Gábor Pogátsa

Characteristics of coronary endothelial dysfunction in experimental diabetes

OBJECTIVE To study the influence of diabetes on the endothelium-dependent vasodilation in the coronary arterial bed. METHODS The effects of acetylcholine (ACh 2-36 pmol.kg-1; 18 nmol.1(-1)-9.8 mumol.1(-1); 0.1-10 mumol.1(-1), L-arginine (1 mmol.1(-1) and sodium nitroprusside (1 nmol.1(-1)-100 mumol.1(-1)) were measured on coronary conductivity, vascular tone and cGMP release (RIA) in healthy and diabetic dogs. RESULTS ACh-mediated (in cumulative intra-arterial infusion) increase in coronary conductivity was reduced (P < 0.01) in the diabetic dogs in vivo, whereas no increase in cGMP release was observed in isolated diabetic coronaries (P < 0.05) which could not be enhanced by L-arginine (P < 0.05). Inhibition of cyclo-oxygenase after 20 min further impaired (P < 0.01) responsiveness to ACh in vivo and diminished the ACh response in isolated coronary strips of the diabetic dogs, but not in those of the controls. Relaxation in response to sodium nitroprusside was not altered by diabetes. CONCLUSIONS Diminished vasodilation in diabetes is due to a defect in endothelial nitric oxide production and action. Vasodilating prostanoids do not sufficiently compensate this defect.

Divergent cardiac effects of the first and second generation hypoglycemic sulfonylurea compounds

The effects of first and second generation hypoglycemic sulfonylureas on the incidence of ventricular ectopic beats and on the duration of transitional ventricular fibrillation in the ischemic rat heart were investigated. First generation sulfonylurea compounds (tolbutamide, carbutamide and gliclazide) in 105 preparations increased, while second generation sulfonylurea compounds (glibenclamide and glipizide) in 50 preparations decreased in a dose-dependent manner both the number of ventricular ectopic beats and the duration of transitional ventricular fibrillation during the first 30 min after ligation of the left anterior descending coronary artery. Therefore, second generation sulfonylureas should be preferred in the treatment of type 2 diabetics with ischemic heart diseases, if satisfactory metabolic control cannot be achieved by a treatment regimen and diet alone.

QT interval prolongation in type 2 (non-insulin-dependent) diabetic patients with cardiac autonomic neuropathy

SummaryQT interval alterations were measured in 41 non-insulin-dependent (type 2) diabetic patients and 14 age- and sex-matched control subjects. Cardiac autonomic neuropathy (CAN) was assessed by noninvasive tests (deep breathing, Valsalva maneuver and lying-to-standing) and diabetics were divided into three groups according to the results of these tests: diabetics with definitive (n=14), early (n=13) and without (n=14) CAN. The corrected values of QT intervals (QTc) at rest were significantly longer in diabetics with definitive (447±5 ms; p<0.001), early (426±5 ms; p<0.05) and without (424±5 ms; p<0.05) CAN than in controls (407±5 ms). Moreover, QTc intervals at rest were significantly (p<0.01) longer in diabetics with definitive CAN than in diabetics with early and without CAN. QTc intervals at maximum tachycardia, induced by Valsalva maneuver, were considerably longer in diabetics with definitive CAN (451±6 ms) than in controls (407±6 ms; p<0.001) and in diabetics with early (434±6 ms; p<0.05) or without (422±6 ms; p<0.01) CAN. Furthermore, QTc intervals at maximum tachycardia were significantly (p<0.01) longer in diabetics with early CAN than in controls. QTc intervals at maximum bradycardia after Valsalva maneuver were significantly longer in diabetics with definitive (446±5 ms; p<0.001), early (434±5 ms; p<0.001) and without (424±5 ms; p<0.01) CAN than in controls (403±5 ms). Moreover, QTc intervals at maximum bradycardia were considerably (p<0.01) longer in diabetics with definitive than without CAN. At least one abnormal (>440 ms) QTc period was found in 19 out of 27 patients with early or definitive CAN, but 4 of 14 diabetics without any signs of CAN and none of the controls exibited abnormal QTc period. It was concluded that QTc interval prolongation due to imbalance of autonomic nervous tone could be observed in type 2 diabetic patients with CAN, suggesting a possible role in sudden cardiac death.

