The sympathetic nervous system plays an important role in the pathogenesis of hypertension, yet the precise determinants of sympathetic activation are unresolved. Furthermore, the efferent mechanisms that account for long-term sympathetically-induced alterations in arterial pressure are unclear. In this regard, there is considerable controversy as to whether alterations in renal excretory function are of paramount importance in mediating the chronic effects of the nervous system on arterial pressure. In short, progress in understanding the above issues has been limited by the lack of clinical and experimental methods for critically studying sympathetic function in the chronic regulation of arterial pressure. Because of the crucial role of the baroreflex in acute regulation of arterial pressure, there has been a long-standing interest in the possibility that baroreflexes might chronically influence the level of sympathetic activity and arterial pressure in hypertension. The potential importance of such a relationship has been highlighted by clinical observations demonstrating that the sympathetic arm of the baroreflex is impaired in primary hypertension. However, because the baroreflex resets in the direction of the ambient pressure, a role for the baroreflex in long-term pressure control is often discounted. On the other hand, because of technical limitations, it is important to emphasize that there is little empirical evidence from chronic studies that supports the notion that baroreflex resetting is complete in hypertension. In fact, recent innovative studies in animals with experimentally-induced hypertension suggest that the baroreflex does not totally reset and has sustained sympathoinhibitory effects in hypertension. These studies further indicate baroreflex activation chronically suppresses renal sympathetic nerve activity and promotes sodium excretion, responses expected to attenuate the severity of hypertension. The relevance of these studies to clinical hypertension, however, is limited by their relatively short duration (most commonly one week). In the proposed studies, we will use a novel approach to evaluate several aspects of baroreflex function over at least 3 weeks of controlled baroreflex activation. We will use a combination of sophisticated techniques in chronically instrumented dogs to determine whether the central nervous system contributes to chronic resetting of the baroreflex and whether chronic activation of the baroreflex does indeed have sustained effects to inhibit renal sympathetic nerve activity and promote sodium excretion. To achieve these goals, the carotid baroreflex will be chronically activated by electrical stimulation of the carotid sinuses. Chronic electrical activation of the carotid baroreflex leads to sustained suppression of sympathetic activity and arterial pressure and is an ideal technique for determining the importance of central resetting in attenuating the sympathoinhibition induced by increased baroreceptor activity because it allows for precise control of central afferent input patterns. Additionally, in combination with other measures, this methodology permits direct evaluation of the chronic effects of baroreflex activation on renal sympathetic outflow and excretory function. Isotope dilution methodology will be used in these studies to determine whole body and renal norepinephrine spillover to plasma as indices of central and renal specific sympathetic outflow. These studies will provide unique insight into the chronic functional effects of the baroreflex in hypertension and the importance of the kidneys in mediating long-term changes in-arterial pressure during alterations in central sympathetic outflow.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL051971-19
Application #
8374561
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
19
Fiscal Year
2012
Total Cost
$286,379
Indirect Cost
$92,896
Name
University of Mississippi Medical Center
Department
Type
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Jung, Mira; Ma, Yonggang; Iyer, Rugmani Padmanabhan et al. (2017) IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol 112:33
Ma, Yonggang; Iyer, Rugmani Padmanabhan; Jung, Mira et al. (2017) Cardiac Fibroblast Activation Post-Myocardial Infarction: Current Knowledge Gaps. Trends Pharmacol Sci 38:448-458
Feng, Ruiqi; Liu, Jia; Wang, Zhenhua et al. (2017) The structure-activity relationship of ginsenosides on hypoxia-reoxygenation induced apoptosis of cardiomyocytes. Biochem Biophys Res Commun 494:556-568
Muntner, Paul; Abdalla, Marwah; Correa, Adolfo et al. (2017) Hypertension in Blacks: Unanswered Questions and Future Directions for the JHS (Jackson Heart Study). Hypertension 69:761-769
Chade, Alejandro R (2017) Small Vessels, Big Role: Renal Microcirculation and Progression of Renal Injury. Hypertension 69:551-563
Drummond, Heather A; Xiang, Lusha; Chade, Alejandro R et al. (2017) Enhanced maximal exercise capacity, vasodilation to electrical muscle contraction, and hind limb vascular density in ASIC1a null mice. Physiol Rep 5:
Faulkner, Jessica L; Amaral, Lorena M; Cornelius, Denise C et al. (2017) Vitamin D supplementation reduces some AT1-AA-induced downstream targets implicated in preeclampsia including hypertension. Am J Physiol Regul Integr Comp Physiol 312:R125-R131
Blair, Evan T; Clemmer, John S; Harkey, H Louis et al. (2017) Physiologic Mechanisms of Water and Electrolyte Disturbances After Transsphenoidal Pituitary Surgery. World Neurosurg 107:429-436
Bakrania, Bhavisha A; Spradley, Frank T; Satchell, Simon C et al. (2017) Heme oxygenase-1 is a potent inhibitor of placental ischemia-mediated endothelin-1 production in cultured human glomerular endothelial cells. Am J Physiol Regul Integr Comp Physiol :
Taylor, Erin B; Ryan, Michael J (2017) Immunosuppression With Mycophenolate Mofetil Attenuates Hypertension in an Experimental Model of Autoimmune Disease. J Am Heart Assoc 6:

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