Cavernosal dysfunction in a rabbit model of hyperhomocysteinaemia.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Jones
Robert W A
RW
Bristol Heart Institute, Royal Infirmary, University of Bristol, Bristol BS2 8HW, UK.
Jeremy
Jamie Y
JY
Koupparis
Anthony
A
Persad
Raj
R
Shukla
Nilima
N
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000503:physiopathology; D018783:Impotence, Vasculogenic / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D010413:Penis / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D013481:Superoxides / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D013481:Superoxides; D010656:Phenylephrine; D009569:Nitric Oxide; D006152:Cyclic GMP