Molecular mechanisms of detrusor and corporal myocyte contraction: identifying targets for pharmacotherapy of bladder and erectile dysfunction

Abstract

The Post-Genomic age presents many new challenges and opportunities for the improved understanding, diagnosis and treatment of human disease. The long-term goal is to identify molecular correlates of disease processes, and use this information to develop novel and more effective therapeutics. A major hurdle in this regard is ensuring that the molecular targets of interest are indeed relevant to the physiology and/or pathophysiology of the processes being studied, and, moreover, to determine if they are specific to the tissue/organ being investigated. As a first step in this direction, we have reviewed the literature pertaining to bladder and erectile physiology/pharmacology and dysfunction and attempted to summarize some of the critical molecular mechanisms regulating detrusor and corporal myocyte tone. Because of the vast amount of published data, we have limited the scope of this review to consideration of the calcium-mobilizing and calcium-sensitizing pathways in these cells. Despite obvious differences in phenotypic characteristics of the detrusor and corporal myocyte, there are some common molecular changes that may contribute to, for example, the increased myocyte contractility characteristic of bladder and erectile dysfunction (i.e. increased Rho kinase activity and decreased K þ channel function). Of course, there are also some important distinctions in the pathways that modulate contractility in these two cell types (i.e. the contribution of ryanodine-sensitive calcium stores and the nitric oxide/cGMP pathways). This report highlights some of these similarities and distinctions in the hope that it will encourage scientific discourse and research activity in this area, eventually leading to an improved quality of life for those millions of individuals that are afflicted with bladder and erectile dysfunction.

Diabetes slows the recovery from urinary incontinence due to simulated childbirth in female rats

“…Current theories on the pathophysiology of lower urinary tract complications of DM include dysfunction of neuropathic and myopathic components of the pelvic floor (9,10,14,23,26,33). Vaginal delivery can injure the same nerve, muscle, and connective tissues of the pelvic floor, which are responsible for maintaining continence (16,30,31,36,40).…”

Muscarinic receptor expression and receptor-mediated detrusor contraction: comparison of juvenile and adult porcine tissue

“…The latter process is thought to be essential for detrusor contraction because force development is diminished in Ca 2+ channel (Ca v 1.2) knockout mice [35] or in the presence of the L-type Ca 2+ channel blocker nifedipine [22,28,38]. Thus, muscarinic receptor-induced detrusor contractions involve Ca 2+ entry via L-type Ca 2+ channels followed by uptake of Ca 2+ into intracellular stores and a subsequent release either via IP 3 -dependent or Ca 2+ -induced processes via ryanodine receptors [7,10,26].…”

Molecular characterisation and functional interrogation of a local natriuretic peptide system in rodent pituitaries, αT3-1 and LβT2 gonadotroph cells

“…Further support for CNP as a regulator of reproductive function comes from several studies that have shown CNP to potently stimulate cGMP production in GNRH neurons (Olcese et al 1994), pituitary gonadotrophs (McArdle et al 1993), and endocrine cells of the testis, ovaries, placenta and uterus (Khurana & Pandey 1993, Huang et al 1996, Middendorff et al 1996, Acuff et al 1997, Jankowski et al 1997, Gutkowska et al 1999, Stepan et al 2001, Walther & Stepan 2004, implicating CNP function at all levels of the hypothalamo-pituitarygonadal (HPG) axis. Furthermore, cGMP is a useful pharmacological target in the treatment of male reproductive disorders (Rosen & McKenna 2002, Christ & Hodges 2006. However, despite an ever-increasing literature detailing CNP effects in HPG tissues, understanding of the regulation and function of CNP and GC-B in neuroendocrine tissues remains poor.…”