Reduced coronary NO production in conscious dogs after the development of alloxan-induced diabetes

Abstract

The role of nitric oxide (NO) in the control of coronary blood flow (CBF) during the development of diabetes is unknown. To study this, mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and CBF. With heart rate controlled (150 beats/min), veratrine (1–10 μg/kg) caused dose-dependent increases in CBF; e.g., 5 μg/kg of veratrine increased CBF by 57 ± 7% from 41 ± 1.3 ml/min ( P < 0.05). The dogs developed diabetes 4–5 wk after injection of alloxan (40–60 mg/kg iv, blood glucose levels were 384 ± 18 mg/dl). After diabetes the same doses of veratrine caused smaller increases in CBF; i.e., 5 μg/kg of veratrine increased CBF by 32 ± 2% ( P < 0.05 compared with control) from 28 ± 4 ml/min. ACh- and adenosine-induced coronary vasodilation were reduced after diabetes as well. In anesthetized dogs after diabetes, vagal stimulation caused smaller increases in CBF. ACh and bradykinin caused smaller increases in[Formula: see text] production in coronary microvessels from diabetic dogs. Furthermore, despite the fact that mRNA for endothelial cell NO synthase from the aorta was increased twofold with the use of Northern blotting, the protein for aortic endothelial constitutive NO synthase was reduced by 66% after diabetes, as determined by Western blotting. Our results indicate that the NO-dependent coronary vasodilation by the Bezold-Jarisch reflex is impaired in conscious dogs after diabetes. The mechanism responsible for the impaired endothelium-dependent coronary vasodilation is most likely the decreased release of NO from the endothelium.

Lowering serum urate does not improve endothelial function in patients with type 2 diabetes

“…Endothelial dysfunction is believed to play a key role in the early development of atherosclerosis and precedes plaque development [2]. Experiments carried out in animal models of diabetes have shown impaired endothelium-dependent vasomotion [3]. Blood flow responses to endothelial NO-dependent vasodilators, for example acetylcholine, are characteristically impaired in patients with diabetes [4][5][6].…”

Coronary Microvascular Adaptation to Myocardial Metabolic Demand Can Be Restored by Inhibition of Iron-Catalyzed Formation of Oxygen Free Radicals in Type 2 Diabetic Patients

“…On the other hand, it is well established that oxygen-derived free radical production, which is increased in diabetes (8,9), could impair endothelium-dependent vasodilation since it has been proved that superoxide anions could inactivate nitric oxide (10). Lastly, several studies have shown that nitric oxide production was reduced in diabetes in both peripheral and coronary vascular beds (11,12).We had previously demonstrated that a low dose of deferoxamine (DFX), an iron chelator that prevents ironcatalyzed generation of hydroxyl radicals, restored normal dilation of epicardial coronary arteries in diabetic patients, suggesting that inactivation of nitric oxide by oxygen species may play a role in impairment of coronary vasomotion (13). Similar results have been obtained in peripheral circulation by antioxidant therapy (14 -17).…”

“…On the other hand, it is well established that oxygen-derived free radical production, which is increased in diabetes (8,9), could impair endothelium-dependent vasodilation since it has been proved that superoxide anions could inactivate nitric oxide (10). Lastly, several studies have shown that nitric oxide production was reduced in diabetes in both peripheral and coronary vascular beds (11,12).…”

ATP-Dependent K+ Channels Contribute to Local Metabolic Coronary Vasodilation in Experimental Diabetes

“…(7,8), in chronically instrument-implanted dogs before and after induction of diabetes with alloxan monohydrate (40 -60 mg/kg i.v.) (21).…”

“…After nondiabetic control experiments were conducted, alloxan monohydrate (40 -60 mg/kg) was administered intravenously over 1 min to induce diabetes (21). Alloxan was prepared as a 5% solution in citrate buffer (pH 4.0 -4.5).…”