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钙离子内流和钙敏化对大鼠阴茎小动脉α1-肾上腺素能血管收缩的作用

Contribution of both Ca2+ entry and Ca2+ sensitization to the alpha1-adrenergic vasoconstriction of rat penile small arteries.

作者信息

Villalba Nuria, Stankevicius Edgaras, Garcia-Sacristán Albino, Simonsen Ulf, Prieto Dolores

机构信息

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.

出版信息

Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H1157-69. doi: 10.1152/ajpheart.01034.2006. Epub 2006 Nov 3.

Abstract

Sympathetic adrenergic nerves maintain the flaccid state of the penis through the tonic release of norepinephrine that contracts trabecular and arterial smooth muscle. Simultaneous measurements of intracellular Ca(2+) concentration (Ca(2+)) and tension and experiments with alpha-toxin-permeabilized arteries were performed in branches of the rat dorsal penile artery to investigate the intracellular Ca(2+) signaling pathways underlying alpha(1)-adrenergic vasoconstriction. Phenylephrine increased both Ca(2+) and tension, these increases being abolished by extracellular Ca(2+) removal and reduced by about 50% by the L-type Ca(2+) channel blocker nifedipine (0.3 microM). Non-L-type Ca(2+) entry through store-operated channels was studied by inhibiting the sarcoplasmic reticulum Ca(2+)-ATPase with cyclopiazonic acid (CPA). CPA (30 microM) induced variable phasic contractions that were abolished by extracellular Ca(2+) removal and by the store-operated channels antagonist 2-aminoethoxydiphenyl borate (2-APB, 50 microM) and largely inhibited by nifedipine (0.3 microM). CPA induced a sustained increase in Ca(2+) that was reduced in a Ca(2+)-free medium. Under conditions of L-type channels blockade, Ca(2+) readmission after store depletion with CPA evoked a sustained and marked elevation in Ca(2+) not coupled to contraction. 2-APB (50 microM) inhibited the rise in Ca(2+) evoked by CPA and the nifedipine-insensitive increases in both Ca(2+) and contraction elicited by phenylephrine. In alpha-toxin-permeabilized penile arteries, activation of G proteins with guanosine 5'-O-(3-thiotriphosphate) and of the alpha(1)-adrenoceptor with phenylephrine both enhanced the myofilament sensitivity to Ca(2+). This Ca(2+) sensitization was reduced by selective inhibitors of PKC, tyrosine kinase (TK), and Rho kinase (RhoK) by 43%, 67%, and 82%, respectively. As a whole, the present data suggest the alpha(1)-adrenergic vasoconstriction in penile small arteries involves Ca(2+) entry through both L-type and 2-APB-sensitive receptor-operated channels, as well as Ca(2+) sensitization mechanisms mediated by PKC, TK, and RhoK. A capacitative Ca(2+) entry coupled to noncontractile functions of the smooth muscle cell is also demonstrated.

摘要

交感肾上腺素能神经通过持续释放去甲肾上腺素来维持阴茎的松弛状态,而去甲肾上腺素会使小梁和动脉平滑肌收缩。在大鼠阴茎背动脉分支中,同时测量细胞内钙离子浓度(Ca(2+))和张力,并对用α-毒素通透处理的动脉进行实验,以研究α(1)-肾上腺素能血管收缩背后的细胞内钙离子信号通路。去氧肾上腺素可增加Ca(2+)和张力,细胞外去除钙离子可消除这些增加,而L型钙离子通道阻滞剂硝苯地平(0.3微摩尔)可使其降低约50%。通过用环匹阿尼酸(CPA)抑制肌浆网钙离子-ATP酶来研究通过储存-操纵通道的非L型钙离子内流。CPA(30微摩尔)诱导出可变的相位性收缩,细胞外去除钙离子以及储存-操纵通道拮抗剂2-氨基乙氧基二苯硼酸盐(2-APB,50微摩尔)可消除这种收缩,且硝苯地平(0.3微摩尔)可显著抑制这种收缩。CPA可使Ca(2+)持续增加,在无钙培养基中这种增加会减少。在L型通道被阻断的情况下,用CPA使储存耗竭后再重新引入钙离子会引起Ca(2+)持续且显著升高,但不伴有收缩。2-APB(50微摩尔)可抑制CPA引起的Ca(2+)升高以及去氧肾上腺素引起的Ca(2+)和收缩的硝苯地平不敏感的增加。在用α-毒素通透处理的阴茎动脉中,用鸟苷5'-O-(3-硫代三磷酸)激活G蛋白以及用去氧肾上腺素激活α(1)-肾上腺素受体均可增强肌丝对钙离子的敏感性。蛋白激酶C(PKC)、酪氨酸激酶(TK)和Rho激酶(RhoK)的选择性抑制剂分别可使这种钙离子敏感性降低43%、67%和82%。总体而言,目前的数据表明阴茎小动脉中的α(1)-肾上腺素能血管收缩涉及通过L型和2-APB敏感的受体操纵通道的钙离子内流,以及由PKC、TK和RhoK介导的钙离子敏感性机制。还证明了一种与平滑肌细胞非收缩功能相关的容量性钙离子内流。

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