Influence of diabetic state and that of different sulfonylureas on the size of myocardial infarction with and without ischemic preconditioning in rabbits.

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.

Metabolic energy metabolism in diabetes: therapeutic implications.

Diabetic alterations of myocardial metabolism result mainly from malfunctions of acetyl-coenzyme A carboxylase, carnitine-palmitoyl-transferase-I and pyruvate-dehydrogenase inducing an overshoot of fatty acid oxidation that inhibits glucose oxidation. Gene expression of pyruvate-dehydrogenase and glucose transporters and depression of the third step of the mitochondrial respiratory chain also contribute to the diabetic alterations of myocardial metabolism. Ischaemic cardiovascular alterations are common and treatment is rarely successful in cases of diabetes since fatty acid oxidation is the costliest metabolic pathway for oxygen. Thus, in diabetes, aerobic glycolysis gradually shifts to anaerobic glycolysis under ischaemia, with accumulation of lactate and acid metabolites that in turn induce myocardial deterioration, Animal experiments have demonstrated that elective depression of activity of carnitine-palmitoyl-transferase-I enzyme-activity promotes glucose oxidation and early rapid recovery of myocardial contractility, especially under diabetic conditions. To reduce diabetic alterations of myocardial metabolism, anti-diabetic treatment must be switched to insulin during the acute ischaemic and post-ischaemic period of coronary diseases. Trimetazidine optimizes energy metabolism by selectively inhibiting action of the 3-ketoacyl-coenzyme A thiolase enzyme involved in beta-oxidation and inhibiting the overshoot of fatty oxidation. Trimetazidine, as the first 3-ketoacyl-coenzyme A thiolase inhibitor, therefore provides permanent myocardial cytoprotection in stable angina pectoris. However, in our experience, this beneficial anti-anginal effect is only observed in well-controlled situations.

Hyperglycaemia alters the endothelium-dependent relaxation of canine coronary arteries.

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.

[From type 2 diabetes to metabolic X syndrome]. / A 2-es típusú cukorbetegségtöl a metabolicus X-syndromáig.

The more and more exact and simple determination of insulin provides an opportunity for exploration of the states of insulin resistance. It turned out hereby that the so-called type 1 diabetes is merely a consequence of insulin deficiency and it occurs mainly in the young. In contrary, the so-called type 2 diabetes is a multifactorial, often hyperinsulinaemic condition of insulin resistance and it occurs mainly in the adults. Furthermore, the epidemiological observations of the last decades elucidated that insulin resistance and compensating hyperinsulinaemia are common not only in type 2 diabetes but in other conditions as in ischaemic vascular diseases, hypertension, obesity, lipid alterations, coagulation disturbances, too. It became evident that the so-called late vascular complications of diabetes mellitus may develop before or without the existance of any disturbances in carbohydrate metabolism. These facts encouraged the recognition of metabolic syndrome-X. According to this hypothesis, insulin resistance and compensatorial hyperinsulinaemia are the causes of atherosclerosis, hypertension, upper body obesity, dyslipidaemia, type 2 diabetes and disturbances of coagulation. Following the last years, it became evident that hyperuricaemia, microalbuminuria and even type A personality are common in this syndrome of insulin resistance.

[New concepts in the therapy of diabetic cardiopathies]. / Uj szempontok a diabeteses cardiopathia kezelésében.

