Glucose scavenging of nitric oxide.

Endothelial dysfunction accompanies suboptimal glucose control in patients with diabetes mellitus. A hallmark of endothelial dysfunction is a deficiency in production or bioavailability of vascular nitric oxide (NO). Here we demonstrate that acute exposure of human endothelial cells to glucose, at levels found in plasma of diabetic patients, results in a significant blunting of NO responses to the endothelial nitric oxide synthase (eNOS) agonists bradykinin and A-23187. Monitoring of NO generation by purified recombinant bovine eNOS in vitro, using amperometric electrochemical detection and an NO-selective porphyrinic microelectrode, showed that glucose causes a progressive and concentration-dependent attenuation of detectable NO. Addition of glucose to pure NO solutions similarly elicited a sharp decrease in NO concentration, indicating that glucose promotes NO loss. Electrospray ionization-tandem mass spectrometry, using negative ion monitoring, directly demonstrated the occurrence of a covalent reaction involving unitary addition of NO (or a derived species) to glucose. Collectively, our findings reveal that hyperglycemia promotes the chemical inactivation of NO; this glucose-mediated NO loss may directly contribute to hypertension and endothelial dysfunction in diabetic patients.

alpha(2)-Adrenoceptor antagonists and propensity to take alcoholic beverages.

Rats were maintained on a daily regimen involving a 2h opportunity to take both water and a sweetened alcoholic beverage (12% ethanol, 0.25% saccharin). After 3 weeks on this regimen, rats regularly take substantial amounts of alcohol. After stabilization, injections of alpha(2)-adrenergic antagonists were administered, 15min before the opportunity to drink. Yohimbine and methoxyidazoxan dose relatedly decreased intake of alcoholic beverage and increased intake of water. In Experiment 2, a number of rats were taken off the daily regimen for 9 days, then returned to it. Across the first 12 days of the reinstated daily regimen, half the rats received placebo and half methoxyidazoxan. The group receiving placebo rapidly returned to taking large amounts of alcoholic beverage while the group receiving methoxyidazoxan did not. In Experiment 3, it was shown that a dose of methoxyidazoxan that decreased intakes of alcoholic beverage did not decrease intakes of other palatable beverages. In Experiment 4, it was shown that yohimbine persistently reduced intakes of alcoholic beverage with daily administration. These results indicate that alpha(2)-antagonists might be effective pharmaceutical adjuncts to other treatments for alcohol abuse and alcoholism.