Approximately 4-6% of infants born <32 weeks gestation or <1500 gm birthweight will develop necrotizing enterocolitis (NEC) each year (approximately 9000 cases); of these, approximately 25% will succumb to the disease while approximately 25% will require extensive bowel resection. Additionally, many nurseries specifically delay the onset of enteral nutrition for fear of """"""""causing"""""""" NEC because its pathogenesis is so poorly understood; this arcane practice prolongs hospitalization and increases the cost of neonatal health care. The histopathology of NEC clearly indicates that hypoxic-ischemic injury to the gut occurs at some time during the development of the disease. The experiments proposed to seek to explain the putative link between circulatory events and the development of NEC in a novel fashion. The working hypothesis of the proposal is as follows: newborn gut is developmentally regulated to maintain a very low vascular resistance after birth, an end achieved, in part, by NO and SP, because the relax vascular smooth muscle as well as suppress the local production and vascular action of constrictor stimuli (eg., A-II and ET). This circumstance changes abruptly during systemic hypotension. Increased systemic levels of A-II and ET-1, as well as reduced perfusion pressure, sharply increase gut vascular resistance by two means: directly, by their effect on the tone within the gut vasculature, and indirectly, by their effect on local production and vascular effect of endothelium-derived dilator and constrictor agents. This hypothesis will be tested in 4 experiments: 1) the potential role of locally-produced substance P as a key determinant of newborn gut vascular tone will determined by measuring peptide tissue levels, and by infusing exogenous peptide or blocking its action in vivo and in vitro (in microvessels); 2) the roles of A-I, A-II and ET in causing profound gut ischemia during cardiac tamponade will be determined by measuring the plasma concentration of these peptides and by blocking their effects during tamponade; 3) the effect of increased systemic levels of ET on the local production and vascular effect of A-I, A-II and norepinephrine (NE) will be determined by measuring A-I, A-II production in buffer-perfused mesentery and also by noting the effects of ET infusion on the dose- response relationships for A-II and NE within buffer-perfused arterioles; and 4) the effect of flow rate on the balance between NO, SP, A-II and ET production and vascular effect will be determined within in vitro reservoir (blood-perfused) gut loops and buffer-perfused mesenteric arterioles.
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| Reber, Kristina M; Su, Baogen Y; Clark, K Reed et al. (2002) Developmental expression of eNOS in postnatal swine mesenteric artery. Am J Physiol Gastrointest Liver Physiol 283:G1328-35 |
| Reber, Kristina M; Nankervis, Craig A; Nowicki, Philip T (2002) Newborn intestinal circulation. Physiology and pathophysiology. Clin Perinatol 29:23-39 |
| Reber, K M; Mager, G M; Miller, C E et al. (2001) Relationship between flow rate and NO production in postnatal mesenteric arteries. Am J Physiol Gastrointest Liver Physiol 280:G43-50 |
| Nankervis, C A; Reber, K M; Nowicki, P T (2001) Age-dependent changes in the postnatal intestinal microcirculation. Microcirculation 8:377-87 |
| Nankervis, C A; Dunaway, D J; Nowicki, P T (2001) Determinants of terminal mesenteric artery resistance during the first postnatal month. Am J Physiol Gastrointest Liver Physiol 280:G678-86 |
| Nankervis, C A; Nowicki, P T (2000) Role of endothelin-1 in regulation of the postnatal intestinal circulation. Am J Physiol Gastrointest Liver Physiol 278:G367-75 |
| Nowicki, P T (1999) Effects of sustained low-flow perfusion on the response to vasoconstrictor agents in postnatal intestine. Am J Physiol 276:G1408-16 |
| Nowicki, P T; Minnich, L A (1999) Effects of systemic hypotension on postnatal intestinal circulation: role of angiotensin. Am J Physiol 276:G341-52 |
| Nowicki, P T (1998) Effects of sustained flow reduction on postnatal intestinal circulation. Am J Physiol 275:G758-68 |
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