Do stretch-induced changes in intracellular calcium modify the electrical activity of cardiac muscle?

Abstract

Stretch of the myocardium influences the shape and amplitude of the intracellular Ca(2+)([Ca(2+)](i)) transient. Under isometric conditions stretch immediately increases myofilament Ca(2+) sensitivity, increasing force production and abbreviating the time course of the [Ca(2+)](i) transient (the rapid response). Conversely, muscle shortening can prolong the Ca(2+) transient by decreasing myofilament Ca(2+) sensitivity. During the cardiac cycle, increased ventricular dilation may increase myofilament Ca(2+) sensitivity during diastolic filling and the isovolumic phase of systole, but enhance the decrease in myofilament Ca(2+) sensitivity during the systolic shortening of the ejection phase. If stretch is maintained there is a gradual increase in the amplitude of the Ca(2+) transient and force production, which takes several minutes to develop fully (the slow response). The rapid and slow responses have been reported in whole hearts and single myocytes. Here we review stretch-induced changes in [Ca(2+)](i) and the underlying mechanisms. Myocardial stretch also modifies electrical activity and the opening of stretch-activated channels (SACs) is often used to explain this effect. However, the myocardium has many ionic currents that are regulated by [Ca(2+)](i) and in this review we discuss how stretch-induced changes in [Ca(2+)](i) can influence electrical activity via the modulation of these Ca(2+)-dependent currents. Our recent work in single ventricular myocytes has shown that axial stretch prolongs the action potential. This effect is sensitive to either SAC blockade by streptomycin or the buffering of [Ca(2+)](i) with BAPTA, suggesting that both SACs and [Ca(2+)](i) are important for the full effects of axial stretch on electrical activity to develop.

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

“…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).…”

“…cardiac electrophysiology; mechanical stretch; Fourier analysis STRETCH induces the modulation of electrical and mechanical activity in myocytes. The modulation of electrical activity, also referred to as mechanoelectrical feedback (14,35), includes the depolarization of the resting potential (2,17,21,27,28,31,70), alterations of the shape and duration of action potentials (3,11,21,27,28,31,47,57,70), changes in refractoriness (4,7,9,11,27,36,47,48), and the induction of afterdepolarizations (16,18,34). These electrophysiological changes have been related to the generation of different types of cardiac arrhythmias (7, 9, 13-15, 24, 26, 35, 40, 47).…”

“…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). Thus, besides the effects of substances that block the stretch-activated channels, other substances can modulate the electrophysiological effects of stretch through different mechanisms that affect Ca 2ϩ handling by myocytes.…”

“…The mechanical effects of stretch consist of an immediate and slow increase in force (45,64), involving changes in myofilament Ca 2ϩ sensitivity, in the concentrations of intracellular Ca 2ϩ , and in the magnitude of Ca 2ϩ transients (1,3,29,33,58,69). 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).…”

“…The mechanical effects of stretch consist of an immediate and slow increase in force (45,64), involving changes in myofilament Ca 2ϩ sensitivity, in the concentrations of intracellular Ca 2ϩ , and in the magnitude of Ca 2ϩ transients (1,3,29,33,58,69). 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).…”