Control of Neonatal Circulation

University Of Tennessee Health Sci Ctr, Memphis TN

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Abstract

DESCRIPTION: (Provided By Applicant) Preliminary data suggest that carbon monoxide (CO) is an important messenger in the neonatal cerebral circulation that interacts with nitric oxide (NO) and prostacyclin (PGI2). These data include: cerebral microvessels produce CO that dilates arterioles via a mechanism involving KCa channels, inhibition of either nitric oxide synthase (NOS) or cyclooxygenase (COX) inhibits dilation to CO, and NO, and the PGL, analog, iloprost, can restore dilation to CO following inhibition of NOS and COX. The research will pursue the unifying hypothesis that cerebromicrovascular functions of CO involve interactions with NO and PGI2 via modification of KCa channel activity. Four specific aims will be addressed: 1. Evaluate, in vivo, the hypothesis that NO and PGI2 are permissive factors for CO-induced cerebromicrovascular dilation, 2. Test, in vitro, the hypothesis that NO and PGI2 augment CO activation of KCa channels, 3. Examine the mechanisms by which NO and PGI2 increase KCa channel responses to CO, and 4. Test the hypothesis that NO and/or PGI2 affects KCa channels, membrane potential, and CO induced hyperpolarization via activation of localized Ca2+ transients (Ca sparks). Techniques allowing investigation of intact cerebral microcirculation, isolated, pressurized, perfused cerebral arterioles, and freshly isolated cerebral artenolar myocytes from newborn pigs will be employed. Such research is unique by studying intact cerebral circulation and investigating, at the cellular and molecular levels, the mechanisms by which CO, NO, and PGI2 can interact to affect vascular tone. Cranial windows allow investigation of intact cerebral circulation. Isolated myocytes and perfused pressurized arterioles coupled with microelectrode and patch clamp techniques will be used to examine KCa channel activity and membrane potential. Global cytosolic Ca and Ca sparks in intact arterioles and isolated myocytes will be studied using fluorescent indicator technology with a dual excitation, single emission system and laser scanning confocal microscopy, respectively. Cerebral circulatory disorders in newborns are major causes of morbidity and mortality and can result in life long disabilities in survivors. Control of cerebrovascular circulation is easily impaired by pathological conditions. Better understanding of mechanisms of cerebromicrovascular humoral communication is needed badly.