Differences in Cardioprotective Efficacy of Adrenergic Receptor Antagonists and Ca: Effects on Gross Morphology, Global Cardiac Function, and Twitch Force2+: Effects on Gross Morphology, Global Cardiac Function, and Twitch Force Channel Antagonists in an Animal Model of Dilated Cardiomyopathy: Effects on Gross Morphology, Global Cardiac Function, and Twitch Force

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Abstract

Turkey poults fed furazolidone (Fz) in high concentrations (700 ppm) develop dilated cardiomyopathy (Fz-DCM). We tested whether five cardioactive agents were cardioprotective in this model of heart failure, ie, whether they prevented dilatation and wall thinning and improved contractile performance. We compared the effects of chronic administration of a β1-selective and a nonselective β-receptor antagonist, an β-receptor antagonist, and two Ca2+ channel antagonists in the presence of Fz administration. The greatest cardioprotection was found with treatment with either propranolol or nifedipine. At the gross morphological level, the effect of propranolol (a nonselective β-adrenergic antagonist) was greater than the effect of atenolol (a selective β1-adrenergic antagonist), and the effect of nifedipine was greater than that of verapamil (Ca2+ channel antagonists), with all agents more cardioprotective than phenoxybenzamine (an βl-adrenergic>β2-adrenergic antagonist). Differences in cardioprotective efficacy of each agent increased with increased concentration. These data indicate that the dose and choice of a specific type of Ca2+ channel antagonist or β-receptor antagonist might be important in the treatment of dilated cardiomyopathy. All agents that were cardioprotective caused similar functional improvements at both the whole heart and isolated muscle levels. Compared with control animals, Fz-DCM animals showed a significant reduction in peak left ventricular (LV) developed pressure (92±17 versus 143±24 mm Hg, P<.05), +dP/dt (1151±219 versus 2454±549 mmHg/s), and -dP/dt (1128±291 versus 1875±396 mm Hg/s), with a significant increase in LV end-diastolic volumes (2.8±0.7 versus 0.16±00. mL for control animals, P<.05). In contradistinction, LV +dP/dt and - dP/dt values for animals receiving Fz plus a cardioactive agent that demonstrated cardioprotection were not significantly different from control values. Peak LV developed pressures were also similar for Fz animals receiving an agent that demonstrated cardioprotection and control animals not receiving any pharmacologic agent. Isolated muscles from Fz-DCM animals as well as animals receiving Fz plus cardioprotective pharmacologic agents responded normally with regard to increasing extracellular Ca2+ concentrations. Peak twitch forces were greater for animals receiving cardioprotective agents plus Fz than control animals not receiving any pharmacologic agents or Fz alone. At higher stimulation rates, Fz-DCM muscles demonstrated a significantly reduced peak twitch force (4±0.5 versus 1.5±0.4 g/mm2 for control muscles versus Fz-DCM muscles, respectively). The negative effect of higher stimulation rates on peak twitch force was reversed by agents demonstrating the greatest cardioprotection, eg, propranolol and nifedipine. Finally, muscles from hearts treated with agents shown to be cardioprotective in terms of mechanical performance also had a higher tissue content of certain enzymes important for maintaining normal energy (ATP) supply and normal sarcoplasmic reticulum function. These studies indicate that gross morphological changes correlate with contractile performance at the whole heart and isolated muscle level. Because of the different protection provided by drugs from a similar functional class, it is likely that these cardioactive agents act via mechanisms other than a reduction in heart rate or blood pressure. Rather, we suggest that these agents result in macromolecular remodeling in the myocyte that is conducive to preserved contractile performance.

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