Adreno-Muscarinic Synergy of Contractile Responses From Human Hyperplastic Prostate

Purpose
Adreno-muscarinic synergy, a supra-additional contractile response to simultaneous application of α-adrenoreceptor and muscarinic receptor agonists, is a feature of several lower urinary tract regions that have dual sympathetic and parasympathetic innervation. We tested the hypothesis that synergy is also a feature of prostate tissue obtained from men with benign prostatic enlargement.

Methods
Isolated tissue strips were dissected from prostate ‘chips’, collected after transurethral prostate resection procedures for in vitro experiments, to measure isometric tension at 36°C.

Results
Added separately to the superfusate, phenylephrine and carbachol generated contractions with mean pEC50 (-log10EC50) values of 5.36 and 5.58, respectively, although phenylephrine maximal responses were about six-fold greater. In the presence of carbachol, the mean phenylephrine pEC50 was significantly increased to 5.84 and maximal response increased by 28%; overall, a significant synergistic response was demonstrated. The synergistic response was reduced by muscarinic receptor antagonists, most potently by the M3-selective agent 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide), and less so by M2 and M1-selective inhibitors gallamine and pirenzepine, but with an overall profile indicating M3/M2 mediation of the synergistic response. The magnitude of the synergistic response was variable between prostate chips that provided isolated preparations suggesting regional heterogenicity, although their zonal origin could not be determined.

Conclusions
These experiments show that adreno-muscarinic contractile synergy is a feature of human hyperplastic prostate tissue. This has implications for the use of a combination therapy of α-blockers and anti-muscarinic agent to relieve secondary symptoms associated with benign prostatic hyperplasia, at least in men who can tolerate antimuscarinics without a risk of retention.