Most reasonable cause of diabetic cardiopathy might be the impaired energy fuel supply and metabolism producing inevitably a hypotic condition and needing myocardial cytoprotection. Under diabetic conditions glucose disposal of the heart muscle-decreases, but working myocardial cell remains penetrable for glucose even in the absence of insulin. Therefore, it is worth to stimulate aerobic glycolysis to protect diabetic heart from frequent ischaemic events induced by diabetic late complications, since fatty acids oxidation wastes more oxygen than glycolysis for ATP production. Trimetazidine has an original cytoprotective mode of action reducing oxygen demand without altering heart activity. Consequently, trimetazidine protects structure and functions of the ischemic myocardial cell. On the other hand, glycation and altered turnover of proteins play also an important role in the development of diabetic cardiopathy. Consequently, not only trimetazidine but aminoguanidine could also reduce the development of alterations in diabetic cardiopathy inhibiting the glycation of proteins. Finally, calcium antagonists are also very usefull in myocardial cytoprotection of the diabetic heart, according to the altered cellular calcium regulation and a calcium overload which play the main role in the development of diabetic cardiopathy.

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.

Role of vascular adrenergic mechanisms in the haemodynamic and PGI2 stimulating effects of angiotensin in diabetic dogs.

In aware of the well-known altered vascular responsiveness in the diabetic vasculature, this study aimed to compare the haemodynamic and PGI2 releasing effects of angiotensin in metabolically healthy (12) and alloxan-(560 umol/kg) diabetic (12) dogs as well as to analyze the role of vascular adrenoceptors in this. In vivo the effect of intracoronarially administered angiotensin (63-125-250-500-1000 pmol/kg/min) on coronary blood flow, mean arterial blood pressure, myocardial contractile force and heart rate was investigated without and with pretreatment of 2 umol/kg phentolamine. In vitro PGI2 release by isolated coronary rings was induced by 50 nmol/l angiotensin before and after pretreatment with 5 umol/l phentolamine and measured by radioimmunoassay. Angiotensin enhances dose-dependently both the mean arterial blood pressure and coronary blood flow, while it provokes a considerable (p < 0.05) increase of PGI2 formation by isolated coronary arterial rings. These alterations could be prevented by phentolamine administration both in vivo and in vitro, while this drug did not affect the angiotensin-induced enhancement of diabetic coronary blood flow. On the other hand the increase of blood pressure by angiotensin was found to be more (p < 0.05) expressed in diabetes and it could be further potentiated by phentolamine. PGI2 synthesis by isolated diabetic coronary rings could not be modified either by angiotensin alone or in combination with phentolamine. On the basis of above data, the lack of stimulated vascular PGI2 formation mediated by alpha-adrenergic mechanisms is supposed to causatively contribute to the diminished sensitivity of diabetic coronary arteries to vasodilation.

What kind of cardiovascular alterations could be influenced positively by oral antidiabetic agents?

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.

Comparison of the vasodilatory effects of bradykinin in isolated dog renal arteries and in buffer-perfused dog kidneys.

