Studies in excitation-contraction coupling in isoproterenol-induced hypertrophied rat heart.

Cardiac hypertrophy was induced by daily subcutaneous injections of isoproterenol (0.3 mg/kg. body weight) for 12 consecutive days. A significant increase in whole ventricular weight (35.7%) was achieved. Regionally, the right ventricle produced a greater hypertrophy response than the left ventricle. Contractile force, +Dt/dt, and $-$DT/dt in right ventricular trabecular muscle were significantly increased, suggesting that either Ca$\sp{2+}$ responsiveness of the myofilaments or the availability of (Ca$\sp{2+}\rbrack\rm\sb i$ was increased. The Ca$\sp{2+}$ sensitivity of the myofilaments was investigated using a Triton-100 skinned trabecular preparation. The force-pCa relationship showed no difference in the myofilament Ca$\sp{2+}$ sensitivity. The force-interval relationship was studied to reflect the early recovery of SR Ca$\sp{2+}$ release channels and the late diastolic Ca$\sp{2+}$ influx via sarcolemmal Na-Ca exchange. The SR Ca$\sp{2+}$ release characteristics were not altered, however, Ca$\sp{2+}$ influx via sarcolemmal Na-Ca exchange was enhanced in hypertrophied muscle. A biphasic rate staircase was found in trabecular muscle: negative from 0.1 to 0.5 Hz and positive from 0.5 to 2.5 Hz. Studies using rapid cooling contractures (RCCs) suggest that SR Ca$\sp{2+}$ content determines the amounts of SR Ca$\sp{2+}$ release. Ryanodine, which unloads SR Ca$\sp{2+},$ abolished the negative rate staircase. Nifedipine, $\rm I\sb{Ca}$ blocker, eliminated the positive response. These results suggest that diastolic SR Ca$\sp{2+}$ loading, probably via Na-Ca exchange, contributes to the negative phase, whereas Ca$\sp{2+}$ influx via L-type channel dominates the positive phase. In hypertrophied muscle ((Ca$\rm\sp{2+}\rbrack\sb o$ = 0.5 mM), the positive rate staircase was significantly enhanced, indicating an increased functioning of L-type Ca$\sp{2+}$ channel and a greater SR Ca content. There was a frequency-dependent prolongation of APD$\sb{50}$ and the APD$\sb{50}$ was significantly increased in hypertrophied muscle, suggesting that Ca$\sp{2+}$ influx, probably via $\rm I\sb{Ca},$ was increased with frequency and this pathway was significantly amplified in hypertrophied muscle. The capacity to remove cytoplasmic Ca$\sp{2+}$ was increased by either SR Ca-ATPase pump or sarcolemmal Na-Ca exchange in hypertrophied muscle. In summary, the increased (Ca$\rm\sp{2+}\rbrack\sb i$ handling pathways, such as $\rm I\sb{Ca},$ SR Ca$\sp{2+}$ content, Na-Ca exchange activity, and SR Ca-ATPase pump, contribute to the enhanced contractile function in hypertrophied muscle.Dept. of Biological Sciences. Paper copy at Leddy Library: Theses & Major Papers - Basement, West Bldg. / Call Number: Thesis1993 .T36. Source: Dissertation Abstracts International, Volume: 56-01, Section: B, page: 0116. Adviser: P. B. Taylor. Thesis (Ph.D.)--University of Windsor (Canada), 1993.