Amelioration of diabetes‐induced cavernosal fibrosis by antioxidant and anti‐transforming growth factor‐β1 therapies in inducible nitric oxide synthase‐deficient mice

• Published in: BJU international Vol. 109; no. 4; pp. 586 - 593
• Main Authors: Ferrini, Monica G., Moon, Joanne, Rivera, Steve, Rajfer, Jacob, Gonzalez‐Cadavid, Nestor F.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2012; Wiley-Blackwell
• Subjects: allopurinol; Allopurinol - pharmacology; Animals; Antioxidants - pharmacology; apoptosis; Apoptosis - drug effects; Biological and medical sciences; collagen; decorin; Decorin - pharmacology; Diabetes Mellitus, Experimental - complications; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Inhibitors - pharmacology; erectile dysfunction; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fibrosis - prevention & control; Male; Medical sciences; Mice; Mice, Knockout; molsidomine; Molsidomine - pharmacology; Muscle, Smooth - drug effects; Nephrology. Urinary tract diseases; nitric oxide; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase Type II - deficiency; Oxidative Stress; penis; Penis - pathology; smooth muscle; Transforming Growth Factor beta1 - antagonists & inhibitors; Endocrinopathy; Antianginal agent; Proteoglycan; Decorin; Nephrology; Impotence; Coronary vasodilator agent; Sexual dysfunction; Smooth muscle; Corpus cavernosum; Urology; erectile dysfunction; Pyrazolopyrimidine derivatives; Molsidomine; Male genital diseases; Hypouricemic agent; Erection disorders; Enzyme; Allopurinol; Diabetes mellitus; Glycoprotein; Rodentia; Enzyme inhibitor; Antioxidant; Male genital system; Nitric-oxide synthase; Vertebrata; Mammalia; Treatment; Mouse; Cell death; Penis; Animal; Collagen; Nitric oxide; Fibrosis; Xanthine oxidase; Antihypertensive agent; Oxidoreductases; Transforming growth factor β1; Apoptosis
• ISSN: 1464-4096; 1464-410X
• DOI: 10.1111/j.1464-410X.2011.10397.x

Study Type – Aetiology (case control) Level of Evidence 1b What's known on the subject? and What does the study add? The development of penile fibrosis in diabetes is associated with an increase in oxidative stress and the key pro‐fibrotic factor. TGFβ1 within the corpora. As a consequence, a putative compensatory expression of inducible nitric oxide synthase (iNOS) cause a steady output of nitric oxide and cGMP which act as endogenous antifibrotic agents by quenching oxidative stress and inhibiting collagen synthesis and myofibroblast formation. This study adds to the growing body of evidence that the use of antioxidant or antifibrotic therapies may be effective in preventing and possibly ameliorating penile corporal fibrosis and therefore improving erectile function in diabetes, by targeting different pathways involved in the chronic histological damage that underlies erectile dysfunction. OBJECTIVE •  To investigate whether sustained long‐term separate treatments of diabetic inducible nitric oxide synthase knockout (iNOSKo) mice with allopurinol, an antioxidant inhibiting xanthine oxidoreductase, decorin, a transforming growth factor‐β1 (TGFβ1) ‐binding antagonist, and molsidomine, a long‐life nitric oxide donor, prevent the processes of diabetes‐induced cavernosal fibrosis. MATERIALS AND METHODS •  Eight week old male iNOS knock out (iNOSKo) mice were made diabetic by injecting 150 mg/kg B.W Streptozotocin (1P) with were either left untreated or treated with the oral antioxidant allopurinol (40 mg/kg/day), or decoin (50 mg, 1P, twice), as an anti‐TGFβ1 agent (n = 8/group). •  Glycemia and oxidative stress markers were determined in blood and urine. •  Paraffin‐embedded tissue sections from the penile shaft were subjected to Masson trichrome staining for the smooth muscle (smc)/collagen ratio, and imunostaining for smc content, profibrotic factors, oxidative stress, cell replication and cell death markers followed by quantitative image analysis. RESULTS •  Eight‐week treatment with either allopurinol or decorin counteracted the decrease in smooth muscle cells and the increase in apoptosis and local oxidative stress within the corpora tissue. •  Decorin but not allopurinol increased the smooth muscle cell/collagen ratio, whereas allopurinol but not decorin inhibited systemic oxidative stress. •  Molsidomine was effective in reducing both local and systemic oxidative stress, but did not prevent corporal fibrosis. CONCLUSION •  Both allopurinol and decorin appear as promising approaches either as a single or a combined pharmacological modality for protecting the diabetic corpora from undergoing apoptosis and fibrosis although their functional effects still need to be defined.