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LOCAL CONTROL OF CIRCULATION

RhoA-Rho kinase mediates synergistic ET-1 and phenylephrine contraction of rat corpus cavernosum

Departments of ¹Physiology and ²Biochemistry, Medical College of Georgia, Augusta, Georgia 30912-3000

Submitted 16 June 2003 ; accepted in final form 25 July 2003

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 µM) and PE (100 nM-100 µM) 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 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 ET_A 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.

penile erection; vasoconstrictor interaction; calcium sensitization; smooth muscle

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