A third gasotransmitter, joining NO and CO, is hydrogen sulfide (H2S) that is produced physiologically from L-cysteine catabolized by cystathionine 3-lyase (CSE) and cystathionine 2-synthase (CBS). CSE is the predominant isoform in the vasculature and CBS in whole brain. Reports are emerging of roles of hydrogen sulfide (H2S) in neuronal function in the brain, but no published data exist on H2S and cerebrovascular function. The research proposed is designed to pursue the unifying hypothesis that H2S synthesized by endothelial CSE is an integral component of neonatal cerebral circulatory regulation. To test this hypothesis, four specific aims will be addressed in newborn pigs: 1. Determine the functional significance of H2S in regulation of cerebral arteriolar resistance, 2. Localize and characterize H2S production in the neonatal cerebral vasculature, 3. Investigate, in vivo, the contribution of endothelium to H2S-dependent cerebrovascular responses, and 4. Investigate mechanisms of H2S-induced modifications of cerebral arteriolar tone. To accomplish these aims, techniques will be used that allow investigation of intact newborn cerebral microcirculation in vivo, pressurized isolated cerebral arterioles, freshly isolated cerebral microvessels and smooth muscle cells, and cerebral microvascular endothelial cells in primary culture. Such research is unique by studying intact cerebral circulation and investigating, at the cellular and molecular levels, the mechanisms responsible for controlling the production of the mediator, H2S, and the mechanisms by which H2S can affect vascular tone. Cranial windows allow observation of cerebral circulation, collection of cortical periarachnoid fluid, and topical application of agonists, precursors and inhibitors. Cellular distribution of CSE and CBS and cellular mechanisms for controlling the enzyme activity will be examined. As the indicator of the enzyme activity, we propose a novel analytical method of H2S detection, identification, and quantification by gas chromatography-mass spectrometry. The cellular mechanisms by which H2S may modify vascular tone will be studied at the level of second messengers, ion channels, and membrane potential. Disorders of the cerebral circulation in the newborn period are major causes of morbidity and mortality and can result in lifelong disabilities in survivors. Control of cerebrovascular circulation is easily impaired by pathological conditions. Better understanding of mechanisms of cerebromicrovascular humoral communication in newborns is needed badly.
The single most prominent cause of mortality and morbidity in newborns is hypoxic-ischemic brain injury, which often leads to lifelong disability. Successes in developing approaches to avert and treat perinatal hypoxia- ischemic brain damage have been limited by insufficient understanding of the mechanisms that control perinatal cerebral circulation. The gasotransmitter, H2S, will certainly prove to be one of these major mechanisms of which greater understanding is urgently needed.
|Chang, Jennifer; Fedinec, Alexander L; Kuntamallappanavar, Guruprasad et al. (2016) Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction. J Pharmacol Exp Ther 356:106-15|
|Liu, Jianxiong; Fedinec, Alexander L; Leffler, Charles W et al. (2015) Enteral supplements of a carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by neonatal seizures. J Cereb Blood Flow Metab 35:193-9|
|Pourcyrous, Massroor; Basuroy, Shyamali; Tcheranova, Dilyara et al. (2015) Brain-derived circulating endothelial cells in peripheral blood of newborn infants with seizures: a potential biomarker for cerebrovascular injury. Physiol Rep 3:|
|Bukiya, Anna; Dopico, Alejandro M; Leffler, Charles W et al. (2014) Dietary cholesterol protects against alcohol-induced cerebral artery constriction. Alcohol Clin Exp Res 38:1216-26|
|Nnorom, Chukwuma C; Davis, Corinne; Fedinec, Alexander L et al. (2014) Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain. Physiol Rep 2:|
|Basuroy, Shyamali; Leffler, Charles W; Parfenova, Helena (2013) CORM-A1 prevents blood-brain barrier dysfunction caused by ionotropic glutamate receptor-mediated endothelial oxidative stress and apoptosis. Am J Physiol Cell Physiol 304:C1105-15|
|Bukiya, Anna N; McMillan, Jacob E; Fedinec, Alexander L et al. (2013) Cerebrovascular dilation via selective targeting of the cholane steroid-recognition site in the BK channel Î²1-subunit by a novel nonsteroidal agent. Mol Pharmacol 83:1030-44|
|Liang, Guo Hua; Xi, Qi; Leffler, Charles W et al. (2012) Hydrogen sulfide activates CaÂ²âº sparks to induce cerebral arteriole dilatation. J Physiol 590:2709-20|
|Parfenova, Helena; Leffler, Charles W; Basuroy, Shyamali et al. (2012) Antioxidant roles of heme oxygenase, carbon monoxide, and bilirubin in cerebral circulation during seizures. J Cereb Blood Flow Metab 32:1024-34|
|Parfenova, Helena; Tcheranova, Dilyara; Basuroy, Shyamali et al. (2012) Functional role of astrocyte glutamate receptors and carbon monoxide in cerebral vasodilation response to glutamate. Am J Physiol Heart Circ Physiol 302:H2257-66|
Showing the most recent 10 out of 55 publications