Diabetic myocardial alterations in ultrastructure and function.

Myocardial samples taken from six healthy and six alloxan-diabetic dogs by means of percutaneous needle-biopsy were investigated electronmicroscopically. Specific increase in the number of collagen fibers and that of mitochondria were demonstrated beside the widening of Z bands. In the same experimental animals, a close, inverse correlation was detected (y = 0.0068x + 0.1680; r = 0.8648; F = 29.6705; n = 12) between the values of the left ventricular passive elastic modulus and those of the plasma glucose disappearance rate determined immediately before the haemodynamic investigation. On the basis of the ultrastructural findings, the proliferation of collagen fibers can be made also responsible for functional disorder of the diabetic myocardium.

Altered hyperemic response of the coronary arterial bed in alloxan-diabetes

Reactive hyperemic responses of the coronary arterial bed, provoked by asphyxia or clamping of the coronary artery, were compared in alloxan-diabetic and metabolically healthy dogs. In alloxan-diabetic dogs the response of the coronary arterial bed lasted longer, and its reactivity to hypoxia was lower. Treatment with adenosine caused less vasodilation in diabetic animals than in controls. These changes may be due to the altered reactivity of diabetic vascular smooth muscle.

Potassium channels in the cardiovascular system

In vitro and in vivo studies suggest that opening of ATP-sensitive potassium channels following ischaemia enhances recovery of myocardial contraction, dilates blood vessels and has an antiarrhythmic effect. Different sulphonylurea compounds that block the ATP-sensitive potassium channels exert different effects on cardiac functions. Glibenclamide decrease, arrhythmogenesis during acute myocardial infarction in rats and reduces strophanthin cardiotoxicity in rabbits. Other sulphonylurea compounds, but not glibenclamide, increase arterial blood pressure and myocardial contractility. These effects may be partly secondary to blockade of ATP-sensitive potassium channels and partly due to independent cardiac and extracardiac actions. Glimepiride may have a more advantageous cardiovascular effect than glibenclamide. The studies suggest the hypothesis that deleterious cardiovascular effects of some hypoglycaemic sulphonylurea drugs may contribute to the high cardiovascular mortality rate in diabetes mellitus. An observational study suggested glibenclamide decreased the incidence of fatal myocardial infarction and development of ventricular fibrillation in patients suffering from acute myocardial infarction. Glibenclamide may also decrease the incidence of ventricular ectopic beats in digitalized patients compared with other sulphonylurea compounds. The studies suggested the survival of subjects treated with glibenclamide, insulin, or diet alone after the first attack of angina pectoris or after first acute myocardial infarction may be longer compared with those on other sulphonylurea therapies. Further large scale prospective, randomised studies are needed to determine whether the reported effects can be verified and are sufficiently large to affect clinical prescribing.

Altered Responsiveness of Diabetic Dog Renal Arteries to Acetylcholine and Phenylephrine: Role of Endothelium

The mechanical responses to acetylcholine (ACh), sodium nitroprusside and phenylephrine (PE) were determined in normal and diabetic dog renal arterial strips with and without endothelium. Experimental diabetes increased the sensitivity, IC50 = (2.9 +/- 0.4) X 10(-8) mol/l in normal and (9.6 +/- 1.5) X 10(-9) mol/l in diabetic (p less than 0.01, n = 6) to ACh of endothelium intact renal arterial strips without influencing the maximum relaxation induced by this agonist. In all intact vessels PE produced contractions of equal magnitude. Removal of the endothelium completely abolished the relaxant ability of ACh, and caused a slight increase in the contractile response of both diabetic and normal strips to PE. The maximum contractile force generated by the denuded diabetic vessels in response to PE was significantly (p less than 0.01) greater than the maximum tension produced by the denuded nondiabetic arteries. The sensitivity of the tissues to PE was, however, not modified by either diabetes or endothelium removal. The direct relaxant sodium nitroprusside elicited a similar degree of relaxation in the two groups of arteries. Cyclooxygenase blockade had no effect on either the relaxation or contractile responses of any of the preparations. These findings suggest that short-term diabetes makes dog renal arteries supersensitive to ACh and hyperreactive to PE.

