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


OBJECTIVE
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.


METHODS
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.
Wingard
Christopher J
CJ
Brody School of Medicine at East Carolina University, Department of Physiology, Greenville, NC 27834, USA. wingardc@ecu.edu
Moukdar
Fatiha
F
Prasad
Raju Y
RY
Cathey
Brook L
BL
Wilkinson
Lois
L
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000453:epidemiology*; D004558:Electric Stimulation / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000453:epidemiology / Q000503:physiopathology; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D018783:Impotence, Vasculogenic / Q000201:enzymology / Q000209:etiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000453:epidemiology*; D009569:Nitric Oxide / Q000378:metabolism*; D009765:Obesity / Q000453:epidemiology*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D054460:rho-Associated Kinases / Q000378:metabolism*
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D005464:Fluorobenzenes; D047908:Intracellular Signaling Peptides and Proteins; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D009569:Nitric Oxide; D000068718:Rosuvastatin Calcium; D054460:rho-Associated Kinases