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

Abstract

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 ≈88% to ≈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 ≈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.