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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.

The aim of the present study was to investigate the effects of experimental diabetes and hyperglycaemia per se on the endothelium-dependent relaxation of isolated canine coronary arteries and to analyse the possible involvement of the cyclooxygenase pathway in the alterations induced by hyperglycaemia. Rings from the left anterior descending coronary arteries of 18 metabolically healthy, six alloxan-diabetic and six insulin-treated alloxan diabetic dogs were set up for isometric tension recording. Diabetic coronaries as well as healthy vessels subjected to in vitro hyperglycaemia (25.5 mmol L-1 glucose) showed impaired (P < 0.05) relaxation to acetylcholine (3 nmol L-1-10 micromol L-1) compared with normoglycaemic, i.e. metabolically healthy and insulin-treated diabetic controls, either before or after indomethacin (3 micromol L-1) administration. The maximal dilation elicited by acetylcholine was further decreased (P < 0.05) by the cyclooxygenase inhibitor in the diabetic coronaries only. Relaxation to sodium nitroprusside did not differ among groups. These results suggest that hyperglycaemia may result in impaired endothelium-dependent dilation of coronary arteries. Diminished relaxation of diabetic coronaries is worsened by the inhibition of the synthesis of vasodilator cyclooxygenase products.

Since the first publication of the University Group Diabetes Programme in 1970 the possible deleterious cardiovascular effects of certain hypoglycaemic sulphonylurea products has been well known. In contrast, international knowledge of the advantageous cardiovascular effects of certain sulphonylurea compounds became available recently. Glibenclamide decreases the incidence of fatal myocardial infarction and the development of ventricular fibrillation in patients suffering from acute myocardial infarction. It also lowers the incidence of ventricular ectopic beats in digitalized patients compared with patients treated with other investigated sulphonylurea compounds. The survival of patients treated with glibenclamide, insulin or diet alone is longer after the first attack of angina pectoris or after first acute myocardial infarction compared with those on other investigated sulphonylurea therapy. Glibenclamide decreases arrhythmogenesis during acute myocardial infarction in rats and strophanthin cardiotoxicity in rabbits. Arterial blood pressure and myocardial contractile force are not influenced by glibenclamide whereas these parameters are increased by other investigated sulphonylurea compounds. Consequently, deleterious cardiovascular effects of certain hypoglycaemic sulphonylurea drugs may contribute to the high cardiovascular mortality rate in diabetes mellitus, partly due to the effect on membrane channels and partly due to independent cardiac and extracardiac actions. Finally, recent observations suggest that glimepiride has a more advantageous cardiovascular effect than glibenclamide.

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.

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.

QT 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 less than 0.001), early (426 +/- 5 ms; p less than 0.05) and without (424 +/- 5 ms; p less than 0.05) CAN than in controls (407 +/- 5 ms). Moreover, QTc intervals at rest were significantly (p less than 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 less than 0.001) and in diabetics with early (434 +/- 6 ms; p less than 0.05) or without (422 +/- 6 ms; p less than 0.01) CAN. Furthermore, QTc intervals at maximum tachycardia were significantly (p less than 0.01) longer in diabetics with early CAN than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Theoretical and experimental research data as well as human epidemiological studies on large populations suggest a great difference in influencing cardiovascular processes and alterations among the oral antidiabetic drugs used in the treatment of type II diabetes mellitus. Drugs delaying or inhibiting carbohydrate absorption as well as insulin sensitizers have an unambiguous reducing effect on diabetic cardiovascular complications. Only fluid retention needs precaution during the treatment with thiazolidinedions in patients suffering from heart disease. Among insulin secretizers repaglinid, glibenclamid and glipizide have an ATP-sensitive potassium channel inhibiting effect in the vascular smooth muscle cells, too, reducing hereby vasodilation. Glibenclamide also inhibits ischaemic preconditioning. Therefore, the antidiabetic drug of choice can be decisive in diabetic patients suffering from ischaemic heart diseases or peripheral obliterative disorders. In the case of secondary sulphonylurea resistance and/or severe ischaemic alterations insulin treatment becomes necessary to avoid further cardiovascular complications.