Direct effect of hypoglycemic sulphonylureas on the cardiovascular system of dogs

The effects of first generation sulphonylurea compounds carbutamide, gliclazide and tolbutamide as well as second generation compounds glibenclamide and glipizide on the cardiovascular system were investigated in dogs. Six dogs received each compound intravenously at cumulative dose levels of 74, 296, 1184 mumol/kg of carbutamide and tolbutamide, 0.4, 2.0, 10.0 mumol/kg of glibenclamide and glipizide, and 16, 48 and 144 mumol/kg of gliclazide. Mean arterial blood pressure, myocardial contractile force, cardiac output and heart rate were measured. The rate of change of myocardial contractile force development (positive dF/dt), as well as of myocardial relaxation (negative dF/dt) were measured. The first generation sulphonylureas were found, in dogs, to exert a positive inotropic effect in contrast to second generation compounds. The clinical importance of our findings may be in the potential for the malfunction of the cardiovascular system (based on cardiopathy, neuropathy, atherosclerosis, and obesity), developing in diabetes, to be further impaired by the first generation sulphonylureas. Therefore, second generation sulphonylureas should be preferred in the therapy of type 2 diabetics, if satisfactory metabolic control cannot be achieved by dietary management alone and sulphonylurea treatment becomes necessary.

Effects of hypoxia and adrenergic stimulation induced alterations in PGI2 synthesis by diabetic coronary arteries

Before the onset of histologically detectable alterations in diabetic arteries, a considerable decrease in vasodilatory potential is seen. While analyzing this phenomenon, the role of altered PGI2 synthesis in rings of coronary arteries from metabolically healthy and alloxan-diabetic dogs was measured by radioimmunoassay during baseline, under the influence of phenylephrine (100 mumol/L), and during hypoxia with or without the presence of the alpha adrenergic blocker phentolamine (5 mumol/L). Basal levels of PGI2 synthetized by healthy and diabetic coronaries were no different (7.9 +/- 2.1 and 6.4 +/- 1.4 pg/mg vessel). Phenylephrine potentiated PGI2 synthesis in controls (150 +/- 22%), while it proved to be ineffective in the diabetic animals (98 +/- 6%). Under hypoxic conditions, PGI2 production of healthy coronaries (152 +/- 24%) increased, while that in the diabetic ones (82 +/- 7%) decreased (p less than 0.01). In the presence of phentolamine no difference could be detected between the two groups. Given all these data, the decreased ability of the diabetic coronaries to vasodilate develops due to diminished PGI2 production, presumably controlled by adrenergic mechanisms. Furthermore, the more severe outcome of ischaemic heart disease in diabetes mellitus might be explained by the lack of an enhanced coronary PGI2 synthesis under hypoxic conditions.

Effects of various hypoglycaemic sulphonylureas on the cardiotoxicity of glycosides

SummaryIn diabetic patients it has been shown that tolbutamide and carbutamide enhanced and glibenclamide did not influence the incidence of digitalis intoxication, or that of multifocal ectopic beats or coupling due to premature ectopic ventricular beats during digitalis therapy. In rabbits glibenclamide decreased and tolbutamide and carbutamide increased strophanthidin toxicity in a dose dependent manner. It was concluded that glibenclamide should be preferred to tolbutamide or carbutamide in digitalistreated diabetics, when satisfactorily metabolic control is not achieved with a dietary regime alone.