Aorta and corpus cavernosum dysfunction in diabetic rodents : effects of rosuvastatin and the role of nitric oxide

• Main Author: Nangle, Matthew Robert
• Published: University of Aberdeen 2002
• Subjects: 616; Diabetes mellitus
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252128

Rosuvastatin treatment prevented diabetic deficits in endothelium-dependent relaxation to acetylcholine of mouse aorta and cavernosum, and prevented diabetic deficits in NANC-mediated relaxation, in the presence of atropine and guanethidine, of rat and mouse cavernosum precontracted with the adrenergic agonist phenylephrine. Similarly, rosuvastatin partially reversed established diabetic deficits of endothelium-dependent relaxation of mouse aorta and cavernosum, and NANC-relaxation of mouse cavernosum. However, plasma lipids were unaltered by either diabetes or rosuvastatin treatment in mice, indicating that the beneficial actions of the statin were not dependent on lipid-lowering. Co-treatment with mevalonate, the product of HMG-CoA redustase, ameliorated the beneficial actions of rosuvastatin confirming that the effects were dependent on cholesterol biosynthesis pathway inhibition. The endothelium and NANC-dependent responses of the isolated tissues were dependent on the production of nitric oxide (NO), as they were abolished following tissue incubation with the non-specific NO synthase (NOS) inhibitor <i>N</i>^G-nitro-L-arginine. As specific inhibitors for the endothelial, neuronal and inducible NOS isoforms are lacking, the secondary aim of this thesis was to investigate the specific roles of the NOS isoforms on aortic and cavernosal function of mice lacking the respective NOS genes (NOS KO's). The variations in response from NOS KO aorta and cavernosum were multiple, however, taken together suggest that mice lacking specific NOS isoforms develop compensatory mechanisms to retain NO-dependent functions. In summary, this thesis demonstrates that vascular and nervous NO-dependent functions can be improved by rosuvastatin therapy in diabetic rodents and that further investigation of the roles of the specific NOS isoforms may lead to therapeutic approaches for diabetes mellitus.