Altered penile vascular reactivity and erection in the Zucker obese-diabetic rat

Christopher Wingard, David J Fulton, Shahid Husain, Abdulmaged Traish

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Introduction. The combination of the independent risk factors for erectile dysfunction, obesity, hypertension, and diabetes are manifested collectively in a condition known as metabolic syndrome X. However, the exact mechanism(s) by which the combination of these factors contributes to erectile dysfunction have yet to be elucidated. Aim. We hypothesizedthat protein kinase C (PKC) and Rho-kinase enhanced vascular tone and thus contributed to erectile dysfunction in this condition. Methods. Erectile function was evaluated by recording voltage-dependent increases in intracavernosal pressure following stimulation of the cavernosal nerve in 16- to 20-week-old lean and obese-diabetic Zucker rats. Cavernosal tissue contractile and relaxation responses were evaluated in vitro when contracted with phenylephrine, endothelin-1 and relaxed by Rho-kinase, PKC inhibitors or sodium nitroprusside. Additionally, cavernosal tissue Rho-kinase, protein kinase, and nitric oxide synthase isoform expression were evaluated by Western blot. Results. The voltage-dependent erectile responses were suppressed by >30% in the obese-diabetic Zucker rat. The maximal stress generated by cavernosal tissue from the obese-diabetic was significantly greater than the lean response by greater than 0.8.mN/mm2 for both phenylephrine and endothelin stimulation. The PKC inhibitor, chelerythrine, inhibited more than 30% of the phenylephrine-induced and 70% of the endothelin-1-induced contractions. Rho-kinase inhibition, with either Y-27632 or HA-1077, revealed impaired relaxations of nearly 30% in tissue from obese-diabetic animals. Western blot analysis revealed increased protein expression of PKC α and δ and Rho-kinase α; and β but no loss for endothelial or neuronal nitric oxide synthase. Conclusions. In this rodent model both PKC and Rho-kinase signaling elements may contribute to an enhanced vasoconstriction state of the penile smooth muscle that was differentially dependent on the agonist used. The enhanced vasoconstrictive state of the tissue could contribute to the reduced voltage-dependent erectile response in the obese-diabetic Zucker rat.

Original languageEnglish (US)
Pages (from-to)348-363
Number of pages16
JournalJournal of Sexual Medicine
Volume4
Issue number2
DOIs
StatePublished - Jan 1 2007

Fingerprint

rho-Associated Kinases
Blood Vessels
Zucker Rats
Phenylephrine
Erectile Dysfunction
Protein C Inhibitor
Endothelin-1
Protein Kinase Inhibitors
Protein Kinase C
Western Blotting
Metabolic Syndrome X
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type III
Endothelins
Nitroprusside
Vasoconstriction
Nitric Oxide Synthase
Protein Kinases
Smooth Muscle
Rodentia

Keywords

  • Endothelin-1
  • Metabolic syndrome X
  • Nitric oxide synthase
  • PKC
  • Rho-kinase
  • Smooth muscle

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology
  • Urology

Cite this

Altered penile vascular reactivity and erection in the Zucker obese-diabetic rat. / Wingard, Christopher; Fulton, David J; Husain, Shahid; Traish, Abdulmaged.

In: Journal of Sexual Medicine, Vol. 4, No. 2, 01.01.2007, p. 348-363.

