Defective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy

The effects of insulin and thyroid hormone treatments on cardiac sarcoplasmic reticular function were investigated in chronic streptozotocin-induced diabetes in rats. ATP-dependent Ca2+ transport and Ca2+-stimulated ATPase activities were depressed significantly in microsomal samples from diabetic rats in comparison with control (P less than 0.05). This defect was seen at various times of incubation (1-20 min) and different concentrations of free Ca2+ (10(-7) to 10(-5) M Ca2+) and was accompanied by changes in the protein composition and phospholipid contents of the microsomal fraction. The defect in calcium transport in microsomal vesicles was not evident until 28 days after streptozotocin (65 mg/kg iv) injection, whereas increases in plasma glucose levels due to insulin-deficiency occurred within 3 days. All changes in function and composition of the sarcoplasmic reticulum were reversed by insulin administration to the diabetic rats. Although the plasma level of thyroid hormone was decreased in the diabetic rat, thyroid hormone treatment did not restore microsomal calcium transport in the diabetic animals. The results of this study provide some evidence that the depression in cardiac sarcoplasmic reticular calcium accumulation during diabetes is a consequence of insulin deficiency and associated chronic metabolic changes but the hypothyroid condition that accompanies experimental diabetes does not appear to play any role in this defect.     

Alterations of sarcolemmal Na+-Ca2+ exchange in catecholamine-induced cardiomyopathy

Rats were injected intraperitoneally with 40 mg/kg body weight isoproterenol and the heart sarcolemma was isolated 3, 9 and 24 hours later. The heart/body weight ratio increased and varying degrees of change in cardiac ultrastructure were apparent at 9 and 24 hours after isoproterenol injection. Na+-dependent Ca2+ uptake activities of heart sarcolemma were depressed at 3, 9 and 24 hours; such alterations in 24 hour preparations were evident at different times of incubation and at different concentrations of Ca2+. No differences in Na+-induced Ca2+ release or Na+-K+ ATPase activities were observed between the control and experimental membranes. The control and isoproterenol-treated heart sarcolemmal preparations were minimally but equally contaminated by other subcellular organelles. Although there was no significant change in the phospholipid composition, the protein pattern as determined by gel electrophoresis was altered in sarcolemma at 24 hours of isoproterenol treatment. These results indicate an abnormality of heart sarcolemmal Na+-dependent Ca+ uptake during the development of catecholamine-induced cardiotoxicity. It is suggested that a depression in the ability of the cell to remove Ca2+ through the Na+-Ca2+ exchange in sarcolemma may contribute to the development of intracellular Ca2+ overload in catecholamine induced cardiomyopathy.     

Myocardial cell damage and cardiovascular changes due to i.v. infusion of adrenochrome in rats.

In vivo effects of adrenochrome (1-32 mg/kg), an oxidation product of catecholamines, on the heart ultrastructure, ECG and blood pressure were studied in rats over a period of 60 min following a single i.v. injection of the drug. One milligram of the drug had no influence on the myocardium or the cardiovascular system, whereas maximum changes in these parameters were recorded at 32 mg/kg of adrenochrome. The maximum structural damage, reached within 5-10 min, included marked swelling of mitochondria and sarcotubular system, intracellular and perinuclear oedema, hypercontraction of myofibrils and partial separation of the intercalated disc. Ultrastructural changes in the myocardium due to 4 and 8 mg of adrenochrome were not accompanied by any cardiovascular effects and the changes were fully reversed within 60 min of the injection of the drug. However, at 16 and 32 mg/kg of adrenochrome both heart rate and blood pressure were depressed within 5 min of drug administration. At these concentrations of adrenochrome arrhythmias, mainly due to premature ventricular contractions, were also noticed. Ultrastructural and cardiovascular changes seen at these higher concentrations of adrenochrome showed only a partial recovery. The data indicates that adrenochrome-induced ultrastructural changes in the heart are due to a direct myocardial effect of the drug which may not involve haemodynamic changes and the latter are most probably a consequence of this effect. However, the present study has not been able to rule out direct vascular effects at higher concentrations of adrenochrome.     