This study was undertaken to investigate the role of nitric oxide (NO), cyclooxygenase products and bradykinin (Bk) receptors in the Bk evoked responses of canine renal arteries and perfused kidneys. Rings of isolated canine renal arteries were mounted in organ chambers for measurement of isometric force. The isolated canine kidneys were perfused with Krebs-solution (constant flow) and the perfusion pressure was continuously recorded. The influence of the cyclooxygenase inhibitor indomethacin and the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginin (L-NOARG) on the vasocontractile responses to phenylephrine (PE) were examined in both preparations. Furthermore, the effects of Bk on the tone of canine isolated renal arteries and on the vasopressor responses of isolated buffer-perfused kidneys of dogs were tested in the absence and presence of enzyme inhibitors and the B2 kinin receptor antagonist HOE-140. It was found that indomethacin enhanced the contractile responses of large renal arteries to PE by 77 +/- 10%. In intact artery rings L-NOARG (0.1 mM) caused an additional potentiation of the PE-induced contractions in the presence of indomethacin (from 11.5 +/- 1.2 mN to 21.6 +/- 1.7 mN). However, L-NOARG failed to affect contractile responses to PE in endothelium-denuded rings. Bk produced a concentration-dependent relaxation of the precontracted endothelium-intact renal arteries. The IC50 value for Bk was 11.2 +/- 3.7 nM. The relaxant activity of the peptide in renal artery rings was not affected by indomethacin (3 microM). However, in the presence of L-NOARG a significantly higher concentration (IC50 = 860 +/- 300 nM) of Bk was required to relax renal arteries. The Bk receptor antagonist HOE-140 (10 nM for 40 min) attenuated the relaxant effect of Bk in renal artery rings (from an IC50 of 14.2 +/- 2.5 nM to 216 +/- 37 nM). Indomethacin (3 microM for 20 min) did not significantly alter the arteriolar vasoconstriction (from 45 +/- 4 mm Hg to 48 +/- 5 mm Hg, n = 5) evoked by PE. By contrast, L-NOARG (0.1 mM) potentiated (from 56 +/- 7 mm Hg to 94 +/- 11 mm Hg) the PE-induced vasopressor responses in perfused kidneys. Bk reduced the size of the pressor responses at relatively low concentrations (2-60 nM) but the dose-response curve was flat and the maximum inhibitory effect hardly exceeded 50 percent. Indomethacin (3 microM) did not modify the inhibitory effect of Bk in perfused kidney. In the presence of L-NOARG, Bk depressed the PE induced vasopressor effects with a maximum of 18 +/- 20%. Preincubation of the kidney preparations with the Bk antagonist HOE 140 (10 nM for 40 min) almost completely abolished the inhibitory effect of Bk on the PE induced vasopressor responses. The results suggest that the endothelial NO plays a fundamental role in the relaxant effect of Bk and considerably modulates vascular reactivity to PE in canine renal vasculature. Furthermore, significant difference exists between conduit and resistance vessels of dog's kidney in the effect of indomethacin on the adrenergic contractions.

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.

Captopril produces endothelium-dependent relaxation of dog isolated renal arteries. Potential role of bradykinin.

The effects of the angiotensin-converting enzyme inhibitors, captopril, lisinopril and enalapril-maleate (the latter being a prodrug that has to be converted into enalaprilat), and bradykinin were investigated in the presence or absence of indomethacin and bradykinin receptor antagonists in dog renal arterial rings precontracted with either prostaglandin F2 alpha or phenylephrine. At a high precontraction level (10 microM of prostaglandin F2 alpha), captopril did not relax the arteries. However, when the tension was low (0.5 microM), both captopril and lisinopril produced endothelium-dependent relaxations. The maximum relaxations for captopril and lisinopril were 57 +/- 6% and 64 +/- 15%, respectively. Enalapril-maleate failed to relax the renal arteries even when the vascular tone was low. In endothelium-intact arteries precontracted with phenylephrine (0.2 microM), captopril and lisinopril produced a maximum relaxation of 60 +/- 9% and 29 +/- 5%, respectively, in arteries with intact endothelium, whilst responses to enalapril-maleate were inconsistent. Renal artery rings with rubbed endothelium failed to relax in response to bradykinin or captopril. We observed significant variations in both captopril- and lisinopril-induced endothelium-dependent relaxations in one tenth of the preparations. The relaxations to bradykinin and captopril were not affected by indomethacin (3 microM), whereas they were markedly attenuated by NG-nitro-L-arginine (0.1 mM). The bradykinin-antagonist, N alpha-adamantane-acetyl-D-Arg-(Hyp3, Thi5,8, D-Phe7)BK, or the specific bradykinin2 receptor antagonist, HOE140, completely abolished the relaxation responses to captopril and reduced the potency of bradykinin, but failed to affect the acetylcholine-induced responses. The results suggest that the relaxant effect of captopril is mediated by endogenous bradykinin or by activation of bradykinin receptors. The proposed mechanisms by which captopril relaxes the renal arteries are: (1) inhibition of tissue kininase II, which leads to accumulation of endogenous bradykinin; (2) shift in angiotensin I metabolism towards (a) relaxant angiotensin derivative(s); and (3) interaction with bradykinin receptors.

