Ageing‐related corpora veno‐occlusive dysfunction in the rat is ameliorated by pioglitazone

Abstract

To determine whether ageing-related changes in the penile corpora cavernosa, namely corporal veno-occlusive dysfunction (CVOD), loss of smooth muscle cells (SMCs), and excessive collagen deposition, can be ameliorated by the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist pioglitazone, in a rat model of ageing as we have shown in a rat model of type 2 diabetes. Male Fischer 344 rats (16-18 months old) were fed chow containing 0%, 0.001% or 0.02% pioglitazone for 2 or 4.5 months, using 5 month old rats as 'young' controls. Functional changes were determined by dynamic-infusion cavernosometry (DIC). Histological changes were assessed by histochemistry and immunohistochemistry followed by quantitative image analysis and/or quantitative Western blot. Reactive oxygen species were estimated in blood. Pioglitazone at both doses reduced the high DIC 'drop rate' present in the untreated aged groups to the level seen in the young rats. The papaverine response was increased to young control levels by short-term high-dose pioglitazone and the long-term low-dose treatment, but not by the short-term low-dose treatment. Pioglitazone at all doses and durations of treatment failed to reverse the decreased corporal SMC/collagen ratio and SMC content, oxidative stress, or the elevated contents of collagen, or transforming growth factor beta1, seen in the aged penis, but did reduce the collagen III/I ratio, and at a high dose increased apoptosis. Both treatments inhibited the Rho-kinase system, by increasing Src homology region 2-containing protein tyrosine phosphatase and reducing Vav. PPARgamma were detected in corporal SMCs. Pioglitazone ameliorated ageing-related CVOD, possibly by a PPARgamma-mediated inhibition of Rho-kinase and not by a protective effect on the corporal smooth muscle.