Proerectile effects of the Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4- methyl-5-isoquinolinyl)sulfonyl]homopiperazine (H-1152) in the rat penis

Cleber E. Teixeira, Zhekang Ying, R. Clinton Webb

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29 Citations (Scopus)

Abstract

The Rho-kinase pathway mediates Ca2+ sensitization in the penile circulation, which maintains the penis in the flaccid state. We aimed to investigate the functional effect of a novel Rho-kinase inhibitor, H-1152 [(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine], both in vitro and in vivo as well as to demonstrate the expression of Rho guanine nucleotide exchange factors (RhoGEFs) in the rat corpus cavernosum (CC), by using a semiquantitative reverse transcription-polymerase chain reaction assay to measure their mRNA expression. Cumulative addition of H-1152 (0.001-3 μM) or Y-27632 [0.01-30 μM; (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)- cyclohexanecarboxamide] caused sustained relaxations of precontracted CC strips, which were not affected by inhibition of the nitric oxide signaling pathway. Addition of H-1152 (0.1 μM), Y-27632 (1 μM), or sodium nitroprusside (SNP; 0.1 μM) caused rightward shifts in the curves to phenylephrine (PE), but it had little effect on the contractions mediated by electrical field stimulation (EFS). It is noteworthy that when H-1152 or Y-27632 was combined with SNP, a marked synergistic inhibition was noted both on PE- and EFS-induced contractions. Intraperitoneal administration of H-1152 (100 nmol/kg) had a discrete effect on mean arterial pressure and significantly enhanced erectile responses evoked by stimulation of the cavernous nerve. The mRNA expression for PDZ-RhoGEF, p115RhoGEF, and leukemia-associated RhoGEF in cavernosal segments was visualized by electrophoresis on agarose gel. The results indicate that H-1152 is a powerful Rho-kinase inhibitor, giving rise to its therapeutic potential in the treatment of erectile dysfunction. The regulator of G-protein signaling-containing RhoGEFs may represent key components of the molecular mechanisms associated with the abnormal function of the cavernosal smooth muscle.

Original languageEnglish (US)
Pages (from-to)155-162
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume315
Issue number1
DOIs
StatePublished - Oct 1 2005

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rho-Associated Kinases
Penis
Rho Guanine Nucleotide Exchange Factors
Phenylephrine
Electric Stimulation
Single Nucleotide Polymorphism
GTP-Binding Protein Regulators
Messenger RNA
Agar Gel Electrophoresis
Nitroprusside
Erectile Dysfunction
2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine
Reverse Transcription
Smooth Muscle
Arterial Pressure
Nitric Oxide
Leukemia
Polymerase Chain Reaction
Y 27632

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Proerectile effects of the Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4- methyl-5-isoquinolinyl)sulfonyl]homopiperazine (H-1152) in the rat penis",
abstract = "The Rho-kinase pathway mediates Ca2+ sensitization in the penile circulation, which maintains the penis in the flaccid state. We aimed to investigate the functional effect of a novel Rho-kinase inhibitor, H-1152 [(S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine], both in vitro and in vivo as well as to demonstrate the expression of Rho guanine nucleotide exchange factors (RhoGEFs) in the rat corpus cavernosum (CC), by using a semiquantitative reverse transcription-polymerase chain reaction assay to measure their mRNA expression. Cumulative addition of H-1152 (0.001-3 μM) or Y-27632 [0.01-30 μM; (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)- cyclohexanecarboxamide] caused sustained relaxations of precontracted CC strips, which were not affected by inhibition of the nitric oxide signaling pathway. Addition of H-1152 (0.1 μM), Y-27632 (1 μM), or sodium nitroprusside (SNP; 0.1 μM) caused rightward shifts in the curves to phenylephrine (PE), but it had little effect on the contractions mediated by electrical field stimulation (EFS). It is noteworthy that when H-1152 or Y-27632 was combined with SNP, a marked synergistic inhibition was noted both on PE- and EFS-induced contractions. Intraperitoneal administration of H-1152 (100 nmol/kg) had a discrete effect on mean arterial pressure and significantly enhanced erectile responses evoked by stimulation of the cavernous nerve. The mRNA expression for PDZ-RhoGEF, p115RhoGEF, and leukemia-associated RhoGEF in cavernosal segments was visualized by electrophoresis on agarose gel. The results indicate that H-1152 is a powerful Rho-kinase inhibitor, giving rise to its therapeutic potential in the treatment of erectile dysfunction. The regulator of G-protein signaling-containing RhoGEFs may represent key components of the molecular mechanisms associated with the abnormal function of the cavernosal smooth muscle.",
author = "Teixeira, {Cleber E.} and Zhekang Ying and Webb, {R. Clinton}",
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AU - Ying, Zhekang

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