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


OBJECTIVE
We hypothesized that 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/mm(2) 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 alpha and delta and Rho-kinase alpha and beta 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.
Wingard
Christopher
C
Brody School of Medicine at East Carolina University-Physiology, Greenville, NC, USA. wingarddc.ecu.edu
Fulton
David
D
Husain
Shahid
S
D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018783:Impotence, Vasculogenic / Q000201:enzymology / Q000209:etiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications*; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000150:complications; D010410:Penile Erection; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D054460:rho-Associated Kinases
D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases