Antagonism of prostate α1A-adrenoceptors by verapamil in human prostate smooth muscle contraction.

Abstract

Voiding symptoms and hypertension are common comorbidities. α₁-Blockers are the first-line medication for the treatment of voiding symptoms. Off-target antagonism of α₁-adrenoceptors by cardiovascular drugs may add to the side effects of α₁-blockers but may also hold the potential to avoid polypharmacy. Here, we examined α₁-adrenergic antagonism by the calcium channel blocker verapamil in the human prostate. Prostate tissues were obtained from radical prostatectomy. Contractions were examined by organ bath. Verapamil caused concentration-dependent inhibitions of α₁-adrenergic and electric field stimulation-induced contractions and increases of EC₅₀ values for α₁-agonists. E_max values for phenylephrine, methoxamine, noradrenaline, and electric field stimulation were decreased by 41%, 17%, 41%, and 39% by 1-μM verapamil and by 62%, 36%, 51%, and 93% by 10-μM verapamil. EC₅₀ values for phenylephrine, methoxamine, and noradrenaline were increased by 0.47, 0.36, and 0.18 orders of magnitude by 1-μM verapamil and by 0.83, 1.22, and 1.54 orders of magnitude by 10-μM verapamil. The 100-nM verapamil increased the EC₅₀ values for noradrenaline by 0.43 magnitudes but only slightly (<0.2 magnitudes) for phenylephrine and methoxamine. U46619-induced contractions were unchanged by 10-μM verapamil. E_max values for endothelin-1-induced contractions were reduced by 14% by 10-μM verapamil. Antagonism of α₁-adrenoceptors by verapamil in the human prostate begins at concentrations corresponding to plasma concentrations at high doses. Improvements of voiding symptoms through this antagonism may help to avoid polypharmacy in elderly populations, but application in BPH may be limited by drug-drug interactions and additive side effects. SIGNIFICANCE STATEMENT: Our findings align verapamil concentrations antagonizing α₁-adrenergic contractions of human prostate tissues with known plasma levels. Improvements of voiding symptoms appear possible, but application in benign prostatic hyperplasia may be limited by drug-drug interactions and additive side effects.