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Reversal of voltage-dependent erectile responses in the Zucker obese-diabetic rat by rosuvastatin-altered RhoA/Rho-kinase signaling.

Wingard, Christopher J; Moukdar, Fatiha; Prasad, Raju Y; Cathey, Brook L; Wilkinson, Lois.
J Sex Med; 6 Suppl 3: 269-78, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19267849

INTRODUCTION:

The combination of independent risk factors for erectile dysfunction, obesity, hypertension, and diabetes are collectively manifested in a condition known as metabolic syndrome X (MSX). However, the regulatory mechanisms responsible for the erectile dysfunction (ED) are not fully understood. Clinical studies suggest that a pleiotropic effect of statin's ability to enhance vascular relaxation might be through an impact on nitric oxide signaling or through a regulation of RhoA activation.

AIM:

We hypothesized that regulatory aspects of short-term statin therapy involve the alteration of the RhoA/Rho-kinase signaling cascade and will reverse the ED seen in a rat model of MSX.

MAIN OUTCOME MEASURES:

The magnitude and sensitivity of the voltage-dependent maintenance of intracavernosal blood pressure and mean arterial blood pressure. These responses were correlated with tissue protein and mRNA expression levels of RhoA and Rho kinases.

METHODS:

Erectile function was evaluated by assessing voltage-dependent stimulation of the cavernosal nerve in 16-20 weeks old lean and obese-diabetic Zucker rats treated with 5 mg/kg/day of rosuvastatin intraperitoneally for 3 days. Cavernosal tissue RhoA and Rho-kinases expression levels were evaluated by real-time reverse transcriptase-polymerase chain reaction, Western blot.

RESULTS:

The voltage-dependent erectile responses were suppressed by >30% in the obese-diabetic Zucker rat. The 3-day treatment with rosuvastatin partially restored the erectile response. The Rho-kinase inhibitor, H-1152, dose dependently increased the erectile responses and shifted the voltage sensitivity with statin treatment. Analysis of protein expression levels suggested elevation of RhoA and Rho kinases in obese-diabetics and statin treatment lowering Rho-kinase II. The RhoA and Rho-kinase II mRNA levels were significantly reduced in the rosuvastatin-treated obese-diabetic animals.

CONCLUSIONS:

These results support a hypothesis that short-term statin therapy may lower RhoA/Rho-kinase expression levels and improve cavernosal blood pressure response to Rho-kinase inhibition and voltage-stimulation, and reversing an augmented vasoconstricted state associated with diabetes and/or hypertension in MSX.
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