The sensitivity of the myocardium to ischemia and the level of protection achieved by ischemic preconditioning is shaped by the joint influence of several mechanisms in diabetes mellitus. In vivo studies were made in alloxan diabetic and non-diabetic control rabbits to assess if the effects of preconditioning and sulfonylurea pretreatment with either glibenclamide or glimepiride (0.05-0.2-0.6 micromol kg (-1)) influence the extent of the infarcted area caused by one hour ligature of the left coronary artery. For our study, we defined preconditioning as 2 minutes of ischemia followed by 2 minutes of reperfusion, which was repeated 3 times. The interrelationship of the diabetic pathophysiological state, and sulfonylurea treatment during ischemic preconditioning were studied by comparing the infarcted areas and the rate of infarction to risk areas in left ventricular slices using computer planimetry. In healthy control rabbits preconditioning reduced infarcted area (29.6 +/- 3.0% vs. 48.8 +/- 2.8% p < 0.0005), while in diabetic rabbits this protection did not occur (53.3 +/- 7.3% vs. 56.6 +/- 4.4% NS). Glibenclamide in all of applied doses prevented the protective effect in control animals (infarction/ risk area: HP: 0.47 +/- 0.04 vs. HP Glib-0.05 : 0.69+/-0.06 p< 0.004 vs. HP Glib-0.2 : 0.72+/-0.09 p< 0.002 vs. HP Glib-0.6 : 0.75 +/- 0.04 p< 0.001). In contrast, in diabetic rabbits low dose of glibenclamide contributed to the same development of preconditioning. However the highest dose of glibenclamide (infarction/risk area: DP Glib-0.6 : 0.77 +/- 0.17 vs. DP Glib-0.05 : 0.55 < 0.03 p < 0.047) and the consequences of the diabetic state blocked the salutary effect. Glimepiride had no considerable influence on the protective effect, either in control nor in diabetic animals. Glibenclamide and glimepiride, presumably due to their different sulfonylurea receptor affinity in the heart, resulted in different influence on preconditioning in healthy control animals. Glibenclamide treatment seemed to be more harmful when less K (+)ATP channels were activated. The accomplishment of myocardial preconditioning in diabetes mellitus is claimed to be determined by the interaction of both metabolically influenced K (+)ATP channel activity and the dose of sulfonylurea.

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·l−1–9.8 μmol·l−1; 0.1–10 μmol·l−1), l-arginine (1 mmol·l−1) and sodium nitroprusside (1 nmol·l−1–100 μmol·l−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

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.

The aim of this study was to clarify whether or not arachidonic acid metabolic disorders are caused by a substrate inavailability and whether such disorders might contribute to circulatory disturbances in the diabetic myocardium. Norepinephrine induced a decrease in the conductivity of both coronary arterial bed and myocardial microcirculation in alloxan-diabetic dogs. It was markedly (p less than 0.05) attenuated both by indomethacin and acetylsalicylic acid pretreatments indicating an imbalance among the vasoactive prostanoids in diabetes. TXA2 release from the diabetic coronary rings was found to be elevated and could be normalized after the blockade of vascular adrenoceptors by phentolamine (p less than 0.05). PGI2 synthesis was also enhanced by adrenergic blockade in the diabetic arterial rings. After pretreatment with 14C arachidonic acid, in order to measure substrate availability, the arachidonic acid metabolic rate was less in the diabetic coronary arteries than in healty vessels (p less than 0.05). Ten mumol/l norepinephrine decreased arachidonic acid metabolism in the presence of prelabelled substrate in the diabetic animals, compared to an increase observed in metabolically healthy dogs. Therefore diabetes appears to diminish arachidonic acid metabolism and uptake independent of adrenoceptors and to induce an imbalance between vasoconstrictor and vasodilator cyclooxygenase products, resulting in elevated TXA2 release controlled by adrenergic mechanisms which may contribute to an impairment in myocardial microcirculation.

