Cellular basis for contractile dysfunction in the diaphragm from a rabbit infarct model of heart failure

Abnormal respiratory muscle function is thought to contribute to breathless ness and exercise intolerance in heart failure but little is known about po ssible alterations in the function of such muscle. We have measured tetanic force and intracellular Ca2+ concentration ([Ca2+](i)) in isolated, arteri ally perfused hemidiaphragm preparations from a rabbit coronary artery liga tion model of heart failure. Increasing stimulation frequency (10-100 Hz) c aused a progressive increase of force and [Ca2+](i) in control preparations , whereas force and [Ca2+](i) only increased between 10 and 25 Hz stimulati on (decreasing at higher frequencies) in preparations from ligated animals. Cyclopiazonic acid produced a dose-dependent shift in the relationship bet ween stimulation frequency and [Ca2+](i) in control preparations that was s imilar to the shift observed in the diaphragm of coronary-ligated animals. These data indicate that the in vitro contractile characteristics of the di aphragm are significantly altered in our model and that altered [Ca2+](i) r egulation contributes to the reduced diaphragm strength observed in heart f ailure.