Research output: Contribution to journalArticle

Wingard, Christopher ; Fulton, David J ; Husain, Shahid ; Traish, Abdulmaged. / Altered penile vascular reactivity and erection in the Zucker obese-diabetic rat. In: Journal of Sexual Medicine. 2007 ; Vol. 4, No. 2. pp. 348-363.
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AU - Fulton, David J

AU - Husain, Shahid

AU - Traish, Abdulmaged

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Introduction. The combination of the independent risk factors for erectile dysfunction, obesity, hypertension, and diabetes are manifested collectively in a condition known as metabolic syndrome X. However, the exact mechanism(s) by which the combination of these factors contributes to erectile dysfunction have yet to be elucidated. Aim. We hypothesizedthat protein kinase C (PKC) and Rho-kinase enhanced vascular tone and thus contributed to erectile dysfunction in this condition. Methods. Erectile function was evaluated by recording voltage-dependent increases in intracavernosal pressure following stimulation of the cavernosal nerve in 16- to 20-week-old lean and obese-diabetic Zucker rats. Cavernosal tissue contractile and relaxation responses were evaluated in vitro when contracted with phenylephrine, endothelin-1 and relaxed by Rho-kinase, PKC inhibitors or sodium nitroprusside. Additionally, cavernosal tissue Rho-kinase, protein kinase, and nitric oxide synthase isoform expression were evaluated by Western blot. Results. The voltage-dependent erectile responses were suppressed by >30% in the obese-diabetic Zucker rat. The maximal stress generated by cavernosal tissue from the obese-diabetic was significantly greater than the lean response by greater than 0.8.mN/mm2 for both phenylephrine and endothelin stimulation. The PKC inhibitor, chelerythrine, inhibited more than 30% of the phenylephrine-induced and 70% of the endothelin-1-induced contractions. Rho-kinase inhibition, with either Y-27632 or HA-1077, revealed impaired relaxations of nearly 30% in tissue from obese-diabetic animals. Western blot analysis revealed increased protein expression of PKC α and δ and Rho-kinase α; and β but no loss for endothelial or neuronal nitric oxide synthase. Conclusions. In this rodent model both PKC and Rho-kinase signaling elements may contribute to an enhanced vasoconstriction state of the penile smooth muscle that was differentially dependent on the agonist used. The enhanced vasoconstrictive state of the tissue could contribute to the reduced voltage-dependent erectile response in the obese-diabetic Zucker rat.

AB - Introduction. The combination of the independent risk factors for erectile dysfunction, obesity, hypertension, and diabetes are manifested collectively in a condition known as metabolic syndrome X. However, the exact mechanism(s) by which the combination of these factors contributes to erectile dysfunction have yet to be elucidated. Aim. We hypothesizedthat protein kinase C (PKC) and Rho-kinase enhanced vascular tone and thus contributed to erectile dysfunction in this condition. Methods. Erectile function was evaluated by recording voltage-dependent increases in intracavernosal pressure following stimulation of the cavernosal nerve in 16- to 20-week-old lean and obese-diabetic Zucker rats. Cavernosal tissue contractile and relaxation responses were evaluated in vitro when contracted with phenylephrine, endothelin-1 and relaxed by Rho-kinase, PKC inhibitors or sodium nitroprusside. Additionally, cavernosal tissue Rho-kinase, protein kinase, and nitric oxide synthase isoform expression were evaluated by Western blot. Results. The voltage-dependent erectile responses were suppressed by >30% in the obese-diabetic Zucker rat. The maximal stress generated by cavernosal tissue from the obese-diabetic was significantly greater than the lean response by greater than 0.8.mN/mm2 for both phenylephrine and endothelin stimulation. The PKC inhibitor, chelerythrine, inhibited more than 30% of the phenylephrine-induced and 70% of the endothelin-1-induced contractions. Rho-kinase inhibition, with either Y-27632 or HA-1077, revealed impaired relaxations of nearly 30% in tissue from obese-diabetic animals. Western blot analysis revealed increased protein expression of PKC α and δ and Rho-kinase α; and β but no loss for endothelial or neuronal nitric oxide synthase. Conclusions. In this rodent model both PKC and Rho-kinase signaling elements may contribute to an enhanced vasoconstriction state of the penile smooth muscle that was differentially dependent on the agonist used. The enhanced vasoconstrictive state of the tissue could contribute to the reduced voltage-dependent erectile response in the obese-diabetic Zucker rat.

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KW - Smooth muscle

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