Am. Emsley et al., Investigation of the inhibitory effects of homocysteine and copper on nitric oxide-mediated relaxation of rat isolated aorta, BR J PHARM, 126(4), 1999, pp. 1034-1040
1 Elevated plasma levels of homocysteine (HC) and copper have both been ass
ociated with the development of inflammatory vascular diseases, such as ath
erosclerosis. In this study, the effects of a combination of HC and copper
on nitric oxide (NO)-mediated relaxation of isolated rat aortic rings were
investigated.
2 Exposure to HC (10-100 mu M; 30 min) had no effect on relaxation to acety
lcholine (ACh; 0.01-10 mu M, n = 4). Pre-incubation of aortic rings with a
higher concentration of HC for an extended period (1 mM: 180 min) significa
ntly inhibited endothelium-dependent relaxation (n=4), but this inhibition
was prevented by the presence of the copper chelator bathocuprione (10 mu M
, 180 min, n = 6).
3 Exposure to HC (100 mu M) and copper (10-100 mu M; 30 min) caused a coppe
r concentration-dependent inhibition of endothelium-dependent relaxation (n
=4). This inhibitory effect was reduced in the presence of either superoxid
e dismutase (SOD; 100 u ml(-1); n=4) or catalase (100 u ml(-1); n=4), and f
urther reduced by the presence of both enzymes (n=5).
4 HC and copper (100 mu M; 30 min) significantly inhibited endothelium-inde
pendent relaxation to glyceryl trinitrate (0.01-10 mu M; n=8). In contrast,
HC (1 mM), alone or in combination with copper (100 mu M), did not inhibit
relaxation to the endothelium-independent relaxant sodium nitroprusside (0
.01-10 mu M; n=4).
5 These data indicate that the presence of copper greatly enhances the inhi
bitory actions of HC on NO-mediated relaxation of isolated aortic rings. Th
e reduction of inhibition by catalase and SOD indicates a possible role for
copper-catalyzed generation of superoxide and hydrogen peroxide leading to
an increased inactivation or decreased production of endothelium-derived N
O.