With increased cardiac work, the production of energy is precisely matched to meet the new demand. Mechanisms to explain this have included ADP, ATP, Pi or NADHm as control signals. Recent attention has been focused on NADHm since increased [NADH]m may increase energy production. However, it is unclear whether and how increased work is coupled to increased [NADH]m. The central hypothesis is that increased work causes increased cytosolic and subsequently mitochondrial [Ca2+] ([Ca2+]c and [Ca2+]m), which stimulates dehydrogenases to increase NADHm production and [NADH]m. Focal questions are: Does increased work cause increased [NADH]m? 1. Does increased [Ca2+]c or [Ca2+]m cause increased [NADH]m? 2. Is PDH the control site for increasing [NADH]m? 3. Does [NADH]m control the oxidative phosphorylation rate? Rat trabeculae will be isolated, and work, [NADH]m, [Ca2+]c, [Ca2+]m and oxygen consumption will be measured. Work will be altered by protocols that either increase [Ca2+]c (altering pacing rate and [Ca2+]o) or do not (altering sarcomere length). From this, it may be determined whether or not increased work causes increased [NADH]m, as well as the possible influence of [Ca2+]c. This will be further investigated by directly determining the relationships between work & [Ca2+]c, [Ca2+]c & [Ca2+]m and [Ca2+]m & [NADH]m. From these studies it may be concluded whether increased [NADH]m is, indeed, caused by increased [Ca2+]m during increased work. To determine if PDH is a key regulatory enzyme, substrate will be altered to either bypass PDH or not. If increased [NADH]m increases oxygen consumption rate, it will be concluded that [NADH]m controls oxidative phosphorylation. It is possible that the regulatory mechanisms also depend on the energy state of the heart, so work regime, temperature and redox and phosphorylation potentials (by altering substrate) will be varied.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29HL057562-06
Application #
6460205
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Liang, Isabella Y
Project Start
1997-01-01
Project End
2002-12-31
Budget Start
2001-05-01
Budget End
2002-12-31
Support Year
6
Fiscal Year
2001
Total Cost
$77,251
Indirect Cost
Name
Novasite Pharmaceuticals, Inc.
Department
Type
DUNS #
113386366
City
San Diego
State
CA
Country
United States
Zip Code
92121