Age Related Differences in Responsiveness to Sildenafil and Tamsulosin are due to Myogenic Smooth Muscle Tone in the Human Prostate

Lee, Sophie N.; Chakrabarty, Basu; Wittmer, Brad; Papargiris, Melissa; Ryan, Andrew; Frydenberg, Mark; Lawrentschuk, Nathan; Middendorff, Ralf; Risbridger, Gail P.; Ellem, Stuart John; Exintaris, Betty

doi:10.1038/s41598-017-07861-x

Cited by 9 publications

(9 citation statements)

References 29 publications

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“…Growth of the transitional zone underlies BPH, but also occurs throughout life ( Pradidarcheep et al, 2011 ; Timms and Hofkamp, 2011 ). However, patterns of contractility and smooth muscle tone differ between the three prostate zones and change with age ( Lee et al, 2017 ; Chakrabarty et al, 2019 ). Consequently, our findings can not be necessarily extrapolated to the central or peripheral zones and do not cover all age groups, what may represent putative limitations of our study.…”

Section: Discussionmentioning

confidence: 99%

Concentration-dependent alpha1-Adrenoceptor Antagonism and Inhibition of Neurogenic Smooth Muscle Contraction by Mirabegron in the Human Prostate

et al. 2021

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Introduction: Mirabegron is available for treatment of storage symptoms in overactive bladder, which may be improved by β3-adrenoceptor-induced bladder smooth muscle relaxation. In addition to storage symptoms, lower urinary tract symptoms in men include obstructive symptoms attributed to benign prostatic hyperplasia, caused by increased prostate smooth muscle tone and prostate enlargement. In contrast to the bladder and storage symptoms, effects of mirabegron on prostate smooth muscle contraction and obstructive symptoms are poorly understood. Evidence from non-human smooth muscle suggested antagonism of α1-adrenoceptors as an important off-target effect of mirabegron. As α1-adrenergic contraction is crucial in pathophysiology and medical treatment of obstructive symptoms, we here examined effects of mirabegron on contractions of human prostate tissues and on proliferation of prostate stromal cells.Methods: Contractions were induced in an organ bath. Effects of mirabegron on proliferation, viability, and cAMP levels in cultured stromal cells were examined by EdU assays, CCK-8 assays and enzyme-linked immunosorbent assay.Results: Mirabegron in concentrations of 5 and 10 μM, but not 1 µM inhibited electric field stimulation-induced contractions of human prostate tissues. Mirabegron in concentrations of 5 and 10 µM shifted concentration response curves for noradrenaline-, methoxamine- and phenylephrine-induced contractions to the right, including recovery of contractions at high concentrations of α1-adrenergic agonists, increased EC50 values, but unchanged Emax values. Rightshifts of noradrenaline concentration response curves and inhibition of EFS-induced contractions were resistant to L-748,337, l-NAME, and BPIPP. 1 µM mirabegron was without effect on α1-adrenergic contractions. Endothelin-1- and U46619-induced contractions were not affected or only inhibited to neglectable extent. Effects of mirabegron (0.5–10 µM) on proliferation and viability of stromal cells were neglectable or small, reaching maximum decreases of 8% in proliferation assays and 17% in viability assays. Mirabegron did not induce detectable increases of cAMP levels in cultured stromal cells.Conclusion: Mirabegron inhibits neurogenic and α1-adrenergic human prostate smooth muscle contractions. This inhibition may be based on antagonism of α1-adrenoceptors by mirabegron, and does not include activation of β3-adrenoceptors and requires concentrations ranging 50-100fold higher than plasma concentrations reported from normal dosing. Non-adrenergic contractions and proliferation of prostate stromal cells are not inhibited by mirabegron.

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Section: Discussionmentioning

confidence: 99%

Concentration-dependent alpha1-Adrenoceptor Antagonism and Inhibition of Neurogenic Smooth Muscle Contraction by Mirabegron in the Human Prostate

et al. 2021

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“…Using perinatal exposure to a persistent environmental contaminant (TCDD) as a model for exposure to a range of common environmental contaminants that activate the AHR, we find that the intrauterine and early postnatal environment shapes prostate noradrenergic axon density, leading to lasting changes in prostate smooth muscle response and voiding function that persist into adulthood. It is unclear why prostate baseline tension, smooth muscle activity and responsiveness to α-adrenergic receptor blockers varies so considerably among human males with LUTD ( Lee et al, 2017 ). We posit that maternal chemical exposures during fetal urogenital development may underlie this variability, creating a susceptible phenotype that sensitizes males to voiding dysfunction with advancing age.…”

