Blood pressure sensitivity to salt intake appears in both hypertensives and normotensives and represents a major health problem as it is associated with increased cardiovascular risk. Prior investigations have suggested a central role for the L-arginine-nitric oxide (NO) system in salt sensitivity. Despite significant prior contributions, fundamental questions about the role of NO in the regulation of vascular tone remain unanswered and this impedes current efforts to optimize available interventions and/or develop new therapeutic strategies. Therefore, this research proposal aims to fill an important gap in the understanding of the mechanisms that regulate vascular resistance and to translate this knowledge into clinically testable hypotheses for improved therapeutic practice in hypertension. The central hypothesis of this study is that regulation of vascular resistance emerges from the nonlinear interaction of Ca2+ and NO-dependent signaling pathways. Altered NO/Ca2+ dynamics contribute to a different phenotype in the microcirculation of salt-sensitive hypertensives. In this study we follow an innovative synergistic approach of theoretical modeling and in vitro experimentation to elucidate signaling mechanisms in the microcirculation. Mathematical models integrate biophysically detailed mechanisms at the cellular level to describe physiological function at a macroscale tissue level. The overall goal is to provide a theoretical framework that will guide the development of novel therapeutic strategies in salt sensitivity. In vitro experimental studies assist in model development and test model generated hypotheses. Microcirculatory phenotype and vascular reactivity are assessed in an animal model of salt sensitive hypertension. Synergistic strategies of NO stimulation combined with inhibition of the angiotensin system or effectors of Ca2+ homeostasis are evaluated for their ability to restore normal vascular function. ? ? Relevance: Salt intake affects blood pressure levels in a large percentage of the population. This condition, referred to as salt sensitivity, represents a major public health problem as it is associated with an increased risk for cardiovascular disease. In this study we utilize a novel approach of combining computational modeling and experimentation to investigate the mechanisms that link salt intake and blood pressure. Preliminary results suggest that combination of available pharmaceutics can have beneficial effects in restoring function in the microcirculation and will be tested in hypertensive animals. ? ? ?
| Kapela, Adam; Behringer, Erik J; Segal, Steven S et al. (2018) Biophysical properties of microvascular endothelium: Requirements for initiating and conducting electrical signals. Microcirculation 25: |
| Parikh, Jaimit; Kapela, Adam; Tsoukias, Nikolaos M (2017) Can endothelial hemoglobin-? regulate nitric oxide vasodilatory signaling? Am J Physiol Heart Circ Physiol 312:H854-H866 |
| Parikh, Jaimit; Kapela, Adam; Tsoukias, Nikolaos M (2015) Stochastic model of endothelial TRPV4 calcium sparklets: effect of bursting and cooperativity on EDH. Biophys J 108:1566-1576 |
| Gadkari, Tushar V; Cortes, Natalie; Madrasi, Kumpal et al. (2013) Agmatine induced NO dependent rat mesenteric artery relaxation and its impairment in salt-sensitive hypertension. Nitric Oxide 35:65-71 |
| Namin, Shabnam M; Nofallah, Sara; Joshi, Mahesh S et al. (2013) Kinetic analysis of DAF-FM activation by NO: toward calibration of a NO-sensitive fluorescent dye. Nitric Oxide 28:39-46 |
| Nagaraja, Sridevi; Kapela, Adam; Tran, Cam H et al. (2013) Role of microprojections in myoendothelial feedback--a theoretical study. J Physiol 591:2795-812 |
| Madrasi, Kumpal; Joshi, Mahesh S; Gadkari, Tushar et al. (2012) Glutathiyl radical as an intermediate in glutathione nitrosation. Free Radic Biol Med 53:1968-76 |
| Nagaraja, Sridevi; Kapela, Adam; Tsoukias, Nikolaos M (2012) Intercellular communication in the vascular wall: a modeling perspective. Microcirculation 19:391-402 |
| Yu, Hong; Shao, Hongwei; Yan, Jing et al. (2012) Bone marrow transplantation improves endothelial function in hypertensive Dahl salt-sensitive rats. J Am Soc Hypertens 6:331-7 |
| Tran, Cam Ha T; Taylor, Mark S; Plane, Frances et al. (2012) Endothelial Ca2+ wavelets and the induction of myoendothelial feedback. Am J Physiol Cell Physiol 302:C1226-42 |
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