Homocysteine enhances impairment of endothelium-dependent relaxation and guanosine cyclic monophosphate formation in aortae from diabetic rabbits

Abstract

Aims/hypothesis. Both diabetes mellitus and hyperhomocysteinaemia are risk factors for cardiovascular disease and are associated with impaired endothelial nitric oxide and with excess superoxide formation. To explore potential vasculopathic interactions between these risk factors, the effect of homocysteine on endothelium-dependent relaxation and cyclic GMP formation was investigated in aortae from diabetic rabbits. Methods. Rabbits were rendered diabetic by intravenous injection of alloxan. Six months later, the aortae were excised, cut into rings and mounted in an organ bath for isometric measurement of acetylcholineevoked relaxation in rings pre-contracted with phenylephrine. Cyclic GMP formation by aortic rings after stimulation with acetylcholine, calcium ionophore A23187 and sodium nitroprusside was assessed using radioimmunoassay. The effect of homocysteine on these parameters was then studied.Results. Ach-evoked relaxation and cyclic GMP formation induced with acetylcholine and calcium ionophore A23187 were impaired in aortae from diabetic rabbits compared with the control rabbits, effects that were reversed with superoxide dimutase (SOD) and augmented by 10-100 µmol/l homocysteine, an effect again reversed by SOD. Conclusion/interpretation. These data show that the bioavailability of nitric oxide is reduced in aortae from diabetic rabbits due to excess production of superoxide, an effect augmented by homocysteine. These results indicate that patients with diabetes mellitus could be susceptible to homocysteine-mediated angiopathy at lower concentrations than those that promote vasculopathy in non-diabetic patients. [Diabetologia (2002[Diabetologia ( ) 45:1325[Diabetologia ( -1331

The administration of folic acid reduces intravascular oxidative stress in diabetic rabbits

“…Blood was sampled at sacrifice for plasma glucose. Urine was also monitored over the duration of diabetes for glucose, ketone bodies, and proteins with Multistix (Ames Division, Miles Laboratories, Stoke Poges, Buckinghamshire, United Kingdom) as previously described [11,29]. Any animals displaying ketonuria or proteinuria were excluded from the study.…”

“…Ethical approval for the study had been obtained from the local Committee at the University of Bristol. Male New Zealand white rabbits (3 kg) were injected intravenously with alloxan (Sigma Chemical, Poole Dorset, United Kingdom) via the lateral ear vein at a stat dose of 65 mg/ kg [11,29]; and age-matched controls, with saline alone. The diabetic rabbits were fed ad libitum with SDS standard rabbit chow (SDS, Whitham, United Kingdom) and allowed free access to water.…”

“…Because NO U provides vasculoprotection [8], this interaction has been deemed important in the etiology of diabetic angiopathy [7]. Increased O 2 U-formation and a concomitant decrease in NO U formation by vascular tissue from animal models of both DM [9,10] and HHC [11,12], as well as in patients with DM [13,14] and HHC [15,16], are well documented. The overproduction of O 2 U-in both DM and HHC has been ascribed, in part, to the intravascular overexpression of nicotinamide adenine nucleotide phosphate oxidase (NADPH) oxidase [2,11,12].…”

Adiponectin Levels and Cardiovascular Risk Factors in Japanese Men with Type 2 Diabetes

“…It has been shown that high tHcy [10,11], low folate [12,13] and high g-GT [14] predict cardiovascular disease. It is suggested that association between tHcy and cardiovascular disease is stronger in diabetic patients than in non-diabetic subjects [15,16].In the present study we analyzed the association between these cardiovascular risk factors and adiponectin levels in male type 2 diabetic patients. Since insulin affects adiponectin [17] and tHcy [18,19], diabetic patients who are not subject to insulin therapy were studied.…”

Diabetic Nephropathy: A Cardiovascular Risk Factor

“…In addition, the increased susceptibility of diabetic subjects to hyperhomocysteinaemia may be secondary to an acceleration of glucose-induced oxidative stress on endothelial cells (Soedamah-Muthu et al, 2005). This hypothesis is supported by animal studies showing that homocysteine-induced endothelial dysfunction occurs much more readily in the presence of diabetes than in its absence (Schukla et al, 2002).…”