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

Abstract

Wingard, Christopher J., Shahid Husain, Jan Williams, and Sharita James. RhoA-Rho kinase mediates synergistic ET-1 and phenylephrine contraction of rat corpus cavernosum. Am J Physiol Regul Integr Comp Physiol 285: R1145-R1152, 2003. First published July 31, 2003 10.1152/ ajpregu.00329.2003.-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 M) and PE (100 nM-100 M) 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 EC 50 for PE (90 Ϯ 12 to 45 Ϯ 5 M). The active stress generated by cavernosal strips during the ET-1 ϩ PE combined stimulation (4.9 Ϯ 0.2 mN/mm 2 ) was greater than the combined stress generated with ET-1 (0.4 Ϯ 0.1 mN/mm 2 ) or PE (3.3 Ϯ 0.2 mN/mm 2 ) 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 ϩ 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 THE PHYSIOLOGY OF AN ERECTION involves a complex balance of contraction and relaxation processes regulating the contractile activity of smooth muscle associated with the penile circulation (1, 4, 18). Maintenance of the flaccid state of the penis requires the vasoconstriction of the blood vessels supplying the penis, as well as the smooth muscle lining cavernosal sinuses. Contraction of cavernosal smooth muscle can be induced by a variety of vasoconstrictor agents, which ultimately restrict blood flow entering the penis and blood volume contained in the cavernosal tissue. The adrenergic agonist norepinephrine (NE) (9, 26, 29) and endothelin-1 (ET-1) (3, 23) are two vasoconstrictors believed to play important roles in regulating the penile blood flow. However, the mechanisms by which ET-1 and NE interact to maintain smooth muscle constriction of the erectile tissue are not well understood.We have found that exogenous applications of adrenergic agonists and ET-1 exert strong vasoconstrictor actions and suppress normal erectile responses (8,22). These vasoconstrictor responses were inhibited by ␣-adrenergic receptor and ET A -recept...

Alterations of NOS, arginase, and DDAH protein expression in rabbit cavernous tissue after administration of cigarette smoke extract

“…MMA, monomethylarginine; ADMA, asymmetric dimethylarginine; SDMA, symmetric dimethylarginine. It is well established that cyclic GMP is an important second messenger to modulate endothelin-1 production (26) and that endothelin-1 is one of the potent vasoconstrictors believed to play an important role in regulating penile blood flow (3,40) and to contribute to some forms of ED (55). Therefore, increased endothelin-1 possibly resulting from impaired NO production (21, 41) may be involved in causing ED with CSE.…”

Urologic Complications of Diabetes

“…Vasoconstrictor signaling pathways are important physiological modulators of the erectile process, and perturbations in these pathways may contribute to the pathophysiology of ED (77). In experimental diabetes, penile smooth muscle has augmented force responses to two important vasoconstrictors, endothelin-1 (ET-1) and the ␣-adrenergic agonist phenylephrine (78).…”

Endothelial dysfunction in diabetic erectile dysfunction

“…The RhoA/Rho-kinase pathway, which subserves a vasoconstrictor mechanism (evoked by norepinephrine through a-adrenergic receptors, endothelin-1, angiotensins and thromboxane A 2 ), is operative in the penis. [95][96][97][98] This pathway is responsible for calcium-independent increase in vascular smooth muscle tone, known as calcium sensitization. RhoA-activated Rho-kinase (a and b isoforms) phosphorylates and inhibits regulatory myosin phosphatase target subunit 1 of myosin light chain phosphatase at Thr-696 and inhibits its activity, promoting smooth muscle contraction.…”