Abstract
Increased myocardial contractility by beta-adrenergic stimulation requires precise coordination between cardiac myocyte membrane potential, calcium handling, and myofilament mechanics. From a myofilament standpoint, more stoke volume at a given end-diastolic volume ideally would involve both faster loaded shortening for more ejection coupled with greater shortening-induced cooperative deactivation to assist in relaxation, which would help assure adequate filling at higher heart rates. We tested if myofilaments elicit these characteristics by direct measurement of myocardial sarcomere shortening during load clamps before and after PKA treatment, a downstream beta-adrenergic signaling molecule. Rat skinned ventricular cardiac myocyte preparations (n = 6) were attached between a force transducer and motor, calcium activated to elicit ∼30% maximal force, and then light-to-moderate load clamps were induced by a servo-controlled feedback system. Initial sarcomere length was set at ∼2.25 μm and sarcomere shortening was monitored during the load clamps using an IonOptix SarcLen system at 240 Hz. Interestingly, PKA seemed to result in the aforementioned ideal changes in sarcomere mechanics. First, loaded sarcomere shortening velocities were faster following PKA treatment (control = 0.838 ± 0.198 μm/sec/sarcomere (n= 20) at loads of 0.17 ± 0.06 isometric force (Po); PKA = 1.215 ± 0.071 μm/sec/sarcomere (n = 31) at loads of 0.15 ± 0.07 Po (p < 0.001) (means ± SD)). In addition, PKA appeared to yield greater shortening-induced cooperative deactivation during load clamps by exhibiting greater curvature of sarcomere length traces, which was indexed by the rate constant of sarcomere shortening (kshortening), (Control kshortening = 4.27 ± 1.47; PKA kshortening = 6.93 ± 2.48 (p < 0.001) (means ± SD)). These findings illustrate the fine tuning of the myofilament clock to help match the resetting of the membrane and calcium clocks after beta-adrenergic stimulation.
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