Current knowledge about hypertension suggests that an elevated peripheral resistance mains high levels of arterial pressure. This increase in peripheral resistance may be caused by a vasoconstriction resulting from an impaired dilator influence of nitric oxide derived from the endothelium. Reduced synthesis of nitric oxide by the endothelium is one possible mechanism to cause vasoconstriction but it is equally possible that numerous other cellular processes are mechanistically associated with abnormal signaling properties of nitric oxide in hypertension. In this research application, we propose that an impaired activity of nitric oxide synthase in glucocorticoid hypertension is due to a reduction in the amount of tetrahydrobiopterin, an essential co- factor for limiting enzyme for production of tetrahydropterin, contributes to reduced nitric oxide synthase activity and impaired vasodilation and hypertension. The research will focus on four aspects of this endothelium- vascular myocyte signaling system in rodents made hypertensive with implantation of dexamethasone: 1) to characterize functional and integrative determinants of the elevated arterial pressure and increased vasoconstriction of glucocorticoid hypertension (early and late changes); 2) to define the role of tetrahydiobiopterin and endothelium-derived nitric oxide in the altered reactivity characteristic of glucocorticoid hypertension; 3) to evaluate glucocorticoid action in mice who have low endothelial nitric oxide activity (arginine analog-induced hypertensive mice and eNOS knockout mice); and 4) to determine how glucocorticoid excess during pregnancy """"""""programs"""""""" adult hypertension in offspring. The techniques used to evaluate characteristics of glucocorticoid hypertension and the endothelium-vascular myocyte signaling system include: 1) measurement of blood pressure using a telemetry system; 2) evaluation of hormonal status and other metabolic parameters; 3) isometric recording of contractile behavior of isolated arteries and measures of pressor activity in perfused mesentery and hindquarters; 4) pharmacological interventions to evaluate the role of the endothelium; 5) interventions to biochemical determination of biopterins. It is anticipated that this study will yield important information about impaired dilator activity of nitric oxide in glucocorticoid hypertension.
| Rocchini, Albert P; Yang, John Q; Smith, Marla J et al. (2010) Serial changes in norepinephrine kinetics associated with feeding dogs a high-fat diet. J Clin Hypertens (Greenwich) 12:117-24 |
| Kamal, Mohamed A; Keep, Richard F; Smith, David E (2008) Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity. Drug Metab Pharmacokinet 23:236-42 |
| Duan, Sheng Zhong; Ivashchenko, Christine Y; Whitesall, Steven E et al. (2007) Direct monitoring pressure overload predicts cardiac hypertrophy in mice. Physiol Meas 28:1329-39 |
| Hu, Yongjun; Shen, Hong; Keep, Richard F et al. (2007) Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity. J Neurochem 103:2058-65 |
| Ennis, Steven R; Keep, Richard F (2007) Effect of sustained-mild and transient-severe hyperglycemia on ischemia-induced blood-brain barrier opening. J Cereb Blood Flow Metab 27:1573-82 |
| Shen, Hong; Ocheltree, Scott M; Hu, Yongjun et al. (2007) Impact of genetic knockout of PEPT2 on cefadroxil pharmacokinetics, renal tubular reabsorption, and brain penetration in mice. Drug Metab Dispos 35:1209-16 |
| Carello, Katari A; Whitesall, Steven E; Lloyd, Mary C et al. (2006) Asymmetrical dimethylarginine plasma clearance persists after acute total nephrectomy in rats. Am J Physiol Heart Circ Physiol 290:H209-16 |
| Xiang, Jianming; Hu, Yongjun; Smith, David E et al. (2006) PEPT2-mediated transport of 5-aminolevulinic acid and carnosine in astrocytes. Brain Res 1122:18-23 |
| Ennis, Steven R; Keep, Richard F (2006) The effects of cerebral ischemia on the rat choroid plexus. J Cereb Blood Flow Metab 26:675-83 |
| Xiang, Jianming; Chiang, Pei-Pei; Hu, Yongjun et al. (2006) Role of PEPT2 in glycylsarcosine transport in astrocyte and glioma cultures. Neurosci Lett 396:225-9 |
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