The broad objective of this proposal is to define the role of atrial natriuretic peptide (ANF) in the regulation of fetal blood volume and cardiac function in health and disease. The proposal is based on the hypothesis that ANF modulates fetal cardiac function by directly and rapidly decreasing blood volume through its effect on vascular permeation of fluid and protein into the interstitial compartment. In this model, the fetal cardiac atria operate as a sense organ that monitors cardiac filling and responds with elaboration of ANF, a chemical signal that regulates the balance of intra-and extra-vascular fluid volume, in order to maintain the most advantageous relationship between cardiac filling and cardiac output. ANF may play a fundamental role in orchestrating the critical relationship between ventricular stroke volume, cardiac growth, and hemodynamic stability. ANF levels are routinely found to be extremely high in infants dying from fetal hydrops. Among the infants born with hydrops 50 to 98% do not survive. Work form our laboratory has determined that ANF increases fluid and protein permeation in fetal tissues. The finding that ANF is central in the pathophysiology of fetal hydrops would suggest a therapeutic use for our laboratory has determined that ANF increases fluid and protein permeation in fetal tissues. The finding that ANF is central in the pathophysiology of fetal hydrops would suggest a therapeutic use for the recently discovered ANF receptor antagonists HS-142-1.
The specific aims of this investigation are to: 1) Determine if ANF concentrations in the physiologic range cause decreases in fetal blood volume and modulate cardiac function. 2) Determine if decreased fetal ANF circulating concentrations and ANF receptor blockage cause increased blood volume, and ventricular stroke volume by decreasing vascular permeation of water and albumin. 3) Determine if chronic administration of ANF produces hydrops fetalis and if ANF receptor blockade prevents edema formation in a sheep model of chronic fetal anemia induced hydrops. To accomplish these aims in the chronically instrumented near term fetal lamb: a) ANF will be infused to produce increments of circulating hormone within the range found during saline volume loading. b) Bilateral atrial appendage ligation will be performed, the ANF receptor antagonist HS-142- 1 administered and vascular permeation of albumin in response to volume expansion will be measured and, c) Intravascular and interstitial fluid volume will be measured before and during a five day chronic administration of ANF to the fetus and the ANF receptor antagonist HS- 142-1 will be administered to fetuses made hydropic by chronic isovolumic hemorrhage.
These specific aims i ntegrate the long term commitment to understanding the role of ANF in fetal and newborn fluid physiology with a laboratory possessing expertise in fetal hemodynamics and ventricular function.
| Silberbach, M; Gorenc, T; Hershberger, R E et al. (1999) Extracellular signal-regulated protein kinase activation is required for the anti-hypertrophic effect of atrial natriuretic factor in neonatal rat ventricular myocytes. J Biol Chem 274:24858-64 |
| Silberbach, M; Woods, L L; Hohimer, A R et al. (1995) Role of endogenous atrial natriuretic peptide in chronic anemia in the ovine fetus: effects of a non-peptide antagonist for atrial natriuretic peptide receptor. Pediatr Res 38:722-8 |
| Silberbach, M; Anderson, D F; Reller, M D et al. (1994) Effect of atrial natriuretic peptide on vascular permeation in the ovine fetus. Pediatr Res 35:555-9 |
