Postrest inotropy in rabbit ventricle: Na+-Ca2+ exchange determines sarcoplasmic reticulum Ca2+ content

Abstract

To determine whether Na+-Ca2+ exchange is a physiologically significant Ca2+ efflux mechanism in rabbit ventricle, we investigated the effects exerted on postrest contractions by interventions that alter the transmembrane distribution of Na+ or Ca2+ so as to retard Ca2+ efflux via this system. Contractions elicited after rest periods of 0.25-10 min in duration were studied. The following interventions increased postrest contractions much more than those elicited by rhythmic stimulation: 1) Na+ pump inhibition by cardiac glycosides or by a reduction in extracellular K+, 2) reduction of extracellular Na+ (maintaining a constant [Ca2+]-to-[Na+]2 ratio), and 3) elevation of extracellular Ca2+. In contrast, isoproterenol, norepinephrine, and histamine produced comparable increases in both rhythmically stimulated and postrest contractions, suggesting that the postrest contractile potentiation was not just the result of a general increase in inotropic state. Ryanodine, which appears to antagonize sarcoplasmic reticulum (SR) Ca2+ release in cardiac muscle, markedly reduced the amplitude of the postrest contractions, but only modestly decreased rhythmically stimulated responses. Results suggest 1) that Ca2+ released from SR is involved in postrest response, 2) that Na+-Ca2+ exchange serves as a Ca2+ efflux pathway in normally polarized resting rabbit ventricle, and 3) that this activity in part determines the amount of Ca2+ available for release from SR.

Investigations of Calsequestrin as a Target for Anthracyclines: Comparison of Functional Effects of Daunorubicin, Daunorubicinol, and Trifluoperazine

“…TFP at 300 M inhibits both steady-state and PRP30 contractions. Because the ability of a rest interval to augment contractility depends more on SR Ca 2ϩ than on Ca 2ϩ from other sites (Bers, 1985;Sutko et al, 1986;Bose et al, 1988;, these results also suggest the TFP-dependent inhibition observed in these experiments involves changes to the regulation of SR Ca 2ϩ . Analogous experiments, performed in our laboratory and designed to evaluate the effects of daunorubicin on cardiac contractility, yielded results similar to those observed with TFP .…”

Effects of Postnatal Maturation on Postrest Potentiation in Isolated Rabbit Atria

“…2). In view of the well-accepted relationship between inotropy, the ratio of extracellular calcium-to-sodium, and calcium loading of the SR (14,22), we interpreted these results as evidence for age-related differences in calcium loading and/or of the SR. In support of this interpretation, the inotropic effects of increasing extracellular calcium-to-sodium ratio on postrest contraction of immature atrial strips was use dependent (Fig.…”

“…Second, net transsarcolemmal calcium influx estimated by extracellular calcium depletion does not correlate with the force of the first postrest contraction, in contrast to the correlation observed for other inotropic interventions (9,18). Third, it is unlikely that a rest would increase calcium influx since the slow inward calcium current and net calcium influx via the Na/Ca exchange are depolarization dependent (14). Thus, substantial evidence has accumulated to indicate that potentiation of the first contraction after a rest interval is due to an increase in calcium release from the SR.…”

Diminished post-rest potentiation of contractile force in human dilated cardiomyopathy. Functional evidence for alterations in intracellular Ca2+ handling.

“…Recently, an increase in mRNA levels, protein expression and activity of the Na ϩ /Ca 2ϩ exchanger in human dilated cardiomyopathy was reported (22,23 -eliminating mechanisms, such as the Ca 2ϩ pumps, are of minor relevance for relaxation. In addition, rest decay of contractile force in rabbit myocardium can be substantially slowed by inhibition of the Na ϩ /Ca 2ϩ exchanger (56). In consequence, less Ca 2ϩ is extruded out of the cell, and more Ca 2ϩ is available for reuptake to the SR.…”