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Both diabetes mellitus (DM) and elevated plasma copper concentrations are risk factors for cardiovascular disease (CVD). DM is associated with impaired endothelial nitric oxide (NO) and with excess superoxide (O2*-) formation. Copper is also elevated in DM and is also associated with the generation of O2*-. To explore possible interactions between DM and copper, the effect of exogenous copper (CuCl2) on endothelium-dependent relaxation and cyclic guanosine monophosphate (GMP) formation was investigated in aortae from diabetic rabbits. Rabbits were rendered diabetic by intravenous injection of alloxan. Six months after induction of DM, the aortae were excised, cut into rings, and mounted in an organ bath for isometric measurement of acetylcholine (Ach)-evoked relaxation in rings precontracted with phenylephrine (PE). In parallel studies, cyclic (c)GMP formation by aortic rings following stimulation with Ach, calcium ionophore A23187 (A23187) and sodium nitroprusside (SNP) was assessed using radioimmunoassay. The effect of copper on these parameters was then studied using the same methods. Ach-evoked relaxation and Ach- and A23187-evoked cGMP formation were significantly impaired in aortae from diabetic rabbits compared to controls, effects that were reversed with superoxide dismutase (SOD) and catalase (CAT). In contrast, there were no significant differences in SNP-stimulated relaxation or cGMP formation in aortae from diabetic rabbits compared to controls. Copper (1 to 10 micromol/L) promoted a further significant inhibition of Ach-stimulated relaxation in aortae from diabetic but not control rabbits. This reduction by copper was again reversed by SOD and CAT. We conclude that copper augments the reduction of NO bioavailability, which is already impaired in aortae from diabetic rabbits due to excess production of O2*- and H2O2. These results indicate that patients with DM may be susceptible to copper-mediated vasculopathy at much lower concentrations than those that promote vasculopathy in nondiabetic patients.

In view of the observations that (1) plasma histamine concentrations are significantly higher in diabetic patients and diabetic rats than those in controls, and (2) tissue concentrations of histamine are elevated in rats with experimental diabetes, we have investigated histamine synthesis, as reflected by histidine decarboxylase (HDC) activity, and histamine catabolism, as reflected by histaminase activity, in various tissues of the diabetic rat. Rats with streptozotocin-induced diabetes mellitus (DM) showed an increase in histamine synthesis in various tissues; this was most marked in the aorta and to a lesser, but significant, extent in the kidneys, lungs, and heart, but not in the brain, stomach, or skin. Tissue content of histamine was significantly increased in all tissues except the stomach and skin. We conclude that tissue histamine synthesis is significantly increased in diabetic animals and that this increase is most marked in the aorta. The elevation in HDC activity in these tissues probably accounts for the increase in tissue and plasma concentrations of histamine in diabetic animals, since there is no change in histamine catabolism. This increase in histamine synthesis and release may contribute to the pathogenesis of endothelial damage in diabetic microangiopathy and macroangiopathy.

The effects of prolonged fasting and experimental nonketonuric diabetes on rat aortic prostacyclin (PGl2) synthesis were compared. Whereas fasting (for 48 hours or longer) resulted in a marked increase in trauma-, adrenaline-, and U46619-stimulated aortic PGI2 synthesis, prolonged experimental (streptozotocin-induced) nonketonuric diabetes caused a marked decrease in aortic PGI2 synthesis stimulated by the above agonists. Arachidonic acid (AA)-stimulated aortic PGI2 synthesis in fasted and diabetic rats, however, was not different from that in controls. The reduction in adrenaline- and U46619-stimulated, but not AA-induced, PGI2 synthesis in the diabetic rat suggests that the diminished production of PGI2 in diabetes may be due to diminished phospholipase A2 (or of the phospholipase C-diglyceride lipase system) activity, diminished AA stores, or both. The opposite effects of prolonged fasting and diabetes on aortic PGI2 synthesis suggest that caution should be exercised when comparing the metabolic consequences of starvation with those of diabetes.