Abnormal Cai2+ handling is the primary cause of mechanical alternans: study in ferret ventricular muscles

We tested the hypothesis that mechanical alternans of the heart is due to alternations in intracellular calcium (Cai2+) levels. Eight papillary muscles were isolated from the right ventricles of male ferrets and were chemically loaded with aequorin to record cytoplasmic Cai2+. To produce a steady-state mechanical alternans, the preparations were perfused with a physiological salt solution containing a low calcium concentration (0.25 mM), at 22 degrees C, and stimulated at 0.5-1.0 Hz in the presence of carbachol and propranolol. The aequorin signal (Cai2+) and isometric contraction were simultaneously recorded. In each muscle, the strong beats (beats with higher peak tension) were associated with larger Ca2+ transients than the weak beats. The relationships between peak Cai2+ and peak tension, both during strong and weak beats, were similarly modified by short-term frequency responses. On the other hand, the time courses of the isometric contractions and Ca2+ transients during strong beats and weak beats were superimposable. These data indicate that mechanical alternans is caused by an alternate change of Cai2+ available for activation of the myofilaments. Prolongation of the time for recycling Ca2+ by the sarcoplasmic reticulum, i.e., a depressed uptake function of the Ca2+ pump with concomitant slow transportation of Ca2+ from the uptake compartment to the release compartment in the sarcoplasmic reticulum, is suggested as a cause of the abnormal Cai2+ handling during mechanical alternans.