Adreno-Muscarinic Synergy of Contractile Responses From Human Hyperplastic Prostate
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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.
Abstract
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.
참고문헌 (33)
- Roehrborn CG, "Pathology of benign prostatic hyperplasia", Int J Impot Res, 20(Suppl 3), pp.S11~S18 (2008)
- Thomas AW, "The natural history of lower urinary tract dysfunction in men : minimum 10-year urodynamic follow-up of untreated bladder outlet obstruction", BJU Int, 96, pp.1301~1306 (2005)
- Schwinn DA, "α1-adrenoceptor subtypes and lower urinary tract symptoms", Int J Urol, 15, pp.193~199 (2008)
- Ruggieri MR, "Human prostate muscarinic receptor subtypes", J Pharmacol Exp Ther, 274, pp.976~982 (1995)
- Witte LP, "Cholinergic innervation and muscarinic receptors in the human prostate", Eur Urol, 54, pp.326~334 (2008)
- Ventura S, "Cholinergic innervation and function in the prostate gland", Pharmacol Ther, 94, pp.93~112 (2002)
- Roosen A, "Synergistic effects in neuromuscular activation and calcium-sensitisation in the bladder trigone", BJU Int, 101, pp.610~614 (2008)
- Roosen A, "Characteristics of spontaneous activity in the bladder trigone", Eur Urol, 56, pp.346~353 (2009)
- Roosen A, "Adreno-muscarinic synergy in the bladder trigone : calcium-dependent and-independent mechanisms", Cell Calcium, 45, pp.11~17 (2009)
- Walther S, "Adreno-muscarinic synergy in the male human urinary outflow tract", Neurourol Urodyn, 37, pp.2128~2134 (2018)
- Athanasopoulos A, "Antimuscarinics and bladder outlet obstruction:from a contra-indication to an indication?", Neurourol Urodyn, 29(Suppl 1), pp.S46~S50 (2010)
- Athanasopoulos A, "The role of antimuscarinics in the management of men with symptoms of overactive bladder associated with concomitant bladder outlet obstruction : an update", Eur Urol, 60, pp.94~105 (2011)
- Chapple CR, "Antimuscarinics in men with lower urinary tract symptoms suggestive of bladder outlet obstruction due to benign prostatic hyperplasia", Curr Opin Urol, 20, pp.43~48 (2010)
- Wu C, "The role of the L-type Ca2+ channel in refilling functional intracellular Ca2+ stores in guinea-pig detrusor smooth muscle", J Physiol, 538, pp.357~369 (2002)
- Tallarida RJ, "An overview of drug combination analysis with isobolograms", J Pharmocol Exp Ther, 319, pp.1~7 (2006)
- Cheng HC, "The influence of cooperativity on the determination of dissociation constants : examination of the Cheng–Prusoff equation, the Scatchard analysis, the Schild analysis and related power equations", Pharmacol Res, 50, pp.21~40 (2004)
- Huang R, "Inhibition of α1-adrenergic, non-adrenergic and neurogenic human prostate smooth muscle contraction and of stromal cell growth by isoflavones genistein and daidzein", Nutrients, 14, pp.4943~ (2022)
- Hennenberg M, "Inhibition of adrenergic and non-adrenergic smooth muscle contraction in the human prostate by the phosphodiesterase 10-selective inhibitor TC-E 5005", Prostate, 76, pp.1364~1374 (2016)
- Gup DI, "Contractile properties of human prostate adenomas and the development of infravesical obstruction", Prostate, 15, pp.105~114 (1989)
- Normandin DE, "Pharmacological characterization of the isolated canine prostate", J Urol, 155, pp.1758~1761 (1996)
- Hennenberg M, "Non-adrenergic, tamsulosin-insensitive smooth muscle contraction is sufficient to replace α1-adrenergic tension in the human prostate", Prostate, 77, pp.697~707 (2017)
- Hedlund H, "Alpha-adrenoceptors and muscarinic receptors in the isolated human prostate", J Urol, 134, pp.1291~1298 (1985)
- Yazawa H, "Characterization of muscarinic cholinoceptor in primary culture of smooth muscle cells from human prostate", J Urol, 152, pp.2173~2177 (1994)
- Witte LP, "Muscarinic receptor subtype mRNA expression in the human prostate : association with age, pathological diagnosis, prostate size, or potentially interfering medications?", Naunyn Schmiedebergs Arch Pharmacol, 387, pp.207~214 (2014)
- White CW, "Contractions of the mouse prostate elicited by acetylcholine are mediated by M3 muscarinic receptors", J Pharmacol Exp Ther, 339, pp.870~877 (2011)
- Dörje F, "Antagonist binding profiles of five cloned human muscarinic receptor subtypes", J Pharmacol Exp Ther, 256, pp.727~733 (1991)
- Yamanishi T, "The role of M2-muscarinic receptors in mediating contraction of the pig urinary bladder in vitro", Br J Pharmacol, 131, pp.1482~1488 (2000)
- Sellers DJ, "M3 muscarinic receptors but not M2 mediate contraction of the porcine detrusor muscle in vitro", J Auton Pharmacol, 20, pp.171~176 (2000)
- Lazareno S, "Pharmacological characterization of acetylcholine-stimulated 35S-GTPgS binding mediated by human muscarinic m1-m4 receptors : antagonist studies", Br J Pharmacol, 109, pp.1120~1127 (1993)
- Hao N, "Antimuscarinics and α-blockers or α-blockers monotherapy on lower urinary tract symptoms-a meta-analysis", Urology, 83, pp.556~562 (2014)
- Filson CP, "The efficacy and safety of combined therapy with α-blockers and anticholinergics for men with benign prostatic hyperplasia : a meta-analysis", J Urol, 190, pp.2153~2160 (2013)
- Drake MJ, "Long-term safety and efficacy of single-tablet combinations of solifenacin and tamsulosin oral controlled absorption system in men with storage and voiding lower urinary tract symptoms : results from the NEPTUNE Study and NEPTUNE II open-label extension", Eur Urol, 67, pp.262~270 (2015)
- Lenfant L, "Role of antimuscarinics combined with alpha-blockers in the management of urinary storage symptoms in patients with benign prostatic hyperplasia : an updated systematic review and meta-analysis", J Urol, 209, pp.314~324 (2023)