Mechanisms Underlying the Increase in Force and Ca ²⁺ Transient That Follow Stretch of Cardiac Muscle

Abstract

Myocardial stretch produces an increase in developed force (DF) that occurs in two phases: the first (rapidly occurring) is generally attributed to an increase in myofilament calcium responsiveness and the second (gradually developing) to an increase in [Ca(2+)](i). Rat ventricular trabeculae were stretched from approximately 88% to approximately 98% of L(max), and the second force phase was analyzed. Intracellular pH, [Na(+)](i), and Ca(2+) transients were measured by epifluorescence with BCECF-AM, SBFI-AM, and fura-2, respectively. After stretch, DF increased by 1.94+/-0.2 g/mm(2) (P<0.01, n = 4), with the second phase accounting for 28+/-2% of the total increase (P<0.001, n = 4). During this phase, SBFI(340/380) ratio increased from 0.73+/-0.01 to 0.76+/-0.01 (P<0.05, n = 5) with an estimated [Na(+)](i) rise of approximately 6 mmol/L. [Ca(2+)](i) transient, expressed as fura-2(340/380) ratio, increased by 9.2+/-3.6% (P<0.05, n = 5). The increase in [Na(+)](i) was blocked by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA). The second phase in force and the increases in [Na(+)](i) and [Ca(2+)](i) transient were blunted by AT(1) or ET(A) blockade. Our data indicate that the second force phase and the increase in [Ca(2+)](i) transient after stretch result from activation of the Na(+)/H(+) exchanger (NHE) increasing [Na(+)](i) and leading to a secondary increase in [Ca(2+)](i) transient. This reflects an autocrine-paracrine mechanism whereby stretch triggers the release of angiotensin II, which in turn releases endothelin and activates the NHE through ET(A) receptors.

The slow force response to stretch in atrial and ventricular myocardium from human heart: Functional relevance and subcellular mechanisms

“…The SFR was originally characterised in cat papillary muscles (Parmley and Chuck, 1973). Since then, it has been observed in a variety of cardiac preparations ranging from whole hearts to single myocytes in various species including cat (Parmley and Chuck, 1973;Perez et al, 2001), dog (Todaka et al, 1998), ferret (Calaghan and White, 2001), guineapig (White et al, 1995), rabbit (von Lewinski et al, 2003), rat (Alvarez et al, 1999;Hongo et al, 1996;Kentish and Wrzosek, 1998), and human (von Lewinski et al, 2004). This implicates that the SFR is a general phenomenon of physiological relevance and that the underlying mechanisms of the SFR, just like the FSM, are intrinsic to the cardiac myocyte.…”

“…Based on experimental and modelling studies various signalling pathways and mechanisms have been proposed to contribute to the SFR. The list of channels, transporters, and signalling molecules possibly involved in the SFR includes angiotensin II (Alvarez et al, 1999;Perez et al, 2001), endothelins (Alvarez et al, 1999;Calaghan and White, 2001;Ennis et al, 2005;Perez et al, 2001), stretch-activated non-selective cation channels (SACs) (Calaghan and White, 2004;Niederer and Smith, 2007), the Na + /H + exchanger (NHE) (Alvarez et al, 1999;Calaghan and White, 2004;Luers et al, 2005;Perez et al, 2001;von Lewinski et al, 2003), the Na + /Ca 2+ exchanger (NCX) (Luers et al, 2005;Perez et al, 2001;von Lewinski et al, 2003), the Na + / K + pump (Bluhm et al, 1998), cAMP (Calaghan et al, 1999;Todaka et al, 1998), phosphatidyinositol-3 kinase (PI3K) (Vila Petroff et al, 2001), and nitric oxide (NO) (Vila Petroff et al, 2001), and is likely to be extended further. The significance of each mechanism may vary depending on experimental conditions (e.g.…”

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

“…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).…”

Impaired angiotensin II–extracellular signal-regulated kinase signaling in failing human ventricular myocytes

“…However, when incubation time was prolonged (>15 min), Ang II induced a concentration-dependent increase in rat myocyte contractility, an effect completely blocked by ET-1 antagonists [15,27]. Likewise, the progressive increases in force and in Ca þ transients occurring over 15 min in stretched papillary muscles were blocked by both AT1 and endothelin receptor antagonists [28].…”