[Pen-type insulin dispenser for intensive insulin therapy]. / A "pen" inzulinadagoló eszköz alkalmazása az intenzív inzulinkezelésben.

The authors investigate the advantage of the intensified insulin therapy and the use of pen-type devices in the practice of the Diabetic Outpatient Clinic of National Institute of Cardiology. The metabolic control improved markedly during intensified insulin therapy already after a short time as three months without any change in the applied dosage. Furthermore pen-type devices have been recognized to let the patients better accept the daily more than two injections, to improve the life-style, and last but not least to decrease the waste quantity of insulin. Authors want to draw attention to the fact that more than 33% of diabetic patients with intensified insulin therapy have a higher demand for insulin, then it could be injected by the pen devices used at this time and by cartridges available in Hungary at this moment. Therefore, availabilities of both cartridges of 3 ml volume would become necessary without any delay.

Disturbed lipid metabolism in diabetic coronary vessels.

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.

Effect of glimepiride on the electrical activity of isolated rabbit heart muscle.

The effect of glimepiride (CAS 93479-97-1) on the electrical threshold, conduction time, effective refractory period and automaticity of left atrium and right ventricle in the isolated rabbit heart was investigated and compared with those of chlorpropamide and glibenclamide. From the sulphonylureas investigated only glibenclamide diminished the electrical activity of rabbit heart muscle preparations. Chlorpropamide and glimepiride have a mild effect to change the basic parameters on the opposite direction. It seems that glimepiride does not have a significant effect on cardiac muscle in vitro.

The effect of sulphonylurea therapy on the outcome of coronary heart diseases in diabetic patients.

A retrospective study was performed on 1040 diabetic patients. The survival time of those treated with first generation sulphonylureas (n = 227) was considerably (P < 0.001) shorter after the first attack of angina pectoris (5 +/- 1 years, mean +/- S.E.) or acute myocardial infarction (6 +/- 1 years) than of those (9 +/- 1 years) on glibenclamide treatment (n = 144), with regime alone (n = 282) or treated with insulin (n = 387). The systolic blood pressure of patients with first generation sulphonylureas (166 +/- 1/91 +/- 1 mmHg) proved to be higher (P < 0.01) than those treated with glibenclamide (159 +/- 1/91 +/- 1 mmHg) or being on regime alone (155 +/- 1/89 +/- 1 mmHg) or on insulin (156 +/- 1/89 +/- 1 mmHg) treatments. Serum sodium level was found to be lower (P < 0.05) in patients treated with any kind of sulphonylureas (138 +/- 1 mmol/l) than in the other patients (143 +/- 1 mmol/l). During an observation period, 576 of patients died, 412 of them due to cardiovascular or renal failures. Among the diabetic subjects suffering from coronary heart disease no difference could be detected in risk factors except for higher systolic blood pressure. The shorter survival time of patients treated with first-generation sulphonylureas might be explained by the arrhythmogenic activity of first-generation sulphonylureas. Improvement in therapy, metabolic and cardiovascular alterations during the survey can not be responsible for the shorter survival time of patients treated with first generation-sulphonylureas.

[Diabetic cardiopathy. Pathophysiologic concepts and therapeutic approaches]. / Diabetische Kardiopathie. Pathophysiologische Konzepte und therapeutische Ansätze.

Epidemiological data reviewed suggest that diabetes itself increases the cardiac risk of diabetics (types I and II), independently from the development of coronary heart disease and in addition to other risk factors (hypertension, hypercholesterolemia, hypertriglyceridemia, smoking and others), presumably by a specific myocardial disease called "diabetic cardiopathy", or according to the recommendations of the WHO, "diabetic heart muscle disease." Disturbances of the left and right ventricular function as well as the autonomic function of the heart can be understood as signs of this specific cardiopathy. The pathophysiological mechanisms underlying this disease are not yet fully known; however, recent evidence is presented that diabetes leads to a facet of metabolic dysfunctions regarding glucose and energy metabolism, calcium homeostasis and the expression of specific proteins that diminish the ability of the heart to respond to increased workload and increase the vulnerability of the heart in diabetes. Since preliminary experimental data indicate that inhibitors of the angiotensin-converting enzyme can protect the heart in diabetes, it is intriguing to suggest that increased release of angiotensin II plays a significant role in the change from reduced adaptability to irreversible damage of the heart in diabetes.

