The goal of the proposed research is to better understand partitioning of energy input and the efficiency of energy utilization in the isolated, supported rabbit left ventricle (LV). In the first portion of the proposed work, we will study a new approach to partition VO(2) into that-used for crossbridge cycling and that used for other purposes by using the drug 2,3-butanedione monoxime (BDM). At relatively low concentration, this drug selectively inhibits crossbridge cycling. The relationship between VO: and pressure-time integral as low-dose BDM is administered will be employed to estimate force-independent VO: [the VO: used for (excitation-contraction coupling + resting metabolism)]. Force-dependent VO:, or that used for crossbridge cycling, equals total V02 minus force-independent VO:. To calculate efficiency, pressure-volume area (PVA) will be used as an expression of total energy output of the contractile machinery. Efficiency is thus PVA + force-dependent V02. Using this approach, the relation between force-independent V02 and LV volume will be determined, as will the influence of load on efficiency. In the second portion of the proposed work, the effect on VO: partitioning and contractile efficiency of three positive inotropic interventions will be assessed. The interventions are designed to have differing effects on crossbridge cycling rate. In the last portion of the proposal, this approach will be applied to several models of chronic hypertrophic stress, including hyper- and hypothyroidism and chronic pressure overload due to renal hypertension. The models are designed to produce variations in both myosin isoenzyme distribution and the architecture/geometry of the LV. The latter work constitutes a preliminary attempt to understand whether chronic hypertrophic stress alters V02 partitioning and efficiency In the isolated, supported LV in a fashion which Is analogous to previously demonstrated alterations in isolated muscle.
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