Hypertension afflicts a great number of individuals and is a major cardiovascular risk factor. Dynamic exercise training decreases high blood pressure, but the mechanisms are incompletely understood. Neural mechanisms play a key role in regulating acute changes in arterial pressure, whereas renal mechanisms participate to a greater extent in volume regulation and long term control of pressure. Renal sympathetic nerves modulate sodium reabsorption and renin secretion. Thus, neural and renal mechanisms function in an integrated and concerted manner to regulate arterial pressure. Exercise training may exert its benefit by modulating this integrated system. We hypothesize that in 2 kidney-1 clip hypertension (2K-1C HTN), a rat model of hypertension with an activated renin-angiotensin-aldosterone system and increased sympathetic activity, voluntary dynamic exercise training will decrease efferent renal sympathetic nerve activity (RSNA) by enhancing nitric oxide-induced GABAergic inhibition within the paraventricular nucleus (PVN). In turn, the decrease in efferent RSNA will increase urinary Na excretion by decreasing the abundance and function of the epithelial Na channel (ENaC) in the distal nephron. We have 3 specific aims: (1) To assess whether voluntary wheel exercise will decrease systemic arterial pressure, decrease efferent sympathetic vasomotor tone, and increase arterial baroreflex sensitivity in 2K-1C HTN rats; (2) To ascertain whether voluntary wheel exercise will enhance nitric oxide signaling within the PVN, resulting in increased nitric oxide-induced GABAergic inhibition of efferent RSNA and improved baroreflex function in 2K-1C HTN rats; and (3) To determine whether the attenuated RSNA associated with voluntary wheel exercise will decrease the number of ENaC in the distal nephron of 2K-1C HTN, thereby increasing urinary Na excretion and enhancing the ability to respond to physiological stress such as acute Na loading. We will use a classic pharmacologic approach as well as in vivo transfer of dominant negative constructs for neuronal nitric oxide synthase (nNOS) into the PVN in sedentary and exercise trained sham-clipped and 2K-1C HTN rats and ascertain their hemodynamic parameters, RSNA and baroreflex function in the conscious, unrestrained state. We will measure the abundance of ENaC in microsomes of rat renal cortex and evaluate renal function and urinary Na excretion in sedentary and exercise trained rats with and without renal denervation under normal and acute Na loading conditions. These studies will provide data to direct strategic pharmacologic and nonpharmacologic interventions for cardiovascular health that may be readily translated into clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079102-02
Application #
7115381
Study Section
Special Emphasis Panel (ZRG1-CICS (01))
Program Officer
Ershow, Abby
Project Start
2005-09-01
Project End
2010-06-30
Budget Start
2006-09-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$323,764
Indirect Cost
Name
Wayne State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Massey, Katherine J; Li, Quanwen; Rossi, Noreen F et al. (2016) Phosphorylation of rat kidney Na-K pump at Ser938 is required for rapid angiotensin II-dependent stimulation of activity and trafficking in proximal tubule cells. Am J Physiol Cell Physiol 310:C227-32
Rossi, Noreen F; Chen, Haiping; Maliszewska-Scislo, Maria (2013) Paraventricular nucleus control of blood pressure in two-kidney, one-clip rats: effects of exercise training and resting blood pressure. Am J Physiol Regul Integr Comp Physiol 305:R1390-400
Massey, Katherine J; Li, Quanwen; Rossi, Noreen F et al. (2012) Angiotensin II-dependent phosphorylation at Ser11/Ser18 and Ser938 shifts the E2 conformations of rat kidney Na+/K+-ATPase. Biochem J 443:249-58
Kava, Lauren; Rossi, Noreen F; Mattingly, Raymond et al. (2012) Increased expression of Na,K-ATPase and a selective increase in phosphorylation at Ser-11 in the cortex of the 2-kidney, 1-clip hypertensive rat. Am J Hypertens 25:487-91
Kohan, Donald E; Rossi, Noreen F; Inscho, Edward W et al. (2011) Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev 91:1-77
Rossi, Noreen F; Maliszewska-Scislo, Maria; Chen, Haiping et al. (2010) Neuronal nitric oxide synthase within paraventricular nucleus: blood pressure and baroreflex in two-kidney, one-clip hypertensive rats. Exp Physiol 95:845-57
Augustyniak, Robert A; Singh, Karan; Zeldes, Daniel et al. (2010) Maternal protein restriction leads to hyperresponsiveness to stress and salt-sensitive hypertension in male offspring. Am J Physiol Regul Integr Comp Physiol 298:R1375-82
Rossi, N F; Maliszewska-Scislo, M (2008) Role of paraventricular nucleus vasopressin V1A receptors in the response to endothelin 1 activation of the subfornical organ in the rat. J Physiol Pharmacol 59 Suppl 8:47-59
Yingst, Douglas R; Doci, Tabitha M; Massey, Katherine J et al. (2008) Angiotensin II stimulates elution of Na-K-ATPase from a digoxin-affinity column by increasing the kinetic response to ligands that trigger the decay of E2-P. Am J Physiol Renal Physiol 294:F990-F1000
Maliszewska-Scislo, Maria; Chen, Haiping; Augustyniak, Robert A et al. (2008) Subfornical organ differentially modulates baroreflex function in normotensive and two-kidney, one-clip hypertensive rats. Am J Physiol Regul Integr Comp Physiol 295:R741-50

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