COMPENSATORY ASYMMETRY IN DOWN-REGULATION AND INHIBITION OF THE MYOCARDIAL CA2+ CYCLE IN CONGESTIVE-HEART-FAILURE PRODUCED IN DOGS BY IDIOPATHIC DILATED CARDIOMYOPATHY AND RAPID VENTRICULAR PACING

In this study we used 2.5% myocardial homogenates to study sarcoplasmic reticulum (SR) activity of the Ca2+ pump and Ca2+ release channel (CRC) from dogs with congestive heart failure produced by either rapid ventricular pacing or idiopathic dilated cardiomyopathy. We used the fluorescent indicator dye and ratiometric spectrofluorometry to monitor Ca2+ uptake while the CRC was open and closed with ryanodine. We confirmed and extended conclusions derived from previous studies of the same dogs using isolated SR. Compared to controls, activities of dogs with either form of CHF were decreased by 36% for the Ca2+ pump (33.7±7.3 and 21.6±4.2 nM/s), 78% for the CRC (10.0±2.8 and 1.4±1.2 nM/s), 53% for total Ca2+-cycling (53.1±8.5 and 24.8±4.4 nM/s), and 17% for net Ca2+ uptake (23.7±4.0 and 19.6±4.0 nM/s). In the absence of SR and mitochondrial activity, ionized Ca2+ concentration in myocardial homogenates were 70% abnormally increased in dogs with CHF, probably due to decreased concentration of Ca2+-binding proteins. Comparison of homogenate and isolated SR activities indicated lower-than-normal membrane yields for dogs with CHF. This fractionation artefact previously resulted in up to 50% overestimation of the degree of downregulation of Ca2+-cycling activities in CHF. The CRC activity was found to be decreased due to decreased activity of the Ca2+-ATPase, decreased CRC content, and inhibition. Decreased CRC activity reversed most of the effect of down-regulation of the Ca2+-ATPase pump, which is proposed to conserve energy. Maintenance of net Ca2+-pump activity is expected to maintain the amplitude of the myocardial ionized Ca2+ transient whereas downregulation of the CRC and pump are predicted to reduce the total amount of Ca2+ cycled and slow the rise and fall of the Ca2+ transient. © 1993 Academic Press Limited.