The result of the UGDP study (1) suggested that the increased cardiovascular mortality among diabetics could be related to tolbutamide treatment. The mortality of diabetics in coronary care units is known to be significantly higher than that of metabolically healthy patients (2). The hypoglycaemic sulphonylureas alter the electrical and mechanical functions of the heart directly under “in vitro” (3,4) and “in vivo” conditions (5,6,7). Lasseter et al. (8) and Crass et al. (9) suggested that the increase in Purkinje fibers automaticity, myocardial contractile force, and the elevation of arterial blood pressure induced by hypoglycaemic sulphonylureas might be responsible for the development of increased cardiovascular mortality in diabetics. It was also demonstrated that a second generation sulphonylurea compound, glibenclamide, decreases the automaticity and the conduction time in the Purkinje fibers (3) and did not elevate the arterial blood pressure (5) in contrast to the first generation sulphonylureas (Figure 1). Furthermore, it was demonstrated that in diabetic patients tolbutamide and carbutamide enhanced while glibenclamide did not influence the incidence of digitalis intoxication, or that of multifocal ventricular ectopic beats during digitalis therapy (10). Koltai et al. (11) documented further that the incidence of lethal and nonlethal myocardial infarction is increased in tolutamide, chlorpropamide and carbutamide treated diabetics.

Signs of autonomic cardiac neuropathy and its association with distal somatic neuropathy were investigated in 36 type 1 and 28 type 2 diabetic patients free from clinical symptoms of autonomic neuropathy. Using bedside tests (deep-breathing, Valsalva manoeuvre and lying-to-standing) definitive cardiac autonomic neuropathy was found in 28 patients (44%), early cardiac autonomic neuropathy was observed in 19 patients (30%) while 17 patients (26%) showed no alterations. The values of motor nerve conduction velocity in peroneal nerves (41.8 +/- 0.7 m/s, mean +/- SEM) were significantly (p less than 0.01) lower in patients with definitive cardiac autonomic neuropathy than those (45.8 +/- 1.1 m/s) of patients without any signs of cardiac autonomic neuropathy. These latter values were, however, significantly (p less than 0.001) lower than those (53.7 +/- 0.7 m/s) of control subjects (n = 50). Signs of early or definitive cardiac autonomic neuropathy were recorded in 31 of 35 diabetic patients with distal somatic neuropathy assessed by measurement of motor nerve conduction velocity in peroneal nerves. It was concluded that abnormal results of noninvasive tests for autonomic neuropathy, i.e. alterations in cardiorespiratory reflexes indicating parasympathetic impairment of cardiac innervation could be often found in diabetic patients without clinical signs of autonomic neuropathy. These alterations could be frequently observed in diabetic patients with distal symmetrical somatic neuropathy.

Study objective – The aim was to determine the role of cyclo-oxygenase products in the vasoconstrictor response of femoral arterial bed to noradrenaline and to analyse the role of vascular adrenoceptors in the synthesis of cyclo-oxygenase products. Design – The influence of intra-arterially injected cyclo-oxygenase inhibitors indomethacin and acetylsalicylic acid on alterations in conductance of femoral arterial bed induced by noradrenaline was compared in metabolically healthy and alloxan diabetic dogs. PGI2 and TXA2 synthesising ability of isolated femoral arterial rings was measured with and without inhibition of α adrenoceptors by phentolamine. Subjects – 18 metabolically healthy and 18 alloxan (560 μmol·kg−1) diabetic dogs of either sex, weight 16–28 kg, were studied. Measurements and main results – Noradrenaline produced greater (p

The left ventricular systolic function of 32 patients with insulin-dependent diabetes mellitus was investigated by measurement of systolic time intervals. Patients with clinical signs of sclerosis in the coronary arteries were excluded. Twenty-nine sex- and age-matched healthy people served as controls. Resting values of PEP/LVET ratio and of the corrected pre-ejection period were significantly higher in diabetics than in controls. The alterations of systolic time intervals during volume-loading induced by passive leg-raising as well as by isometric handgrip test indicated an increase in left ventricular performance in healthy people. The unchanged systolic time intervals observed in diabetics during the same loadings indicated a decrease in the functional reserve of the diabetic left ventricle. The systolic time intervals observed in patients with type-1 diabetes could be evaluated as a preclinical abnormality of left ventricular performance and as early signs of diabetic cardiomyopathy.

