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1 Department of Physiology, Medical College of Georgia, Augusta, GA, USA
2 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: Cwingard{at}mail.mcg.edu.
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 (1nM - 30µM) and PE (100nM - 100µM) 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 ± 12µM to 45 ± 5 µM). 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 four fold increase of RhoA in the membrane faction of the tissue homogenates. We conclude that the ET-1+PE combination potentiates vasoconstriction through mutual activation of the RhoA/Rho-kinase pathway. The interactions of these agonists likely play important roles maintenance of the flaccid state and contribute to some forms of erectile dysfunction.
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