Section: Discussionmentioning

confidence: 99%

A mechanism linking perinatal 2,3,7,8 tetrachlorodibenzo-p-dioxin exposure to lower urinary tract dysfunction in adulthood

Turco

Oakes

Stietz

et al. 2021

Disease Models &Amp; Mechanisms

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Benign Prostatic Hyperplasia / Lower Urinary Tract Dysfunction (BPH/LUTD) is a classic disease of aging which affects nearly all men. Symptoms typically present in the fifth or sixth decade and progressively worsen over the remainder of life. Here, we identify a surprising origin of this disease that traces back to the intrauterine environment of the developing male, challenging existing paradigms about when this disease process begins. We delivered a single bolus dose of a widespread environmental contaminant, present in the serum of most Americans (2,3,7,8 tetrachlorodibenzo-p-dioxin, TCDD, 1 µg/kg), and representative of a broader class of environmental contaminants, to pregnant mice and observed an increase in the abundance of a neurotrophic factor, artemin, in the developing mouse prostate. Artemin is required for noradrenergic axon recruitment across multiple tissues and TCDD rapidly increases prostatic noradrenergic axon density in the male fetus. The hyperinnervation does not resolve, but rather persists into adulthood, when it is coupled to autonomic hyperactivity of prostatic smooth muscle and abnormal urinary function, including increased urinary frequency, a bothersome symptom in men. We offer new evidence that prostate neuroanatomical development is malleable and that intrauterine chemical exposures can permanently reprogram prostate neuromuscular function to cause male LUTD in adulthood.

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“…We have previously demonstrated that the frequency of myogenic contractions are significantly upregulated in men with clinically diagnosed BPH 17 , and hypothesised that changes to inherent myogenic contractility are driven by intrinsic factors within the prostate, notably oxytocin levels. The presence of the OXTR in the human prostate was previously described 9 and confirmed in this study (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Organ bath studies. Tension recordings were obtained from transition zone (TZ) specimens as previously described 17 .…”

mentioning

confidence: 99%

Oxytocin receptor antagonists as a novel pharmacological agent for reducing smooth muscle tone in the human prostate

Lee

Kraska

Papargiris

et al. 2021

Sci Rep

Self Cite

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Pharmacotherapies for the treatment of Benign Prostatic Hyperplasia (BPH) are targeted at reducing cellular proliferation (static component) or reducing smooth muscle tone (dynamic component), but response is unpredictable and many patients fail to respond. An impediment to identifying novel pharmacotherapies is the incomplete understanding of paracrine signalling. Oxytocin has been highlighted as a potential paracrine mediator of BPH. To better understand oxytocin signalling, we investigated the effects of exogenous oxytocin on both stromal cell proliferation, and inherent spontaneous prostate contractions using primary models derived from human prostate tissue. We show that the Oxytocin Receptor (OXTR) is widely expressed in the human prostate, and co-localises to contractile cells within the prostate stroma. Exogenous oxytocin did not modulate prostatic fibroblast proliferation, but did significantly (p < 0.05) upregulate the frequency of spontaneous contractions in prostate tissue, indicating a role in generating smooth muscle tone. Application of atosiban, an OXTR antagonist, significantly (p < 0.05) reduced spontaneous contractions. Individual tissue responsiveness to both exogenous oxytocin (R2 = 0.697, p < 0.01) and atosiban (R2 = 0.472, p < 0.05) was greater in tissue collected from older men. Overall, our data suggest that oxytocin is a key regulator of inherent spontaneous prostate contractions, and targeting of the OXTR and associated downstream signalling is an attractive prospect in the development of novel BPH pharmacotherapies.

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Age Related Differences in Responsiveness to Sildenafil and Tamsulosin are due to Myogenic Smooth Muscle Tone in the Human Prostate

Cited by 9 publications

References 29 publications

Concentration-dependent alpha1-Adrenoceptor Antagonism and Inhibition of Neurogenic Smooth Muscle Contraction by Mirabegron in the Human Prostate

Concentration-dependent alpha1-Adrenoceptor Antagonism and Inhibition of Neurogenic Smooth Muscle Contraction by Mirabegron in the Human Prostate

A mechanism linking perinatal 2,3,7,8 tetrachlorodibenzo-p-dioxin exposure to lower urinary tract dysfunction in adulthood

Oxytocin receptor antagonists as a novel pharmacological agent for reducing smooth muscle tone in the human prostate

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