In order to maintain normal cardiac function, myocardial ATP synthesis (by oxidative phosphorylation) must be matched precisely to the rate of ATP hydrolysis, which in turn varies rapidly and widely with changing cardiac work. The control mechanisms which couple these processes are uncertain in the left ventricle (LV), and have not been investigated in the right ventricle (RV). A growing body of in vitro data, as well as in vivo observations from this laboratory, indicate that energy metabolism of the RV and LV may differ substantially; therefore, observations made in the LV may not be applicable to the RV. For example, when equal increases in RV oxygen consumption are produced by pulmonary artery constriction or isoproterenol infusion, opposite changes in the phosphocreatine/ATP ratio are observed: a decrease with PA constriction and an increase with isoproterenol. In addition, these two interventions are associated with marked differences in RV substrate uptake. This application proposes to utilize techniques of in vivo NMR spectroscopy, and regional measurements of myocardial blood flow, oxygen and substrate utilization, and NADH fluorescence to address the following questions in the pig heart in situ: Do changes in phosphate metabolites and mitochondrial redox potential both contribute to the regulation of oxidative phosphorylation in the RV? When does each exert predominant control? Do changes in substrate utilization affect the levels of RV phosphate metabolites and redox potential? In the same animal model, are there differences in the energetic responses to increased workload of the RV versus the LV? It is hoped that the answers to these questions will shed light on the control of a critical physiologic process, and elucidate similarities and differences in the energy metabolism of the two ventricles.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049944-04
Application #
2332507
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1994-02-01
Project End
1999-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Huang, Janice V; Lu, Li; Ye, Shuyu et al. (2013) Impaired contractile recovery after low-flow myocardial ischemia in a porcine model of metabolic syndrome. Am J Physiol Heart Circ Physiol 304:H861-73
Low Wang, Cecilia C; Lu, Li; Leitner, J Wayne et al. (2013) Arterial insulin resistance in Yucatan micropigs with diet-induced obesity and metabolic syndrome. J Diabetes Complications 27:307-15
Sarraf, Mohammad; Lu, Li; Ye, Shuyu et al. (2012) Thiazolidinedione drugs promote onset, alter characteristics, and increase mortality of ischemic ventricular fibrillation in pigs. Cardiovasc Drugs Ther 26:195-204
Ahmad, Hasan A; Lu, Li; Ye, Shuyu et al. (2012) Calpain inhibition preserves talin and attenuates right heart failure in acute pulmonary hypertension. Am J Respir Cell Mol Biol 47:379-86
Huang, Janice V; Greyson, Clifford R; Schwartz, Gregory G (2012) PPAR-? as a therapeutic target in cardiovascular disease: evidence and uncertainty. J Lipid Res 53:1738-54
Lee, Jenny; Xu, Ya; Lu, Li et al. (2010) Multiple abnormalities of myocardial insulin signaling in a porcine model of diet-induced obesity. Am J Physiol Heart Circ Physiol 298:H310-9
Xu, Ya; Lu, Li; Greyson, Clifford et al. (2006) The PPAR-alpha activator fenofibrate fails to provide myocardial protection in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol 290:H1798-807
Xu, Ya; Gen, Michael; Lu, Li et al. (2005) PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs. Am J Physiol Heart Circ Physiol 288:H1314-23
Xu, Ya; Lu, Li; Greyson, Clifford et al. (2003) Deleterious effects of acute treatment with a peroxisome proliferator-activated receptor-gamma activator in myocardial ischemia and reperfusion in pigs. Diabetes 52:1187-94
Lu, L; Xu, Y; Zhu, P et al. (2001) A common mechanism for concurrent changes of diastolic muscle length and systolic function in intact hearts. Am J Physiol Heart Circ Physiol 280:H1513-8

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