Reverse Mode of the Na ⁺ -Ca ²⁺ Exchange After Myocardial Stretch

Abstract

This study was designed to gain additional insight into the mechanism of the slow force response (SFR) to stretch of cardiac muscle. SFR and changes in intracellular Na(+) concentration ([Na(+)](i)) were assessed in cat papillary muscles stretched from 92% to approximately 98% of L(max). The SFR was 120+/-0.6% (n=5) of the rapid initial phase and coincided with an increase in [Na(+)](i). The SFR was markedly depressed by Na(+)-H(+) exchanger inhibition, AT(1) receptor blockade, nonselective endothelin-receptor blockade and selective ET(A)-receptor blockade, extracellular Na(+) removal, and inhibition of the reverse mode of the Na(+)-Ca(2+) exchange by KB-R7943. KB-R7943 prevented the SFR but not the increase in [Na(+)](i). Inhibition of endothelin-converting enzyme activity by phosphoramidon suppressed both the SFR and the increase in [Na(+)](i). The SFR and the increase in [Na(+)](i) after stretch were both present in muscles with their endothelium (vascular and endocardial) made functionally inactive by Triton X-100. In these muscles, phosphoramidon also suppressed the SFR and the increase in [Na(+)](i). The data provide evidence that the last step of the autocrine-paracrine mechanism leading to the SFR to stretch is Ca(2+) entry through the reverse mode of Na(+)-Ca(2+) exchange.

Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na + /H + Exchanger Inhibition

“…29 The elevated NHE-1 activity will increase Na ϩ influx, increasing its cytosolic concentration, which in turn will lead to a secondary increase in Ca 2ϩ i through Na ϩ /Ca 2ϩ exchange. 30,31 The notion that the increase in Ca 2ϩ i is a primary signal for CH is supported by numerous studies. [32][33][34] The rise in Ca 2ϩ i activates several intracellular signaling pathways like protein kinase C 35 and calcium-calmodulin-dependent phosphatase (calcineurin) and kinases involved in the hypertrophic response.…”

Pharmacological modifications of the stretch-induced effects on ventricular fibrillation in perfused rabbit hearts

“…The mechanism of action of the Na ϩ /Ca 2ϩ exchanger blocker KB-R7943 would be different to that of the stretch-activated channel blockers. These channels exhibit nonselective permeability to monovalent and divalent cations, including Na ϩ and Ca 2ϩ (30,51), although other mechanisms may influence Na ϩ influx, such as Na ϩ /H ϩ exchanger activation via direct mechanical signals or mech- (3,46,66,69). In turn, the changes in intracellular Ca 2ϩ concentrations may modulate stretch-activated channel activity (68), and both Na ϩ and Ca 2ϩ concentrations regulate the function of the Na ϩ /Ca 2ϩ exchanger (3,25,59,69).…”

“…These changes have been related to several mechanisms, including the actions of 1) endogenous angiotensin II (1, 46); 2) the Na ϩ /H ϩ exchanger (1, 3, 46, 66); 3) the Na ϩ /Ca 2ϩ exchanger (3, 46, 66, 69); and 4) signaling pathways with the involvement of the second messenger cAMP (3, 10). Na ϩ influx via the stretch-activated channels that have nonselective permeability to various cations (30, 51), or by the activation of angiotensin II and endothelin 1 receptors that stimulate the Na ϩ /H ϩ exchanger (1, 46), or through mechanically mediated enhancement of Na ϩ /H ϩ exchanger activity (66) activates the reverse mode operation of the Na ϩ /Ca 2ϩ exchanger, increasing Ca 2ϩ influx and Ca 2ϩ transients (3,46,66,69).The electrical and mechanical effects of stretch are not independent, and changes in the concentrations of intracellular Ca 2ϩ can influence electrical activity via the modulation of Ca 2ϩ -dependent currents (3, 25). A Ca 2ϩ -dependent inactivation of stretch-activated channel activity has been described (68), and activation of the delayed rectifier K ϩ current and of the Na ϩ /Ca 2ϩ exchanger is also regulated by intracellular Ca 2ϩ concentration (3,25,59).…”

“…These changes have been related to several mechanisms, including the actions of 1) endogenous angiotensin II (1,46); 2) the Na ϩ /H ϩ exchanger (1,3,46,66); 3) the Na ϩ /Ca 2ϩ exchanger (3,46,66,69); and 4) signaling pathways with the involvement of the second messenger cAMP (3,10). Na ϩ influx via the stretch-activated channels that have nonselective permeability to various cations (30,51), or by the activation of angiotensin II and endothelin 1 receptors that stimulate the Na ϩ /H ϩ exchanger (1,46), or through mechanically mediated enhancement of Na ϩ /H ϩ exchanger activity (66) activates the reverse mode operation of the Na ϩ /Ca 2ϩ exchanger, increasing Ca 2ϩ influx and Ca 2ϩ transients (3,46,66,69).…”

Endothelin-1 Stimulates the Na + /Ca 2+ Exchanger Reverse Mode Through Intracellular Na + (Na + i )–Dependent and Na + i -Independent Pathways

“…The lack of changes in pH i after NHE activation when bicarbonate is present in the medium has been suggested previously. 5,6,14 Note that a further increase in Na ϩ i was detected after application of KB-R7943, suggesting that this compound blocked the exchange of Na Although these experiments are suggesting that the PIE of this ET-1 dose is entirely attributable to stimulation of the NCX reverse mode, the possibility exists that the compound used for blocking this NCX operation mode would be acting on other mechanisms. However, as shown in Figure 2, this was not the case.…”