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

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.