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

Abstract

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.

Different Sensitivity to Isoprenalin in Mice of Two Strains and Its Changes with Age

“…The sensitivity to ISO depends on age, with young animals being more resistant (Faltova et al 1983a;Kojima 1983;Herzig et al 1987), sex (Faltova et aI. 1980) and body mass (Faltova et aI.…”

Ca2+ Sensitization of Myocardial Force and Actomyosin ATPase by (D-Ala2, Met5) Enkephalinamide

“…Thin fibres with a diameter of 0.1-0.3 mm and a length of 4-6 mm were attached to a mechanical equipment designed for isometric force measurement as described by Herzig et al [18], using the isometric contraction sensor AE 801 (Senso Nor a.a., Horten, Norway). Contractions were elicited by incubation of the fibres in solutions with various EGTA-buffered Ca 2+ concentrations, containing Na 2 ATP, while phosphoenolpyruvate and pyruvate kinase served as an ATP regenerating system.…”

New mechanisms for positive inotropic agents: Focus on the discovery and development of imazodan

“…Increasing cardiac contractility without increasing cytosolic calcium represents an attractive mechanism for a positive inotropic agent, since increasing intracellular calcium in the failing heart may precipitate calcium overload and cell death [54,55]. In a recent report, Weishaar et al [56] showed that chronic administration of digitalis to cardiomyopathic hamsters exacerbated the rise in myocardial calcium normally observed in these animals and also increased the incidence of myocardial necrosis.…”

“…These other agents include pimobendan [54], MCI-154 [57], BM 14.578 [58], APP 201-533 [55], and DPI-201-106 [59]. Most of these agents, however, have been shown to exert other actions that could increase cardiac contractility, including inhibition of phosphodiesterase (pimobendan and sulmazole), inhibition of Na, KATPase (sulmazole), and stimulation of the sodium fast channel (DPI-201-106) [60][61][62][63].…”