Effects of experimental diabetes on endothelin-induced ventricular arrhythmias in dogs.

Endothelin-1 (ET-1) is known to have a direct arrhythmogenic effect in the mammalian heart. Diabetes mellitus is accompanied by a series of endothelial and cardiac disfunctions; however, little is known about ET-1-induced direct arrhythmias in diabetes mellitus. Therefore, we infused ET-1 (33 pmol/min) into the left anterior descending coronary artery of 28 mongrel dogs, and measured basic hemodynamic parameters, coronary flow and an electrocardiogram. Diabetes mellitus was induced by alloxan (Group 4) and experiments were carried out 8 weeks later. Metabolically healthy dogs served as controls (Group 2). In a further control group, local hyperglycemia was induced by intracoronary glucose infusion (Group 3). ET-1 infusion induced prolongation of the QT-time and frequency-adjusted QT-time in all groups. Other electrophysiological parameters were comparable between the groups. This was followed by the occurence of ventricular premature beats, coupled extra-beats and later sustained ventricular tachycardia. Most of the experiments were terminated by ventricular fibrillation. The onset of arrhythmias was shorter in diabetic dogs as compared with control and locally hyperglycemic animals (18 +/- 8 minutes versus 24 +/- 8 minutes and 30 +/- 28 minutes, P < 0.05). However, there was no difference in the number of ventricular fibrillations, and the total elapsed time until the termination of the experiments. Therefore, the diabetic heart seems to be more prone to ET-1-induced arrhythmias and this is probably not a result of locally high glucose concentrations.

Haemodynamic and metabolic effects of low daily dose sulphonylureas in diabetic dog hearts.

The effects of glibenclamide (GB, CAS 10238-21-8) and those of the latest low daily dose sulphonylurea compound, glimepiride (GM, CAS 93479-97-1) on myocardial haemodynamics and pyruvate-lactate metabolism of healthy and alloxan-diabetic dogs (n = 6 in six groups) were compared. Mean arterial blood pressure, heart rate, blood flow of the left anterior descending coronary artery, myocardial contractile force, the rate of change of myocardial contraction and relaxation were measured and arterial (a. carotis communis) and venous (sinus coronarius) pyruvate and lactate concentrations were determined during i.v. administration of the drugs (0, 0.4, 2, 5, and 8 mumol/kg). Coronary conductivity, pressure-rate product and pyruvate-lactate extraction rates were calculated. Glimepiride reduced the heart rate in diabetic animals. Both compounds decreased myocardial contractile force, coronary blood flow and conductivity and the rate of change of myocardial contraction. However, alterations in blood pressure, pressure-rate product, the rate of change of myocardial relaxation and arterio-venous lactate difference elicited by glibenclamide proved to be more expressed than those by glimepiride. According to the results, glibenclamide and especially glimepiride do not enhance the disturbances of the cardiovascular system in diabetes. By this reason, considering its very low daily dose and favourable haemodynamic effects, glimepiride could preferably be recommended for the treatment of type 2 diabetics with coronary heart disease.

New trends in the development of oral antidiabetic drugs.

A large number of oral antidiabetic agents are available today. This article provides a short review of the pharmacology and some clinical aspects of various oral antidiabetic drugs. It focuses mainly on the newest developing drugs (therapy of the near future) and on the most commonly used older groups for the common approach of every-day practice (sulphonylureas). The primary goal of this review is to compare the electrophysiological effects of glibenclamide in isolated normal and streptozotocin induced diabetic rats and alloxan induced rabbits ventricular preparations, while on the other hand to differentiate the hypoglycaemic sulphonylureas (0.1-1000 mmol/kg) according to their cardiovascular activity in healthy and diabetic animals. In vitro (1-100 micromol/l) as well as chronically treated (5 mg/kg for 10 weeks) glibenclamide prolonged the action potential duration in normal but failed to affect it in diabetic ventricular preparations. Our results suggest that the sensitivity to glibenclamide of K(ATP) channels in diabetic ventricular fibers is drastically decreased. The effects of different sulphonylureas (tolbutamide, glibenclamide, gliclazide, glimepiride) on ventricular ectopic beats as well as the duration of ventricular fibrillation induced by 10 min ischemia/50 min reperfusion in healthy and diabetic rats were compared. Tolbutamide and gliclazide dose-dependently enhanced both parameters both in healthy and diabetic groups. Glibenclamide in healthy rats increased, while in diabetic rats it decreased the arrhythmogenicity. Glimepiride depressed the arrhythmogenicity in both healthy and diabetic animals. Glimepiride proved to dose-dependently enhance the myocardial tissue flow in dog in contrast to glibenclamide. These results confirm that glimepiride has less cardiovascular actions than other sulphonylureas. From the newest oral antidiabetics this review tries to emphasize the most important basic pharmacological properties, mechanism of action, therapeutic use.

The diabetic heart: A review of the lifework of Sophie Maria Koltai.

It is well known that cardiovascular alterations are the principal causes of mortality in patients with diabetes. Premature and accelerated atherosclerosis cannot be the sole cause of diabetic heart disease because functional disorders develop both in experimental and in clinical diabetes before the onset of the detectable morphological changes of the vessel wall. Namely, altered adrenergic responses and prostaglandin metabolism and diminished vasodilatory ability can be seen in diabetic vessels. This leads to enhanced vasoconstriction, which - combined with increased sympathetic activity - may induce myocardial edema and an increase in myocardial stiffness, resulting in diminished heart function. Increased myocardial stiffness due to myocardial dehydration caused by hyperglycemic hyperosmolality can also result in impaired heart function. Thus, myocardial water content plays a key role in the development of diabetic heart dysfunction. Disturbances in the myocardial energy metabolism may also contribute to the diminished cardiac performance in the diabetic state. Some antidiabetic agents may also have deleterious cardiovascular effects. Whether the functional abnormalities observed in the reviewed studies lead to clinically manifest heart disease in diabetes may depend on the superimposition of the classical cardiovascular risk factors. Thus, adequate control of carbohydrate and lipid metabolism and the possible concomitant hypertension may prevent the further impairment of heart function and the development of overt heart disease.