Increased Rho-kinase-mediated prostate contractions associated with impairment of β-adrenergic-cAMP-signaling pathway by chronic nitric oxide deficiency

Abstract

Impairment of nitric oxide (NO) - cyclic GMP signaling pathway is likely to contribute to human begnin prostate hyperplasia (BPH). In the present study we have used a model of chronic NO synthesis inhibition to evaluate the functional alterations of prostate smooth muscle (PSM) machinery, and involvement of Rho-kinase pathway. Wistar rats were treated with the NO inhibitor N(ω)-nitro-l-arginine methyl ester (L-NAME, 20mg/kg/day; 4 weeks), after which contractile responses to phenylephrine (α1-adrenoceptor agonist; 1nM to 100µM), carbachol (muscarinic agonist; 1nM to 1mM) and α,β-methylene ATP (P2X receptor agonist; 1-10µM), as well as to electrical-field stimulation (EFS; 1-32Hz) were evaluated. PSM relaxations to isoproterenol (non-selective β-adrenoceptor agonist, 0.1nM to 10µM) and sodium nitroprusside (NO donor, 1nM to 10mM) were also evaluated. The ratio prostate weight/body weight was 22% greater (P<0.05) in L-NAME compared with control group. The PSM contractions to phenylephrine, carbachol and α,β-methylene ATP were higher in L-NAME (Emax: 3.85±0.25, 3.52±0.35 and 2.03±0.2mN, respectively) compared with control group (Emax: 3.08±0.17, 2.37±0.18 and 1.57±0.18mN, respectively). The PSM contractions induced by EFS were also significantly greater in L-NAME group. Prior incubation with the Rho-kinase inhibitor Y27632 (1µM) fully reversed the enhanced contractions to phenylephrine and carbachol. Isoproterenol-induced PSM relaxations were 34% lower in L-NAME group, which was associated with reduced levels of cAMP in prostate tissue. The relaxations to sodium nitroprusside remained unaltered in L-NAME group. In summary, chronic NO deficiency leads to increased Rho-kinase-mediated PSM contractile responses accompanied by impairment of β-adrenergic-cAMP-signaling pathway.

Purinergic smooth muscle contractions in the human prostate: estimation of relevance and characterization of different agonists

“…In rat prostate tissues, maximum α,β- and β,γ-methylene-ATP-induced contractions amounted to approximately 80% and 100% of EFS-induced contractions (Ventura et al 2003 ). Another study reported values suggesting contractions of rat prostate tissues induced by 10 μM α,β-methylene-ATP amounting to approximately 53% of phenylephrine-induced or 64% of EFS-induced contractions (Calmasini et al 2015 ). Reported data for guinea pig prostates are again hardly conclusive, as they include average maximum contractions of 0.14 g using α,β-methylene-ATP and 0.25 g using β,γ-methylene-ATP, but only a single, representative experiment again suggesting an EFS-induced contraction of 1.1 g (Buljubasich and Ventura 2004 ).…”

Implication of Rho‐kinase and soluble guanylyl cyclase enzymes in prostate smooth muscle dysfunction in middle‐aged rats

“…However, no attempts have been taken to explore the sGC expression/activity in prostates from aging animals. Impairment of the β‐adrenoceptor‐cAMP signaling pathway was suggested to favor the contractile machinery in prostates from NO‐deficient rats, thus contributing to hypercontractility . A number of studies have evaluated the age‐related prostate dysfunction, but few looked at the alterations of prostate in middle‐age.…”

“…Impairment of the b-adrenoceptor-cAMP signaling pathway was suggested to favor the contractile machinery in prostates from NO-deficient rats, thus contributing to hypercontractility. 13 A number of studies have evaluated the age-related prostate dysfunction, but few looked at the alterations of prostate in middle-age. The understanding of the mechanisms that regulate the prostate reactivity in the period before the onset of old age may be important to prevent future complications and for the development of effective BPH therapies.…”

Toll-like receptor 9 regulates metabolic profile and contributes to obesity-induced benign prostatic hyperplasia in mice

“…The β-adrenoceptor activation counteracts the contractile pathways, contributes physiologically to maintain the prostatic tonus in several species and has been proposed as a new pharmacological therapeutic indication for BPH [37,38]. Studies in the literature have shown that impaired βadrenergic signaling plays a role in prostatic dysfunction in animal models of aging and hypertension [39,40]. However, to the best of our knowledge, no previous study evaluated this signaling pathway in prostatic tissue under obesity conditions.…”