Wingard Christopher J, Husain Shahid, Williams Jan, James Sharita
Dept. of Physiology, Medical College of Georgia, 1120 15th St., Augusta GA, 30912, USA.
Am J Physiol Regul Integr Comp Physiol. 2003 Nov;285(5):R1145-52. doi: 10.1152/ajpregu.00329.2003. Epub 2003 Jul 31.
Maintenance of the detumescent state of the penis is believed to involve the actions of several vasoconstrictors. However, our mechanistic understanding of any synergistic vasoconstrictor influences is extremely limited. We tested the hypothesis that a vasoconstrictor combination of endothelin (ET-1) and phenylephrine (PE) augments the constrictor responses in rat corporal cavernosal tissues by a mechanism involving the RhoA-Rho kinase pathway. Independently, ET-1 (1 nM-30 microM) and PE (100 nM-100 microM) both caused dose-dependent contractions of isolated rat cavernosal tissues. In combination, ET-1 (30 nM) augmented the contractile effect of PE and shifted the calculated EC50 for PE (90 +/- 12 to 45 +/- 5 microM). The active stress generated by cavernosal strips during the ET-1 + PE combined stimulation (4.9 +/- 0.2 mN/mm2) was greater than the combined stress generated with ET-1 (0.4 +/- 0.1 mN/mm2) or PE (3.3 +/- 0.2 mN/mm2) stimulations alone. Blockade of ETA receptors (30 nM; A-127722) reversed the augmented stress generation and the Rho-kinase inhibitor Y-27632 differentially and dose-dependently relaxed the tissue. The combined constrictor effect was associated with a fourfold increase of RhoA in the membrane faction of the tissue homogenates. We conclude that the ET-1 + PE combination potentiate vasoconstriction through mutual activation of the RhoA-Rho kinase pathway. The interactions of these agonists likely play important roles in the maintenance of the flaccid state and contribute to some forms of erectile dysfunction.
阴茎疲软状态的维持被认为涉及多种血管收缩剂的作用。然而,我们对任何协同血管收缩剂影响的机制理解极其有限。我们测试了这样一个假设,即内皮素(ET-1)和去氧肾上腺素(PE)的血管收缩剂组合通过涉及RhoA-Rho激酶途径的机制增强大鼠海绵体组织中的收缩反应。单独使用时,ET-1(1 nM - 30 μM)和PE(100 nM - 100 μM)均引起离体大鼠海绵体组织的剂量依赖性收缩。联合使用时,ET-1(30 nM)增强了PE的收缩作用,并将计算得出的PE的EC50值(90±12至45±5 μM)向右移动。在ET-1 + PE联合刺激期间海绵体条带产生的主动张力(4.9±0.2 mN/mm2)大于单独使用ET-1(0.4±0.1 mN/mm2)或PE(3.3±0.2 mN/mm2)刺激时产生的联合张力。阻断ETA受体(30 nM;A-127722)可逆转增强的张力产生,并且Rho激酶抑制剂Y-27632以剂量依赖性方式使组织舒张。联合收缩效应与组织匀浆膜组分中RhoA增加四倍有关。我们得出结论,ET-1 + PE组合通过RhoA-Rho激酶途径的相互激活增强血管收缩。这些激动剂的相互作用可能在维持疲软状态中起重要作用,并导致某些形式的勃起功能障碍。