[Amidaron-induced dermatopathy resulting from unnecessary Cordarone therapy of ventricular parasystole]. / Kamrai parasystolia felesleges Cordarone-kezelése kapacsán jelentkezö amiodaron-dermatopathia.

The case history of a patient is reported who was treated with a variety of antiarrhythmics over a period of years because of refractory ventricular "bigeminy". As the arrhythmia did not respond to any kind of therapy, amiodarone treatment was started, which the patient received in a maintenance dose of 600-400 mg/day for 4 years. More recently, a bluish-grey hyperpigmentation of the face and other areas of the skin exposed to sunlight developed. A cutaneous biopsy of the hand revealed pigment deposits and lamellated lysosomal inclusions characteristic for amiodarone dermatopathy. The interactive, computer-assisted analysis of the ventricular ectopic activity has clearly demonstrated its innocent, parasystolic nature. The differentiation between ventricular extrasystolic and parasystolic activity is essential, because the latter arrhythmia does not require specific antiarrhythmic pharmacotherapy.

[Prospective study of cardiac autonomic neuropathy in diabetes mellitus]. / Kardiális autonom neuropathia prospektív vizsgálata diabetes mellitusban.

For assessment of clinical and prognostic values of cardiac autonomic neuropathy, 53 patients with diabetes mellitus were followed-up for five years. Parasympathetic innervation was assessed by recording heart rate variability during deep breathing, Valsalva manoeuvre and lying-to-standing while sympathetic function was evaluated by measuring postural change in systolic blood pressure. During the follow-up period 1 of 23 diabetic patients died in group without signs of cardiac autonomic neuropathy whereas 2 of 13 diabetics and 10 of 17 diabetics deceased in groups with mild and definitive signs of cardiac autonomic neuropathy, respectively. At reinvestigation, the values of tests for parasympathetic impairment worsened or did not change significantly while improvement in these tests was only exceptionally observed in 40 diabetic patients. No significant change in values of test for sympathetic function was documented during the follow-up period suggesting that parasympathetic (vagal) impairment might precede the sympathetic dysfunction during development of autonomic neuropathy in diabetic patients. No correlation was observed between changes in cardiac autonomic neuropathy and alterations in distal somatic neuropathy (assessed by measurement of motor nerve conduction velocity in peroneal nerves) during the prospective study. Definitive cardiac autonomic neuropathy--as one of the late complications of diabetes mellitus--suggests poor prognosis in diabetic patients.

Is malondialdehyde a marker of the effect of oxygen free radicals in rat heart tissue?

We tested the effect of exogenous purine derived free radicals and H2O2 vs ischemia and reperfusion on the thiobarbituric-acid (TBA)-reactive material and malondialdehyde (MDA) formation in isolated rat hearts using the thiobarbituric acid test and high performance lipid chromatography (HPLC). We could not detect increased thiobarbituric-acid-reactive material or MDA production during 6 mM H2O2 infusion, during free radical generation by purine-derived free radicals, or using ischemia and reperfusion. Increased thiobarbituric-acid-reactive material and MDA tissue levels were detected only during infusion of 12 mM H2O2 (p less than 0.001). We conclude that the generally used thiobarbituric acid assay for MDA is susceptible to artifacts and unsuited as an indirect measure for low-to-medium-levels of oxygen free radicals. Using HPLC assay, which accurately measures MDA, no evidence was found that MDA is a primary and direct lipid peroxidation product of exogenous or endogenous reactive oxygen species.