoassays. The tension induced by NE was dose dependently reversed by the drugs with the following rank order of efficacy: tadalafil greater than RP 73401 greater than rolipram greater than or equal to vardenafil greater than sildenafil. The maximal reversion of tension values ranged from 52.3% (tadalafil) to 17% (sildenafil). Of the PDE inhibitors, only tadalafil induced a 50% reversion of the initial tension. The most prominent enhancement in tissue cyclic adenosine monophosphate was registered in response to RP 73401 (11-fold), and cyclic guanosine monophosphate levels were significantly elevated by tadalafil, vardenafil, and sildenafil (28-fold, 12-fold, and 3-fold, respectively). Our results have demonstrated that drugs interfering with the cyclic nucleotide-mediated pathways can reverse the tension induced by NE in isolated prostatic tissue and elevate cyclic adenosine monophosphate and cyclic guanosine monophosphate. Our findings serve to explain how PDE inhibitors can affect symptoms of lower urinary tract symptoms and benign prostatic hyperplasia.