Nitric oxide acts as a """"""""brake"""""""" on myocardial function and metabolism. It acts through the production of the second messenger cyclic GMP. During heart failure, cyclic GMP's """"""""braking"""""""" effects are reduced although its level increases. There are conflicting reports on the changes in the myocardial functional effects of nitric oxide in aging, although the some of its vascular effects diminish with age. Therefore, we hypothesize: 1. The myocardial functional effects of nitric oxide will be reduced with aging. 2. These changes will, in part, be related to changes in the heart's ability to produce and degrade cyclic GMP. These hypotheses will be studied in isolated young and old rabbit cardiac myocytes as well as in young and aged hearts of anesthetized open-chest rabbits. Myocyte O2 consumption will be measured using oxygen electrodes. Myocyte functional parameters, percent shortening, etc., will be determined using a video edge detector. Nitric oxide synthase will be examined by immunocytochemistry and cyclic GMP levels will be determined by radioimmunoassay. Agents will be added to the young and old ventricular myocytes to alter the level of nitric oxide and/or cyclic GMP. Additional studies will be conducted in vivo on the hearts of anesthetized open-chest rabbits. We will determine regional wall thickening, regional O2 consumption, coronary blood flow and local O2 extraction, endothelial nitric oxide synthase, cyclic GMP, guanylate cyclase and cyclic GMP-phosphodiesterase activity. Agents will be applied to the myocardial surface to alter the myocardial nitric oxide or cyclic GMP levels. The in vivo studies will allow us to determine the importance of the in vitro effects. With the development of our ability to measure myocyte and regional second messenger levels, function and O2 consumption, this grant allows, for the first time, determination of the basic mechanisms through which nitric oxide and cyclic GMP controls function and O2 cost and how aging affects these parameters. If loss of the braking function of nitric oxide on the heart is part of the aging process, we may be able to develop new treatments for cardiovascular problems associated with the aging process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG017648-01
Application #
6043145
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Kohanski, Ronald A
Project Start
1999-09-30
Project End
2001-08-31
Budget Start
1999-09-30
Budget End
2001-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Physiology
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Zhang, Q; Molino, B; Yan, L et al. (2001) Nitric oxide and cGMP protein kinase activity in aged ventricular myocytes. Am J Physiol Heart Circ Physiol 281:H2304-9