The mechanisms responsible for the observed differences in contractile performance between immature and adult mammalian myocardium remain incompletely defined. Because of the structural and functional immaturity of the sarcoplasmic reticulum during the perinatal period, it is likely that the immature sarcolemmal membrane differs functionally from that in the adult heart. However, relatively little is known of the calcium regulatory properties of the sarcolemma with regard to perinatal development. The major specific aim of this proposal is to comprehensively characterize the transarcolemmal sodium-calcium (Na-Ca) exchange mechanism in the developing rabbit. Experimental results from four age groups will be compared: fetal (25-28 days post-conception), newborn (1-7 days of age), immature (14-21 days of age), and adult (6-10 months of age). Sarcolemmal membrane vesicles will be prepared from ventricular tissue by homogenization and sucrose gradient centrifugation. The kinetics of sodium-dependent calcium fluxes will be compared among the age groups. The effects of changes in potential regulatory factors (pH, temperature, sarcolemmal protein phosphorylation/dephosphorylation) will be examined. Na-Ca exchange will also be studied in suspensions of viable, calcium-tolerant myocytes prepared by enzymatic digestion of ventricular myocardium. Age-related comparisons of the effects of amiloride (an inhibitor of Na-Ca exchange in adult myocardium) in vesicles and myocytes will be used to assess the relative sensitivities to Na-Ca inhibition. 3H-Amiloride will be used to determine the binding characteristics of amiloride (binding affinity, binding site density) in vesicles and myocytes from each age group. The effects of changes in Na-Ca exchange activity on contractile function will be assessed in isolated right ventricular papillary muscles obtained from fetal, newborn, immature, and adult rabbits. These experiments will provide information regarding the perinatal development of sarcolemmal Na-Ca exchange. Completion of this project will provide important insights into the mechanisms involved in the perinatal maturation of myocardial contractile function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001695-04
Application #
3082082
Study Section
Research Manpower Review Committee (MR)
Project Start
1985-12-01
Project End
1990-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of South Alabama
Department
Type
Schools of Medicine
DUNS #
City
Mobile
State
AL
Country
United States
Zip Code
36688
Mayer, D C; Strada, S J; Hoff, C et al. (1994) Effects of poloxamer 188 in a rabbit model of hemorrhagic shock. Ann Clin Lab Sci 24:302-11
Mayer, D C; Strada, S J; Hanson, A et al. (1992) Effects of hemorrhagic shock and retransfusion on catalase and superoxide dismutase activities in rabbits. Circ Shock 36:147-53
Artman, M (1992) Sarcolemmal Na(+)-Ca2+ exchange activity and exchanger immunoreactivity in developing rabbit hearts. Am J Physiol 263:H1506-13
Oquist, N L; Strada, S J; Artman, M (1992) Inotropic responses to selective (RO 20-1724 and SQ 65,442) and nonselective (trequinsin) inhibitors of cyclic AMP-specific class IV phosphodiesterase in newborn, immature, and adult rabbit myocardium. Pediatr Res 31:300-4
Kithas, P A; Artman, M; Thompson, W J et al. (1989) Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activities in rabbit ventricular myocardium: relations to post-natal maturation. J Mol Cell Cardiol 21:507-17
Artman, M; Kithas, P A; Wike, J S et al. (1989) Inotropic responses to cyclic nucleotide phosphodiesterase inhibitors in immature and adult rabbit myocardium. J Cardiovasc Pharmacol 13:146-54
Artman, M; Kithas, P A; Wike, J S et al. (1988) Inotropic responses change during postnatal maturation in rabbit. Am J Physiol 255:H335-42
Kithas, P A; Artman, M; Thompson, W J et al. (1988) Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activity in rabbit ventricular myocardium: relations to the effects of cardiotonic drugs. Circ Res 62:782-9
Artman, M; Graham Jr, T P (1987) Guidelines for vasodilator therapy of congestive heart failure in infants and children. Am Heart J 113:994-1005
Artman, M; Parrish, M D; Appleton, S et al. (1987) Hemodynamic effects of hydralazine in infants with idiopathic dilated cardiomyopathy and congestive heart failure. Am Heart J 113:144-50