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.

The aim of the present study was to examine the left ventricular and haemodynamic parameters during acute hypoxia induced by carbon monoxide intoxication and/or after norepinephrine administration in metabolically healthy and alloxan-diabetic dogs. In metabolically healthy animals after carbon monoxide intoxication followed by norepinephrine administration myocardial oedema occurred with a concomitant elevation of diastolic stiffness in the left ventricular wall, resulting in impaired cardiac performance. In the alloxan-diabetic animals no myocardial oedema developed and therefore no further increase of the originally elevated left ventricular diastolic stiffness could be observed. Close correlations were demonstrable between the enhanced water content and diastolic stiffness of the left ventricular wall in metabolically healthy animals as well as between the myocardial contractile force and cardiac output index in both control and diabetic dogs. In contrast to the controls, following norepinephrine administration per se decrease of cardiac performance could be observed in the alloxan-diabetic animals. Based on these results, it can be concluded that an increase of left ventricular diastolic stiffness impairs the cardiac performance in acute hypoxia following norepinephrine administration both in control and in diabetic animals, even if different reasons are responsible for it.

The aim of this study was to clarify the role of altered diabetic vascular reactivity in ischaemic heart disease. In diabetic condition, the necrotic area of myocardial infarction was significantly extended and myocardial oedema failed to develop after administration of norepinephrine 2 or 48 hours after ligation of the left anterior descending coronary artery. In metabolically healthy dogs the necrotic area of myocardial infarction was considerably smaller and an increase in myocardial water content, in myocardial thiocyanate space, in microscopically demonstrable permeability and in diastolic stiffness of left ventricular wall occurred when norepinephrine was administered 2 or 48 hours after coronary infarction. A close correlation was demonstrable between enhanced water content, thiocyanate space and diastolic stiffness in metabolically healthy animals, whereas in diabetic condition diastolic stiffness was primarily increased, and decreased when norepinephrine was infused after coronary ligation. Therefore, the altered vascular reactivity in diabetes is supposed to be responsible for the lack of oedema in the nonischaemic part of myocardium after norepinephrine infusion as well as for the size and severity of myocardial infarction.

Changes in myocardial water content, left ventricular diastolic stiffness, cardiac performance, coronary blood flow, myocardial contractile force, rate of change of myocardial force, and peak acceleration of the aortic volume flow were examined in twenty-five dogs during glucose-induced hyperosmolality before and after pancreatectomy, the latter with and without insulin treatment. Glucose-induced hyperosmolality accounted for myocardial dehydration, increased diastolic stiffness and consequent decrease of left ventricular performance only in the absence of insulin, while coronary blood flow, myocardial contractile force, rate of change of myocardial force and peak acceleration of the aortic volume flow increased independently from the presence or absence of insulin during the glucose-induced hyperosmolality. These findings suggest that the frequent development of heart failure in hyperosmolar diabetic coma could partly be explained by myocardial dehydration and by the consequent decrease in left ventricular compliance and performance.

Hypoglycaemic sulphonylureas inhibit the increased glycogenosis and glucose release of the rat perfused liver produced by β-adrenergic agonists. The β-receptor antagonist propranolol exerted a similar effect. Dichloroisoprenaline increases the hypoglycaemic effect of chlorpropamide given in doses ineffective in the intact rat. Hypoglycaemic sulphonylureas have no effect on the catecholamine sensitivity of the nictitating membrane and heart auricle of the cat, indicating that their ability to inhibit glycogenosis induced by β-receptor agonists is not due to a β-receptor antagonist activity as is the action of propranolol.

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.

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.

