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

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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 [Ca2+]i. Rat ventricular trabeculae were stretched from ≈88% to ≈98% of Lmax, and the second force phase was analyzed. Intracellular pH, [Na+]i, and Ca2+ transients were measured by epifluorescence with BCECF-AM, SBFI-AM, and fura-2, respectively. After stretch, DF increased by 1.94±0.2 g/mm2 (PP340/380 ratio increased from 0.73±0.01 to 0.76±0.01 (P+]i rise of ≈6 mmol/L. [Ca2+]i transient, expressed as fura-2340/380 ratio, increased by 9.2±3.6% (P+]i was blocked by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA). The second phase in force and the increases in [Na+]i and [Ca2+]i transient were blunted by AT1 or ETA blockade. Our data indicate that the second force phase and the increase in [Ca2+]i transient after stretch result from activation of the Na+/H+ exchanger (NHE) increasing [Na+]i and leading to a secondary increase in [Ca2+]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 ETA receptors.