Mechanisms underlying the increase in force and Ca2+ transient that followstretch of cardiac muscle - A possible explanation of the Anrep effect

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 d eveloping) to an increase in [Ca2+](i). Rat ventricular trabeculae were str etched from approximate to 88% to approximate to 98% of L-max, and the seco nd force phase was analyzed. Intracellular pH, [Na+](i), and Ca2+ transient s were measured by epifluorescence with BCECIF-AM, SBFI-AM, and fura-2, res pectively. 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<0.00 1, n=4). During this phase, SBFI340/380 ratio increased from 0.73+/-0.01 to 0.76+/-0.01 (P<0.05, n=5) with an estimated [Na+](i) rise of approximate t o 6 mmol/L. [Ca2+](i) transient, expressed as fura-2(340/380) ratio, increa sed 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 i ncreases in [Na+](i) and [Ca2+](i) transient were blunted by AT(1) or ETA b lockade. Our data indicate that the second force phase and the increase in [Ca2+](i) transient after stretch result from activation of the Na+/H+ exch anger (NHE) increasing [Na+](i) and lending to a secondary increase in [Ca2 +](i) transient. This reflects an autocrine-paracrine mechanism whereby str etch triggers the release of angiotensin II, which in turn releases endothe lin and activates the NHE through ETA receptors.