New approaches to the design and discovery of therapies to prevent erectile dysfunction

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9 Citations (Scopus)

Abstract

Introduction: Nitric oxide (NO) is critically involved in erectile function. Since NO synthase (NOS) and arginase compete for the same substrate l-arginine, limiting arginase activity may provide more NO and thus be a beneficial therapeutic approach to erectile dysfunction (ED). In the corpora cavernosa, excessive arginase activity/expression has been implicated through studies of preclinical and clinical models of ED. Further, the inhibition of arginase has shown to increase vascular system relaxation and enhance blood flow in penile circulation. Further studies, therefore, looking at therapies targeting arginase could prove to be clinically useful.Areas covered: The authors review gene- and cell-based therapies, the involvement of RhoA/Rho-kinase (ROCK), MAPK and arginase in ED.Expert opinion: Extensive literature supports the view that upregulated arginase activity in cavernosal tissue can reduce NOS function and NO production. Excessive arginase activity has been shown to contribute to the progression of aging-, hypertension- and diabetes-induced vascular dysfunction as well as ED. Earlier studies have shown that RhoA/ROCK and subsequent activation of p38 MAPK mediate elevation of arginase expression/activity in diabetic and hypertensive mice. Reducing corporal arginase activity by gene-based or pharmacological therapy and/or inhibition of upstream regulators of arginase expression may provide novel therapeutic approaches in the management of ED.

Original languageEnglish (US)
Pages (from-to)1447-1469
Number of pages23
JournalExpert Opinion on Drug Discovery
Volume9
Issue number12
DOIs
StatePublished - Dec 1 2014

Fingerprint

Arginase
Erectile Dysfunction
Therapeutics
Nitric Oxide
Nitric Oxide Synthase
Blood Vessels
rho-Associated Kinases
Expert Testimony
p38 Mitogen-Activated Protein Kinases
Cell- and Tissue-Based Therapy
Genes
Arginine
Pharmacology

Keywords

  • Arginase
  • Cavernosal smooth muscle relaxation
  • Erectile dysfunction
  • Nitric oxide
  • Penile erection

ASJC Scopus subject areas

  • Drug Discovery

Cite this

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title = "New approaches to the design and discovery of therapies to prevent erectile dysfunction",
abstract = "Introduction: Nitric oxide (NO) is critically involved in erectile function. Since NO synthase (NOS) and arginase compete for the same substrate l-arginine, limiting arginase activity may provide more NO and thus be a beneficial therapeutic approach to erectile dysfunction (ED). In the corpora cavernosa, excessive arginase activity/expression has been implicated through studies of preclinical and clinical models of ED. Further, the inhibition of arginase has shown to increase vascular system relaxation and enhance blood flow in penile circulation. Further studies, therefore, looking at therapies targeting arginase could prove to be clinically useful.Areas covered: The authors review gene- and cell-based therapies, the involvement of RhoA/Rho-kinase (ROCK), MAPK and arginase in ED.Expert opinion: Extensive literature supports the view that upregulated arginase activity in cavernosal tissue can reduce NOS function and NO production. Excessive arginase activity has been shown to contribute to the progression of aging-, hypertension- and diabetes-induced vascular dysfunction as well as ED. Earlier studies have shown that RhoA/ROCK and subsequent activation of p38 MAPK mediate elevation of arginase expression/activity in diabetic and hypertensive mice. Reducing corporal arginase activity by gene-based or pharmacological therapy and/or inhibition of upstream regulators of arginase expression may provide novel therapeutic approaches in the management of ED.",
keywords = "Arginase, Cavernosal smooth muscle relaxation, Erectile dysfunction, Nitric oxide, Penile erection",
author = "{Flores Toque}, {Haroldo Alfredo} and Caldwell, {Robert William}",
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AU - Flores Toque, Haroldo Alfredo

AU - Caldwell, Robert William

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N2 - Introduction: Nitric oxide (NO) is critically involved in erectile function. Since NO synthase (NOS) and arginase compete for the same substrate l-arginine, limiting arginase activity may provide more NO and thus be a beneficial therapeutic approach to erectile dysfunction (ED). In the corpora cavernosa, excessive arginase activity/expression has been implicated through studies of preclinical and clinical models of ED. Further, the inhibition of arginase has shown to increase vascular system relaxation and enhance blood flow in penile circulation. Further studies, therefore, looking at therapies targeting arginase could prove to be clinically useful.Areas covered: The authors review gene- and cell-based therapies, the involvement of RhoA/Rho-kinase (ROCK), MAPK and arginase in ED.Expert opinion: Extensive literature supports the view that upregulated arginase activity in cavernosal tissue can reduce NOS function and NO production. Excessive arginase activity has been shown to contribute to the progression of aging-, hypertension- and diabetes-induced vascular dysfunction as well as ED. Earlier studies have shown that RhoA/ROCK and subsequent activation of p38 MAPK mediate elevation of arginase expression/activity in diabetic and hypertensive mice. Reducing corporal arginase activity by gene-based or pharmacological therapy and/or inhibition of upstream regulators of arginase expression may provide novel therapeutic approaches in the management of ED.

AB - Introduction: Nitric oxide (NO) is critically involved in erectile function. Since NO synthase (NOS) and arginase compete for the same substrate l-arginine, limiting arginase activity may provide more NO and thus be a beneficial therapeutic approach to erectile dysfunction (ED). In the corpora cavernosa, excessive arginase activity/expression has been implicated through studies of preclinical and clinical models of ED. Further, the inhibition of arginase has shown to increase vascular system relaxation and enhance blood flow in penile circulation. Further studies, therefore, looking at therapies targeting arginase could prove to be clinically useful.Areas covered: The authors review gene- and cell-based therapies, the involvement of RhoA/Rho-kinase (ROCK), MAPK and arginase in ED.Expert opinion: Extensive literature supports the view that upregulated arginase activity in cavernosal tissue can reduce NOS function and NO production. Excessive arginase activity has been shown to contribute to the progression of aging-, hypertension- and diabetes-induced vascular dysfunction as well as ED. Earlier studies have shown that RhoA/ROCK and subsequent activation of p38 MAPK mediate elevation of arginase expression/activity in diabetic and hypertensive mice. Reducing corporal arginase activity by gene-based or pharmacological therapy and/or inhibition of upstream regulators of arginase expression may provide novel therapeutic approaches in the management of ED.

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