Methoxamine 20mg/1ml solution for injection ampoules

BackgroundApart from antagonizing ß-adrenoceptors, carvedilol antagonizes vascular α1-adrenoceptors and activates G protein-independent signaling. Even though it is a commonly used antihypertensive and α1-adrenoceptors are essential for the treatment of voiding symptoms in benign prostatic hyperplasia, its actions in the human prostate are still unknown. Here, we examined carvedilol effects on contractions of human prostate tissues, and on stromal cell growth.MethodsContractions of prostate tissues from radical prostatectomy were induced by electric field stimulation (EFS) or α1-agonists. Growth-related functions were examined in cultured stromal cells.ResultsConcentration-response curves for phenylephrine, methoxamine and noradrenaline were right shifted by carvedilol (0.1-10 µM), around half a magnitude with 100 nM, half to one magnitude with 1 µM, and two magnitudes with 10 µM. Right shifts were reflected by increased EC50 values for agonists, with unchanged Emax values. EFS-induced contractions were reduced by 21-54% with 0.01-1 µM carvedilol, and by 94% by 10 µM. Colony numbers of stromal cells were increased by 500 nM, but reduced by 1-10 µM carvedilol, while all concentrations reduced colony size. Decreases in viability were time-dependent with 0.1-0.3 µM, but complete with 10 µM. Proliferation was slightly increased by 0.1-0.5 µM, but reduced with 1-10 µM.ConclusionsCarvedilol antagonizes α1-adrenoceptors in the human prostate, starting with concentrations in ranges of known plasma levels. In vitro, effect sizes resemble those of α1-blockers used for the treatment of voiding symptoms, which requires concentrations beyond plasma levels. Bidirectional and dynamic effects on the growth of stromal cells may be attributed to "biased agonism".

Abstract licence: CC BY

BackgroundPhospholipases A2 (PLA2 ) may be involved in α1 -adrenergic contraction by formation of thromboxane A2 in different smooth muscle types. However, whether this mechanism occurs with α1 -adrenergic contractions of the prostate, is still unknown. While α1 -adrenoceptor antagonists are the first line option for medical treatment of voiding symptoms in benign prostatic hyperplasia (BPH), improvements are limited, probably by nonadrenergic contractions including thromboxane A2 . Here, we examined effects of PLA2 inhibitors on contractions of human prostate tissues.MethodsProstate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS) and by α1 -adrenergic agonists in an organ bath, after application of the cytosolic PLA2 inhibitors ASB14780 and AACOCF3, the secretory PLA2 inhibitor YM26734, the leukotriene receptor antagonist montelukast, or of solvent to controls.ResultsFrequency-dependent contractions of human prostate tissues induced by EFS were inhibited by 25% at 8 Hz, 38% at 16 Hz and 37% at 32 Hz by ASB14780 (1 µM), and by 32% at 16 Hz and 22% at 32 Hz by AACOCF3 (10 µM). None of both inhibitors affected contractions induced by noradrenaline, phenylephrine or methoxamine. YM26734 (3 µM) and montelukast (0.3 and 1 µM) neither affected EFS-induced contractions, nor contractions by α1 -adrenergic agonists, while all contractions were substantially inhibited by silodosin (100 nM).ConclusionsOur findings suggest presynaptic PLA2 functions in prostate smooth muscle contraction, while contractions induced by α1 -adrenergic agonists occur PLA2 -independent. Lacking sensitivity to montelukast excludes an involvement of PLA2 -derived leukotrienes in promotion of contractile neurotransmission.

Abstract licence: CC BY-NC-ND

Smooth muscle contraction by Pim kinases and ZIPK has been suggested, but evidence for lower urinary tract organs or using Pim-selective inhibitor concentrations is not yet available. Here, we assessed effects of the Pim inhibitors AZD1208 and TCS PIM-1 and the dual ZIPK/Pim inhibitor HS38 on contractions of human prostate and bladder tissues and of porcine interlobar arteries. Human tissues were obtained from radical prostatectomy and radical cystectomy and renal interlobar arteries from pigs. Contractions were studied in an organ bath. Noradrenaline-, phenylephrine- and methoxamine-induced contractions were reduced (up to > 50%) with 500-nM AZD1208 in prostate tissues and to lesser degree and not consistently with all agonists in interlobar arteries. A total of 100-nM AZD1208 or 500-nM TCS PIM-1 did not affect agonist-induced contractions in prostate tissues. Decreases in agonist-induced contractions with 3-µM HS38 in prostate tissues and interlobar arteries were of small extent and did not occur with each agonist. Carbachol-induced contractions in detrusor tissues were unchanged with AZD1208 (500 nM) or HS38. Electric field stimulation-induced contractions were not affected with AZD1208 or HS38 in any tissue, but slightly reduced with 500-nM TCS PIM-1 in prostate tissues. Concentration-dependent effects of Pim inhibitors suggest lacking Pim-driven smooth muscle contraction in the prostate, bladder, and interlobar arteries but point to organ-specific functions of off-targets. Procontractile functions of ZIPK in the prostate and interlobar arteries may be limited and are lacking in the detrusor.

Abstract licence: CC BY

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. Emax 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 (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.

Abstract licence: CC BY