Cavernosal dysfunction in a rabbit model of hyperhomocysteinaemia

Abstract

To investigate the effect of sustained hyperhomocysteinaemia (HHCy) on cavernosal smooth muscle function in a rabbit model of HHCy, developed using a methionine-enriched diet in which cavernosal responses were characterized, as elevated plasma levels of homocysteine may be a risk factor for vasculogenic erectile dysfunction. Six New Zealand White rabbits were fed a diet supplemented with methionine (20 g/kg chow) for 4 weeks, while six control animals were fed a standard diet. Cavernosal strips were mounted in an organ bath and relaxation assessed when stimulated with carbachol, sodium nitroprusside (SNP), or noncholinergic, nonadrenergic (NANC)-mediated relaxation to electrical-field stimulation (EFS). Cavernosal tissue cGMP levels were assessed using an enzyme-linked immunosorbent assay, and superoxide (O(2) (.-)) production assessed using an assay of the superoxide dismutase (SOD)-inhibitable reduction of ferricytochrome c. The methionine-rich diet led to an early but sustained HHCy; cavernosal strips from animals after 4 weeks of HHCy had a significantly impaired relaxation response to carbachol, an index of endothelium-dependent nitric oxide (NO)-mediated relaxation. This impairment was reversed by incubating with either SOD or catalase. Relaxation with either SNP, an index of endothelium-independent NO-mediated relaxation, or NANC-mediated EFS-induced relaxation, was unaffected by HHCy. There was a corresponding significant reduction in cavernosal cGMP levels (index of NO activity) in the HHCy group, with a more than five-fold increase in cavernosal tissue O(2) (.-) production. Supplementing the diet of rabbits with methionine for 4 weeks caused an early and sustained HHCy and promoted a marked inhibitory effect on endothelium-dependent relaxation and NO formation in isolated corpus cavernosum, an effect mediated by reactive oxygen species.