Heart failure and Ca++ activation of the cardiac contractile system: hereditary cardiomyopathy in hamsters (BIO 14.6), isoprenaline overload and the effect of APP 201-533.
In the present paper, two experimental models of heart failure, namely hereditary cardiomyopathy in hamsters (BIO 14.6) and cardiac insufficiency due to mild (0.06 microM) isoprenaline overload of rabbit isolated perfused hearts, were compared in terms of resulting alterations at the level of the functionally isolated contractile system of detergent/glycerol treated skinned cardiac fibres. As the main features of Ca activation of tension in these models, the following were found: 1. Within the same species (RB hamsters, BIO 14.6 hamsters or rabbits), the Ca sensitivity, measured as pCa for half maximal Ca activation, was invariably higher in left than in right ventricular skinned fibres. 2. During the development of hereditary cardiomyopathy (BIO 14.6), maximum Ca-activated tension, measured per unit cross-sectional area, was reduced in an age-dependent manner, without any significant reduction in Ca sensitivity. This effect appeared to be more pronounced in left than in right ventricles. 3. In skinned fibres from right or left ventricular papillary muscles from in vitro isoprenaline pretreated rabbit hearts, no significant alteration in the maximum Ca-activated tension (per unit area) was observed in comparison to non-pretreated control hearts, whereas the Ca sensitivity was reduced. Treatment of control or failing heart skinned fibres with cAMP showed no additivity to the Ca desensitization induced by isoprenaline pretreatment. 4. Skinned fibres from isoprenaline pretreated left ventricular rabbit hearts showed a higher susceptibility to the Ca sensitizing effect of APP 201-533 than fibres from unpretreated control hearts. Mild isoprenaline overload and hereditary cardiomyopathy both are forms of heart failure which are presumably not associated with a lack of activator Ca. It is concluded that cardiotonic agents increasing the cardiac myofibrillar sensitivity to Ca ions would be beneficial in both cases, representing a phenomenologically causative treatment in hearts failing due to isoprenaline pretreatment. A main advantage over "classical" cardiotonic agents like cardiac glycosides, beta adrenergic stimulants or phosphodiesterase inhibitors would be the absence of the risk of drug-induced Ca overload.
Herzig
J W
JW
Department Research CVS, Ciba-Geigy Ltd., Basle, Switzerland.
Gerber
W
W
Salzmann
R
R
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D006224:Cricetinae / Q000502:physiology*; D000242:Cyclic AMP / Q000494:pharmacology; D004195:Disease Models, Animal; D006333:Heart Failure / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol; D008297:Male; D009200:Myocardial Contraction; D010210:Papillary Muscles / Q000378:metabolism / Q000503:physiopathology; D011728:Pyridones / Q000494:pharmacology*; D011817:Rabbits; D013268:Stimulation, Chemical
D002316:Cardiotonic Agents; D011728:Pyridones; C045982:3-amino-6-methyl-5-phenyl-2(1H)-pyridinone; D000242:Cyclic AMP; D007545:Isoproterenol; D002118:Calcium