The first investigation of mechanisms regulating O2 supply-demand balance in the right ventricle (RV) of an intact, conscious animal model is proposed. Scant, earlier studies in isolated hearts and anesthetized models have produced limited and conflicting data resulting in poor understanding of mechanisms matching RV O2 supply to RV O2 demand. The proposed investigation is comprehensive and integrative. Using novel procedures developed in this laboratory for collecting samples of right coronary (RC) venous blood from a conscious animal, contributions of O2 extraction and blood flow reserves in meeting increased RV O2 requirements during inotropic, chronotropic, and hemodynamic stresses produced by exercise, elevated RV afterload, atrial pacing, and ventricular paired pulse stimulation will be investigated. Roles of O2, adenosine, K+ATP channels, alpha-adrenergic vasoconstriction, beta-adrenergic """"""""feedforward"""""""" vasodilation, and nitric oxide (NO) in regulating RC blood flow will be addressed during increases in RV O2 demand and restrictions in O2 supply. Regional RV contractile function will be measured and related to associated changes in regional RC flow and RV O2 consumption, so RV O2 utilization efficiency can be evaluated. Metabolic studies will test the hypothesis that altered myocardial substrate selection improves RV O2 supply-demand balance if O2 supply is limited. The role of NO as a modulator of RV O2 demand as well as RC flow will be assessed. The RV is remarkably able to lower its O2 demand in the face of reduced O2 supply, so it is ideally suited for the proposed investigations of mechanisms responsible for this cardioprotective response to impending ischemia. Dogs will be surgically instrumented for collection of arterial and RC venous samples, so arteriovenous differences in O2, energy metabolites, and adenosine can be determined and RV uptake/release computed; for measuring regional RV segment shortening, RC arterial pressure, RC flow and flow distribution, RV pressure and dP/dt, aortic pressure, pulmonary artery flow; for RC arterial infusion of drugs; for atrial and ventricular pacing; and for elevating pulmonary artery pressure to increase RV afterload. This investigation supports long term objectives to delineate mechanisms regulating myocardial O2 supply and to define myocardial adjustments to perturbations of O2 supply-demand balance. Results will impact treatment of conditions which limit myocardial O2 supply relative to O2 demand.
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| Zong, Pu; Sun, Wei; Setty, Srinath et al. (2004) Alpha-adrenergic vasoconstrictor tone limits right coronary blood flow in exercising dogs. Exp Biol Med (Maywood) 229:312-22 |
| Setty, Srinath; Tune, Johnathan D; Downey, H Fred (2004) Nitric oxide contributes to oxygen demand-supply balance in hypoperfused right ventricle. Cardiovasc Res 64:431-6 |
| Setty, Srinath; Tune, Johnathan D; Downey, H Fred (2002) Nitric oxide modulates right ventricular flow and oxygen consumption during norepinephrine infusion. Am J Physiol Heart Circ Physiol 282:H696-703 |
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