Alterations of phosphatidylethanolamine N-methylation in rat heart by quinidine

To elucidate the molecular mechanism underlying the adverse depression of myocardial contractility observed during antiarrhythmic therapy of quinidine, we investigated its action on the phosphatidylethanolamine N-methyltransferase (EC 2.1.1.17) activities of cardiac subcellular membranes. Rat heart sarcolemma, mitochondria, and microsomes (sarcoplasmic reticular fragments) were isolated, and the three catalytic sites for N-methylation activities were examined with 0.055 (site I), 10 (site II), and 150 (site III) microM concentrations of S-adenosyl-L-[methyl-3H]methionine as a methyl donor. Total methyl group incorporation into sarcolemmal phosphatidylethanolamine was depressed by 10(-6)-10(-3) M quinidine at sites II and III. The activity of site I was stimulated at low (10(-9) M) concentrations and inhibited at high concentrations of the drug. A similar behaviour was observed with procainamide, although the inhibitory effect was less pronounced and was not additive with quinidine. Quinidine-induced inhibition was associated with a depression of Vmax, while the apparent affinity for S-adenosyl-L-methionine was unaltered. Analysis of individual methylated phospholipids confirmed inhibition by quinidine at sites II and III in sarcolemma. Microsomal phosphatidylethanolamine N-methylation was affected by 10(-6) M quinidine only at site II, whereas no changes were noted in mitochondria. Quinidine also inhibited both the positive inotropic response and concomitant increase in tissue N-methylated phospholipids observed upon L-methionine perfusion of rat heart. These results suggest that quinidine alters the intramembranal level of N-methylated phospholipids, and this may serve as a biochemical mechanism contributing to its negative inotropic effect.     

Cardiac effects of beta-adrenergic receptor antagonists: beta-moderators versus beta-blockers

Two adrenergic receptor antagonists, acebutolol and propranolol, were observed to depress rabbit heart contractile force and adrenaline-stimulated adenylate cyclase activity at 1 X 10-(5) to 1 X 10-(3) M and 1 X 10-(6) to 1 X 10-(3) M concentrations, respectively. Acebutolol depressed sarcoplasmic reticular and mitochondrial calcium uptake at 5 X 10-(3) to 10-(2) M concentrations. On the other hand, propranolol was found to decrease calcium uptake activities of sarcoplasmic reticular and mitochondrial fractions at 1 X 10-(4) to 1 X 10-(2) M and 1 X 10-(3) to 1 X 10-(2) M concentrations, respectively. On the basis of these results with calcium transport systems, it is proposed that beta-antagonists with a mild depressant effect, such as acebutolol, may be called beta-moderators, whereas those with a strong effect, such as propranolol, may be called beta-blockers.     

Cardiac myofibrillar ATPase activity in diabetic rats

Diabetes was induced by an intravenous injection of 65 mg/kg streptozotocin and hearts were removed 8 weeks later for the isolation of myofibrils. The basal ATPase activity of myofibrils from diabetic hearts was significantly lower than the controls. Although Ca²⁺-stimulated ATPase activity was also depressed in diabetic myocardium, the dependency of diabetic myofibrils on free calcium concentration was not different from that of control. The basal and Ca²⁺-stimulated ATPase activities in diabetic rats demonstrated a greater sensitivity to KCl than control preparations. The myofibrillar basal ATPase, unlike Ca²⁺-stimulated ATPase, in diabetic animals exhibited a greater sensitivity to ethylene glycol. These results support the view regarding the presence of some subtle structural and conformational changes in diabetic myofibrils.     

Retinal pigment epithelial tear following intravitreal pegaptanib sodium

PURPOSE: To report two cases of a retinal pigment epithelial tear after intravitreal injection of pegaptanib sodium. To our knowledge, this is the first report of this finding after intraocular antivascular endothelial growth factor therapy. DESIGN: Observational case reports. METHODS: Two patients presented with occult choroidal neovascularization and associated serous pigment epithelial detachment that was a result of age-related macular degeneration. Both patients were treated with an intravitreal injection of pegaptanib sodium. RESULTS: One patient developed a retinal pigment epithelium tear one week after the intravitreal injection. The second patient developed a retinal pigment epithelium tear eight weeks after treatment. CONCLUSIONS: Although these cases may represent natural history, there should be a high index of suspicion for retinal pigment epithelium tears in patients who report significant visual deterioration after intravitreal injection of pegaptanib sodium. Further studies are needed to determine whether angiographic subtypes of choroidal neovascular membranes are more susceptible to developing retinal pigment epithelium tears after treatment with antivascular endothelial growth factor agents.     

Pigmentary maculopathy in a patient with Wolfram syndrome

CASE REPORT: We describe a rare association of pigmentary maculopathy with Wolfram syndrome not previously reported in the literature. A 12-year-old boy presented to the retina service with a diagnosis of Wolfram syndrome and a history of poor central vision. The patient was found to have bilateral atrophic pigmentary maculopathy that was confirmed with fluorescein angiography. COMMENTS: Wolfram syndrome may present with a pigmentary maculopathy and this rare finding may assist the clinician in making appropriate genetic referral when this diagnosis is suspected.