DIFFERENCES IN CARDIOPROTECTIVE EFFICACY OF ADRENERGIC-RECEPTOR ANTAGONISTS AND CA2-MODEL OF DILATED CARDIOMYOPATHY - EFFECTS ON GROSS MORPHOLOGY, GLOBAL CARDIAC-FUNCTION, AND TWITCH FORCE( CHANNEL ANTAGONISTSIN AN ANIMAL)

Turkey poults fed furazolidone (Fz) in high concentrations (700 ppm) d evelop dilated cardiomyopathy (Fz-DCM). We tested whether five cardioa ctive agents were cardioprotective in this model of heart failure, ie, whether they prevented dilatation and wall thinning and improved cont ractile performance. We compared the effects of chronic administration of a beta1-selective and a nonselective beta-receptor antagonist, an a-receptor antagonist, and two Ca2+ channel antagonists in the presenc e of Fz administration. The greatest cardioprotection was found with t reatment with either propranolol or nifedipine. At the gross morpholog ical level, the effect of propranolol (a nonselective beta-adrenergic antagonist) was greater than the effect of atenolol (a selective beta1 -adrenergic antagonist), and the effect of nifedipine was greater than that of verapamil (Ca2+ channel antagonists), with all agents more ca rdioprotective than phenoxybenzamine (an alpha1-adrenergic>alpha2-adre nergic antagonist). Differences in cardioprotective efficacy of each a gent increased with increased concentration. These data indicate that the dose and choice of a specific type of Ca2+ channel antagonist or b eta-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 le vels. Compared with control animals, Fz-DCM animals showed a significa nt reduction in peak left ventricular (LV) developed pressure (92+/-17 versus 143+/-24 mm Hg, P<.05), +dP/dt (1151+/-219 versus 2454+/-549 m m Hg/s), and -dP/dt (1128+/-291 versus 1875+/-396 mm Hg/s), with a sig nificant increase in LV end-diastolic volumes (2.8+/-0.7 versus 0.16+/ -0.1 mL for control animals, P<.05). In contradistinction, LV +dP/dt a nd -dP/dt values for animals receiving Fz plus a cardioactive agent th at 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 cont rol animals not receiving any pharmacologic agent. Isolated muscles fr om Fz-DCM animals as well as animals receiving Fz plus cardioprotectiv e pharmacologic agents responded normally with regard to increasing ex tracellular Ca2+ concentrations. Peak twitch forces were greater for a nimals receiving cardioprotective agents plus Fz than control animals not receiving any pharmacologic agents or Fz alone. At higher stimulat ion rates, Fz-DCM muscles demonstrated a significantly reduced peak tw itch force (4+/-0.5 versus 1.5+/-0.4 g/mm2 for control muscles versus Fz-DCM muscles, respectively). The negative effect of higher stimulati on rates on peak twitch force was reversed by agents demonstrating the greatest cardioprotection, eg, propranolol and nifedipine. Finally, m uscles from hearts treated with agents shown to be cardioprotective in terms of mechanical performance also had a higher tissue content of c ertain enzymes important for maintaining normal energy (ATP) supply an d 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 pr otection provided by drugs from a similar functional class, it is like ly that these cardioactive agents act via mechanisms other than a redu ction in heart rate or blood pressure. Rather, we suggest that these a gents result in macromolecular remodeling in the myocyte that is condu cive to preserved contractile performance.