RADIOLIGAND BINDING AND INOTROPIC EFFECTS OF RYANODINE IN THE CARDIOMYOPATHIC SYRIAN-HAMSTER

We compared the radioligand-binding and inotropic effects of ryanodine [known specific regulator of sarcoplasmic reticulum (SR) calcium release channel] on BIO 14.6 cardiomyopathic Syrian hamsters with those on age-matched F1B controls. Scatchard analyses of [H-3]ryanodine binding to cardiac membranes prepared from 1-2-month-old BIO 14.6 and F1B Syrian hamsters revealed the presence of a significant increase in binding capacity (B(max) = 942 +/- 49 vs. 567 +/- 33 fmol/mg protein) with no difference in affinity (K(D) = 3.9 +/- 0.4 vs. 3.5 +/- 0.5 nM, p < 0.01). Ryanodine is a significantly less potent negative inotrope in isolated papillary muscles prepared from 1-2-month-old BIO 14.6 hamsters than in muscles from F1B controls (IC50 = 4.3 +/- 1 vs. 0.5 +/- 0.4-mu-M, p < 0.05). Ryanodine was 200-fold less potent in the 4-6-month-old myopathic muscles than in controls (IC50 = 20 +/- 5 vs. 0.1 +/- 0.01-mu-M, p < 0.01). A paradoxic positive inotropic effect of ryanodine observed in 4-6-month-old myopathic muscles at low concentrations was not seen in controls (EC(max) = 126 +/- 5% at 1 +/- 0.1 x 10(-8) M). These data support the presence of a defect both biochemical and physiologic in the ryanodine-sensitive SR calcium release channel in the BIO 14.6 cardiomyopathic Syrian hamster. Purification, cloning, sequencing, and expression studies will be required to distinguish among primary, secondary, intrinsic, and regulatory defects in the ryanodine-sensitive SR calcium release channel in the cardiomyopathic Syrian hamster.