背景:除了拮抗β-肾上腺素受体,卡维地洛拮抗血管α1-肾上腺素受体并激活不依赖G蛋白的信号传导。尽管它是一种常用的抗高血压药,但α1-肾上腺素受体对于治疗良性前列腺增生的排尿症状至关重要,它在人类前列腺中的作用仍然未知。这里,我们研究了卡维地洛对人体前列腺组织收缩的影响,和基质细胞生长。
方法:通过电场刺激(EFS)或α1-激动剂诱导根治性前列腺切除术的前列腺组织收缩。在培养的基质细胞中检查了与生长相关的功能。
结果:去氧肾上腺素的浓度-响应曲线,甲氧胺和去甲肾上腺素右移卡维地洛(0.1-10µM),大约是100nM的一半量级,1µM的一半到一个数量级,和两个10µM的量级。右移反映了激动剂EC50值的增加,Emax值不变。使用0.01-1µM卡维地洛,EFS引起的收缩减少了21-54%,和10µM的94%。基质细胞的集落数增加了500nM,但减少了1-10µM卡维地洛,而所有浓度都降低了菌落大小。生存力的下降是时间依赖性的,0.1-0.3µM,但以10µM完成。增殖略有增加0.1-0.5μM,但减少了1-10µM。
结论:卡维地洛拮抗人前列腺中的α1-肾上腺素受体,从已知血浆水平范围内的浓度开始。体外,效应大小类似于用于治疗排尿症状的α1受体阻滞剂,这需要浓度超过血浆水平。对基质细胞生长的双向和动态影响可能归因于“偏向激动”。
BACKGROUND: Apart 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.
METHODS: Contractions 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.
RESULTS: Concentration-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.
CONCLUSIONS: Carvedilol 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\".