Proerectile effects of the Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine (H-1152) in the rat penis - PubMed (original) (raw)
. 2005 Oct;315(1):155-62.
doi: 10.1124/jpet.105.086041. Epub 2005 Jun 23.
Affiliations
- PMID: 15976017
- DOI: 10.1124/jpet.105.086041
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 et al. J Pharmacol Exp Ther. 2005 Oct.
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 microM) or Y-27632 [0.01-30 microM; (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 microM), Y-27632 (1 microM), or sodium nitroprusside (SNP; 0.1 microM) 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.
Similar articles
- Up-regulation of the RhoA/Rho-kinase signaling pathway in corpus cavernosum from endothelial nitric-oxide synthase (NOS), but not neuronal NOS, null mice.
Priviero FB, Jin LM, Ying Z, Teixeira CE, Webb RC. Priviero FB, et al. J Pharmacol Exp Ther. 2010 Apr;333(1):184-92. doi: 10.1124/jpet.109.160606. Epub 2010 Jan 21. J Pharmacol Exp Ther. 2010. PMID: 20093396 Free PMC article. - Expression and functional role of the RhoA/Rho-kinase pathway in rat coeliac artery.
Teixeira CE, Jin L, Ying Z, Palmer T, Priviero FB, Webb RC. Teixeira CE, et al. Clin Exp Pharmacol Physiol. 2005 Oct;32(10):817-24. doi: 10.1111/j.1440-1681.2005.04271.x. Clin Exp Pharmacol Physiol. 2005. PMID: 16173942 - Ca2+ sensitization and the regulation of contractility in rat anococcygeus and retractor penis muscle.
Teixeira CE, Jin L, Ying Z, Palmer T, Webb RC. Teixeira CE, et al. Biochem Pharmacol. 2005 May 15;69(10):1483-92. doi: 10.1016/j.bcp.2005.02.018. Biochem Pharmacol. 2005. PMID: 15857612 - [Effects of RhoA/Rho-kinase in the regulation of penile erection].
Xia C, Jiang R. Xia C, et al. Zhonghua Nan Ke Xue. 2007 Jun;13(6):546-9. Zhonghua Nan Ke Xue. 2007. PMID: 17615983 Review. Chinese. - The ups and downs of Rho-kinase and penile erection: upstream regulators and downstream substrates of rho-kinase and their potential role in the erectile response.
Chitaley K, Webb RC, Mills TM. Chitaley K, et al. Int J Impot Res. 2003 Apr;15(2):105-9. doi: 10.1038/sj.ijir.3900964. Int J Impot Res. 2003. PMID: 12789389 Review.
Cited by
- Erectile Dysfunction: Treatments, Advances and New Therapeutic Strategies.
Argiolas A, Argiolas FM, Argiolas G, Melis MR. Argiolas A, et al. Brain Sci. 2023 May 15;13(5):802. doi: 10.3390/brainsci13050802. Brain Sci. 2023. PMID: 37239274 Free PMC article. Review. - Rho-Associated Kinase Inhibitors: Potential Future Treatments for Glaucoma.
Daneshvar R, Amini N. Daneshvar R, et al. J Ophthalmic Vis Res. 2014 Jul-Sep;9(3):395-8. doi: 10.4103/2008-322X.143384. J Ophthalmic Vis Res. 2014. PMID: 26539282 Free PMC article. No abstract available. - The selective Rho-kinase inhibitor azaindole-1 has long-lasting erectile activity in the rat.
Lasker GF, Pankey EA, Allain AV, Murthy SN, Stasch JP, Kadowitz PJ. Lasker GF, et al. Urology. 2013 Feb;81(2):465.e7-14. doi: 10.1016/j.urology.2012.10.039. Urology. 2013. PMID: 23374844 Free PMC article. - Up-regulation of the RhoA/Rho-kinase signaling pathway in corpus cavernosum from endothelial nitric-oxide synthase (NOS), but not neuronal NOS, null mice.
Priviero FB, Jin LM, Ying Z, Teixeira CE, Webb RC. Priviero FB, et al. J Pharmacol Exp Ther. 2010 Apr;333(1):184-92. doi: 10.1124/jpet.109.160606. Epub 2010 Jan 21. J Pharmacol Exp Ther. 2010. PMID: 20093396 Free PMC article. - Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity.
Hahmann C, Schroeter T. Hahmann C, et al. Cell Mol Life Sci. 2010 Jan;67(2):171-7. doi: 10.1007/s00018-009-0189-x. Epub 2009 Nov 12. Cell Mol Life Sci. 2010. PMID: 19907920 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous