Mechanisms underlying the increase in force and Ca²⁺ transient that follow stretch 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 developing) to an increase in [Ca²⁺](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 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 (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. [Ca²⁺] 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 [Ca²⁺](i) transient were blunted by AT₁ or ET(A) 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.