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Effects of Sustained Length-Dependent Activation on In Situ Cross-Bridge Dynamics in Rat Hearts

James T. Pearson ^*, Mikiyasu Shirai ^* , Hirotsugu Tsuchimochi ^*, Daryl O. Schwenke ^*, Takayuki Ishida , Kenji Kangawa , Hiroyuki Suga ^* and Naoto Yagi 

^* Departments of Cardiac Physiology and Biochemistry, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan; Hiroshima International University, Kamo, Hiroshima 724-0694, Japan; and SPring-8/JASRI, Mikazuki, Hyogo 679-5198, Japan

Correspondence: Address reprint requests to Dr. James T. Pearson at his present address, Dept. of Physiology and Monash Centre for Synchrotron Science, Monash University, PO Box 13F, Clayton, Victoria 3800, Australia. Tel.: 61-3-9905-9456; Fax: 61-3-9905-2547; E-mail: james.pearson{at}med.monash.edu.au.

The cellular basis of the length-dependent increases in contractile force in the beating heart has remained unclear. Our aim was to investigate whether length-dependent mediated increases in contractile force are correlated with myosin head proximity to actin filaments, and presumably the number of cross-bridges activated during a contraction. We therefore employed x-ray diffraction analyses of beat-to-beat contractions in spontaneously beating rat hearts under open-chest conditions simultaneous with recordings of left ventricle (LV) pressure-volume. Regional x-ray diffraction patterns were recorded from the anterior LV free wall under steady-state contractions and during acute volume loading (intravenous lactate Ringers infusion at 60 ml/h, <5 min duration) to determine the change in intensity ratio (I_1,0/I_1,1) and myosin interfilament spacing (d_1,0). We found no significant change in end-diastolic (ED) intensity ratio, indicating that the proportion of myosin heads in proximity to actin was unchanged by fiber stretching. Intensity ratio decreased significantly more during the isovolumetric contraction phase during volume loading than under baseline contractions. A significant systolic increase in myosin head proximity to actin filaments correlated with the maximum rate of pressure increase. Hence, a reduction in interfilament spacing at end-diastole (0.5 nm) during stretch increased the proportion of cross-bridges activated. Furthermore, our recordings suggest that d_1,0 expansion was inversely related to LV volume but was restricted during contraction and sarcomere shortening to values smaller than the maximum during isovolumetric relaxation. Since ventricular volume, and presumably sarcomere length, was found to be directly related to interfilament spacing, these findings support a role for interfilament spacing in modulating cross-bridge formation and force developed before shortening.

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