Although much has been learned about systolic function in the fetal sheep, little is known about the relaxation and filling phases of the cardiac cycle in immature hearts. The purpose of this application is to investigate the cellular and functional aspects of diastole in growing lambs. The proposed study is based on the hypothesis that the sarcoplasmic reticulum becomes increasingly important with-maturity as a regulator of Ca++ uptake during relaxation.
The Specific Aims of the study are; 1) to determine the developmental changes in diastolic properties of the heart in sheep at 120, 130, 140, 160, 170 days post-conception 2) to determine the effects of myocardial hypoxia on in vivo diastolic function at the same post-conception ages; 3) to determine the effect of interventricular filling pressure gradients associated with in utero ventilation on the diastolic properties of the mature fetal left ventricle; 4) to determine the relative importance of sarcolemma vs. sarcoplasmic reticulum in the uptake of myoplasma Ca++ during relaxation in isolated ventricular myocytes; 5) to determine in isolated immature myocytes, the mechanisms responsible for alterations in diastolic Ca++ uptake in the presence of Na-K Channel antagonists and beta-adrenergic agonists.
Aims. 1, 2 and 3 will be accomplished in chronically prepared lambs with left ventricular minor axis dimensions measured with implanted sonomicrometry crystals and implanted micromanometer. Pressure-dimension-time relationships will be determined mathematically. The relaxation time constant, T, and the passive pressure-dimension curve will be used to quantitate diastolic changes.
Aims 4 and 5 will study Ca++ transients in isolated cells using the florescent dye indicator, fura-2. This study is designed to: advance our knowledge of the basic mechanisms that underlie normal diastolic function in the immature heart; determine effects of 3 drugs that are known to affect diastolic function in mature myocardium; determine the role of diastolic ventricular interaction in determining increased left ventricular stroke volume at birth; and correlate cellular events with in vivo functional changes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Human Embryology and Development Subcommittee 1 (HED)
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Oregon Health and Science University
Schools of Medicine
United States
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Thornburg, K L; Reller, M D (1999) Coronary flow regulation in the fetal sheep. Am J Physiol 277:R1249-60
Giraud, G D; Morton, M J; Reid, D L et al. (1995) Effects of ductus arteriosus occlusion on pulmonary artery pressure during in utero ventilation in fetal sheep. Exp Physiol 80:129-39
Reller, M D; Burson, M A; Lohr, J L et al. (1995) Nitric oxide is an important determinant of coronary flow at rest and during hypoxemic stress in fetal lambs. Am J Physiol 269:H2074-81
Lohr, J L; Reller, M D; Morton, M J et al. (1994) Atrial myocardial blood flow during acute right ventricular pressure load and adenosine infusion in late gestation fetal sheep. Pediatr Res 35:325-8
Reller, M D; Morton, M J; Giraud, G D et al. (1992) Maximal myocardial blood flow is enhanced by chronic hypoxemia in late gestation fetal sheep. Am J Physiol 263:H1327-9
Reller, M D; Morton, M J; Giraud, G D et al. (1992) Severe right ventricular pressure loading in fetal sheep augments global myocardial blood flow to submaximal levels. Circulation 86:581-8
Thornburg, K L (1991) Fetal response to intrauterine stress. Ciba Found Symp 156:17-29;discussion 29-37