The effects of chronic antidiabetic treatment were examined in a clinically manifest, but non-ketotic diabetic animal model in which increased stabilization of steric structure in the cardiac connective tissue and left ventricular diastolic stiffness have been demonstrated. These changes accounted for decreased left ventricular performance during left ventricular afterload. Each of 8 diabetic dogs was given daily 8-16 IU of insulin, 250-750 mg carbutamide or 2-10 mg glibenclamide, respectively; doses were always adjusted to the actual metabolic requirements and findings were compared to those of 11 untreated diabetic and 6 healthy dogs. After three months, the hemodynamic and metabolic studies showed that the metabolically controlled diabetic dogs had less marked alterations in the connective cardiac tissue, left ventricular diastolic stiffness and performance. Apart from a considerable rise of arterial blood pressure during carbutamide treatment, no other difference was found in the cardiac actions of the three hypoglycemic agents tested.

To examine the mechanism of cardiac dysfunction in diabetes, total circulating blood volume, cardiac and stroke volumes were measured by radioisotope method in 44 patients with type 1 and type 2 diabetes. Considerable difference in actually circulating blood volume could be demonstrated in diabetic patients, which seemed to be dependent on the control of the carbohydrate metabolism. The achievement of well controlled carbohydrate metabolism in diabetics has a great importance with special respect also to the blood volumes.

Before the onset of histologically detectable alterations of diabetic arteries, a considerable decrease of vasodilation ability develops. The role of an altered prostaglandin biosynthesis in this phenomenon was investigated in connection to the altered vascular adrenergic mechanisms. The effect of phenylephrine on prostacyclin production of isolated coronary arterial rings (100 μmol/l) as well as on conductivity of the coronary arterial bed (7.5-15-30-60 pmol·kg−1·min−1) were compared in 12 metabolically healthy and 12 alloxan-diabetic (560 μmol/kg) dogs. Furthermore, the effect of phentolamine (5 μmol/l) on the prostacyclin and thromboxane productions of the isolated vessels (coronary, femoral and basilar arteries) was investigated by radioimmunoassay. Although the basal prostacyclin amounts synthesized by healthy and diabetic coronary vessels were not different (5.1±1.6 and 4.9±1.4pg/mg vessel/30 min), similarly to femoral and basilar arteries, the diabetic arterial rings produced significantly (p

The effect of chlorpropamide on theurinary excretion of glucose and nitrogen by phlorhidrinized fasting rats was studied. Chlorpropamide reduced phlorhizin glycosuria. Chlorpropamide alone produced the same increase of urinary nitrogen excretion as phlorhizin, while giving the 2 drugs together a further increase in the nitrogen excretion was not observed. It is concluded that chlorpropamide affects protein metabolism only by increasing glyconeogenesis in fasting rats.

Glycogenolysis in the liver produced by isoprenaline was inhibited by β-receptor blocking agents using the perfusion technique. Dichloroisoprenaline also inhibited spontaneous glucose release, as did α-receptor stimulation by noradrenaline.

The effect of propranolol and phenoxybenzamine on the decrease of glycogen content of the rat liver due to surgical operation was studied. It was found that propranolol lessens the decrease of the gly

Chlorpropamide present in concentrations of 50 or 100 mg./100 ml. reduces glucose output by isolated rat livers perfused with Tyrode's solution. The release of amino acid nitrogen was increased by chlorpropamide in livers perfused with glucose-free Tyrode's solution but was decreased when both chlorpropamide and glucose were present in the perfusing fluid. Chlorpropamide was without effect on urea production by the isolated perfused liver.

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.

The conductivity of the coronary arterial bed increased in healthy and decreased in alloxan-diabetic dogs in response to intracoronary administration of norepinephrine or sympathetic stimulation. This suggests a modification of adrenergic receptors sensitivity in diabetes.

Contractile responses of isolated coronary arteries from healthy and alloxan-diabetic dogs to prostaglandin F2α were enhanced by indomethacin and inhibited by prostaglandin I2. The potentiation by indomethacin was more prominent in diabetic vessels than in normal arteries.