Voiding symptom severity varies independently from non-adrenergic prostate smooth muscle contractions in patients undergoing surgery for benign prostatic hyperplasia

Abstract

Background: Resistance of voiding symptoms to α₁-blockers in benign prostatic hyperplasia (BPH) has been provisionally explained by non-adrenergic prostate smooth muscle contraction. Here, we examined relationships between contractions and voiding symptoms in prostate tissues from laser-enucleation.

Methods: Tissues were obtained from holmium and thulium laser enucleation. Contractions were induced by endothelin-1, U46619, noradrenaline and electric field stimulation (EFS). E_max values were analyzed for correlation with international prostate symptom score (IPSS), and compared to tissues from patients without surgery for BPH.

Results: Noradrenaline- and EFS-induced contractions were higher with severe (IPSS 20-35) than moderate symptoms (IPSS 8-19) (E_max noradrenaline 66% vs 113% of KCl-induced contractions; EFS 33% vs 66%). Endothelin-1- and U46619-induced contractions were already maximum with moderate symptoms (endothelin-1 117% moderate, 135% severe; U46619 23%, 27%). Within 8-21 points, IPSS increased with E_max values for noradrenaline and EFS (r = 0.545, r = 0.448), but not with endothelin-1- or U46619-induced contractions. Endothelin-1-induced contractions were similar to noradrenaline-induced contractions (E_max endothelin-1 126% of KCl, noradrenaline 96%), and exceeded EFS- (52%) and U46619-induced contractions (25%). E_max values for endothelin-1 were similar between laser-enucleated patients and patients without surgery for BPH (127%), while E_max values for U46619 were higher in tissues from patients without surgery for BPH (59%) compared to laser-enucleated tissues.

Conclusion: Symptom severity increases with α₁-adrenergic, but not with non-adrenergic contractions in patients undergoing surgery for BPH. Endothelin-1-induced contractions are similar to noradrenaline-induced contractions. Conditions necessitating BPH surgery may not necessarily depend on α₁-adrenergic tone, but may involve non-adrenergic contractions or factors beyond contraction.

Keywords: benign prostatic hyperplasia (BPH); holmium laser enucleation of the prostate (HoLEP); human tissue; international prostate symptom score (IPSS); lower urinary tract symptoms (LUTS); smooth muscle contraction; voiding symptoms.

FIGURE 1

Agonist- and EFS-induced contractions in laser-enucleated prostate tissues. Concentration or frequency response curves for noradrenaline (a), EFS (b), endothelin-1 (c) and U46619 (d) were constructed with prostate tissues from HoLEP and ThuLEP for BPH. Data were grouped for moderate (IPSS 9–19) and severe symptoms (IPSS 20–35). Shown are means ± standard deviation (SD) in concentration and frequency response curves, and all single values for E_max, EC₅₀ and Ef₅₀ calculated by curve fitting (each value representing one prostate tissue, examined by single or multiple determinations) together with means (bars). Concentration and frequency response curves were compared by two-way ANOVA. E_max and Ef₅₀ values were compared by unpaired, two-tailed t-test if data were normally distributed in both groups (i.e., EC₅₀ values in (a), (c) and (d)), and by unpaired, two-tailed Mann Whitney test if data were not normally distributed in at least one of both groups (all others). P values ≥0.05 are not shown. Values labelled by grey color could not be calculated by curve fitting as contractions occurred only with highest applied concentrations of U46619 or were not at maximum with the highest applied concentration of endothelin-1, so that these EC₅₀ values were manually set to 4.5 for U46619 or 5.5 for endothelin-1. E_max values from tissues showing no contraction at all are included (corresponding to an E_max of 0% of KCl), but plausible EC₅₀ values from these experiments can not be calculated or assumed, so that these were excluded (1 value in the moderate groups for noradrenaline and EFS, two values per group for U46619, one value in the moderate group for endothelin-1).

FIGURE 2

Correlation analyses for E_max values with IPSS. E_max values for noradrenaline-, EFS-, endothelin-1- and U46619-induced contractions in laser-enucleated prostate tissues were analyzed for correlation with IPSS scores in the same patients. Separated analyses were performed for the complete study populations (IPSS 8–35) (a), for moderate symptoms (IPSS 8–19) (b), severe symptoms (IPSS 20–35) (c), and for a modified IPSS range (IPSS 8–21) (d). Shown are all data, together with r and p values from Pearson correlation analyses. P values ≥0.05 are not shown.

FIGURE 3

Comparison of E_max values for agonist- and EFS-induced contractions. E_max values for noradrenaline, EFS, endothelin-1 and U46619 in laser-enucleated tissues were compared with each other. Separated comparisons were performed for the complete study populations (IPSS 8–35) (a), for moderate symptoms (IPSS 8–19) (b), severe symptoms (IPSS 20–35) (c), and for modified IPSS ranges in (d) (IPSS 8–21) and (e) (IPSS 22–35). Shown are all data, together with p values from one-way ANOVA with Holm-Sidak’s multiple comparison for data showing Gaussian distribution (D'Agostino and Pearson omnibus normality test) (b), or with Dunn’s multiple comparison of data sets without Gaussian distribution (all others). P values ≥0.05 are not shown.

FIGURE 4

Comparison of E_max values for non-adrenergic contractions in laser-enucleated and prostatectomized tissues. E_max values for endothelin-1 (a) and U46619 (b) in prostate tissues from HoLEP and ThuLEP were compared to E_max values in prostate tissues from rPx for prostate cancer in previous studies, published from 2017 to 2024. Shown are single values from each experiment, together with means and p values from one-way ANOVA with Dunn’s multiple comparison (*p = 0.023, **p = 0.0108, ***p > 0.0001, ****p = 0.0144, *****p = 0.0495, ******p = 0.0014). P values ≥ 0.05 are not shown.