title: Mechanisms that may be involved in calcium tolerance of the diabetic heart.
abstract: In diabetes the hearts exhibit impaired membrane functions, but also increased tolerance to Ca2+ (iCaT) However, neither the true meaning nor the molecular mechanisms of these changes are fully understood. The present study is devoted to elucidation of molecular alterations, particularly those induced by non-enzymatic glycation of proteins, that may be responsible for iCaT of the rat hearts in the stage of fully developed, but still compensated diabetic cardiomyopathy (DH). Insulin-dependent diabetes (DIA) was induced by a single i.v. dose of streptozotocin (45 mg.kg-1). Beginning with the subsequent day, animals obtained 6 U insulin daily. Glucose, triglycerides, cholesterol and glycohemoglobin were investigated in blood. ATPase activities, the kinetics of activation of (Na,K)-ATPase by Na+ and K+, further the fluorescence anisotropy of diphenyl-hexatriene as well as the order parameters of membranes in isolated heart sarcolemma (SL) were also investigated. In addition, the degree of glycation and glycation-related potency for radical generation in SL proteins were determined by investigating their fructosamine content. In order to study calcium tolerance of DH in a 'transparent' model, hearts were subjected to calcium paradox (Ca-Pa, 3 min of Ca2+ depletion; 10 min of Ca2+ repletion). In this model of Ca(2+)-overload, Ca2+ ions enter the cardiac cells in a way that is not mediated by receptors. Results revealed that more than 83% of the isolated perfused DH recovered, while the non-DIA control hearts all failed after Ca-Pa. DH exhibited well preserved SL ATPase activities and kinetics of (Na,K)-ATPase activation by Na+, even after the Ca-Pa. This was considered as a reason for their iCaT. Pretreatment and administration of resorcylidene aminoguanidine (RAG 4 or 8 mg.kg-1) during the disease prevented partially the pathobiochemical effects of DIA-induced glycation of SL proteins. DIA-induced perturbations in anisotropy and order parameters of SL were completely prevented by administration of RAG (4 mg.kg-1). Although, the latter treatment exerted little influence on the (Na,K)-ATPase activity, it decreased the calcium tolerance of the DH. Results are supporting our hypothesis that the glycation-induced enhancement in free radical formation and protein crosslinking in SL may participate in adaptive mechanisms that may be also considered as 'positive' and are responsible for iCaT of the DH.
authors.affiliation: Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic.
authors.forename: A
authors.initials: A
authors.lastname: Ziegelhöffer
authors.forename: T
authors.initials: T
authors.lastname: Ravingerová
authors.forename: J
authors.initials: J
authors.lastname: Styk
authors.forename: J
authors.initials: J
authors.lastname: Seboková
authors.forename: I
authors.initials: I
authors.lastname: Waczulíková
authors.forename: A
authors.initials: A
authors.lastname: Breier
authors.forename: A
authors.initials: A
authors.lastname: Dzurba
authors.forename: K
authors.initials: K
authors.lastname: Volkovová
authors.forename: J
authors.initials: J
authors.lastname: Cársky
authors.forename: L
authors.initials: L
authors.lastname: Turecký
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D009202:Cardiomyopathies / Q000150:complications / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000150:complications / Q000201:enzymology; D019270:Fructosamine / Q000032:analysis; D006146:Guanidines / Q000494:pharmacology*; D006454:Hemoglobins / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012508:Sarcolemma / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D006146:Guanidines; D006454:Hemoglobins; D014280:Triglycerides; D019270:Fructosamine; D002784:Cholesterol; D012964:Sodium; D017301:Ca(2+) Mg(2+)-ATPase; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium; D002118:Calcium