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.
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