Tedisamil attenuates foetal transformation of myosin in the hypertrophied rat myocardium.
1 Reduction in repolarizing potassium currents has controversial effects on hypertrophic responses in cardiomyocytes of transgenic models and cultured cardiomyocytes. It remains thus unknown whether a blockade of potassium channels with tedisamil (N,N'dicyclopropylmethylene-9,9-tetramethylene-3,7-diazabicyclo(3.3.1)nonane dihydrochloride) has any effects on cardiac growth during postnatal development or pressure overload. 2 To test the hypothesis that a treatment with tedisamil affects cardiac growth or protein phenotype, sham-operated rats and rats with ascending aorta constriction were treated with tedisamil (36 mg kg day(-1)) for 7 weeks. Left ventricular mass and geometry, relative expression of myosin isoforms, hydroxyproline concentration and isovolumic ventricular function were assessed. 3 Rats with aortic constriction exhibited a marked increase in left ventricular weight and the diastolic pressure-volume relationship was shifted to smaller volumes. The hydroxyproline concentration remained unaltered. The proportion of alpha-myosin heavy chains was, however, reduced (P<0.05). Hypertrophied left ventricles manifested an enhanced overall performance but depressed myocardial contractility. 4 Administration of tedisamil was associated with decreased heart rate (P<0.05). In contrast, cardiac growth in sham-operated rats and concentric left ventricular hypertrophy of pressure-overloaded animals was not significantly altered. Hypertrophied hearts from rats treated with tedisamil expressed more alpha-myosin heavy chains (65+/-4 versus 57+/-4%; P<0.05). Also, maximal rate of wall stress rise and decline was higher (P<0.05) in tedisamil-treated pressure-overloaded rats. 5 In the rat model of pressure-overloaded hypertrophy, tedisamil had no effect on cardiac growth but partially corrected myocardial dysfunction. Postulated mechanism of this effect is the phenotype modification of myosin filaments in hypertrophied myocardium.
Department of Physiology, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait. mturcani@gmx.net
Marian
M
Turcani
Dirk
D
Thormaehlen
Heinz
H
Rupp
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology*; D004562:Electrocardiography; D005333:Fetus / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects; D006909:Hydroxyproline / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009218:Myosins / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left / Q000502:physiology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002316:Cardiotonic Agents; D003521:Cyclopropanes; D007527:Isoenzymes; D003094:Collagen; C059921:tedisamil; D009218:Myosins; D006909:Hydroxyproline