Pregnancy decreases baroreflex gain, resulting in reduced tolerance to hemorrhage and increased maternal mortality. However, the mechanism is unknown. Decreased baroreflex gain is produced in several pathophysiological states, including obesity, metabolic syndrome, diabetes mellitus, congestive heart failure, aging, as well as pregnancy, and a hallmark of each of these states is insulin resistance. This association led us to the novel hypothesis that the decreased gain of pregnancy is secondary to reduced insulin sensitivity, and our recent studies are the first to support this hypothesis. However, where and how insulin resistance impairs baroreflex function has not been studied in any state. Intracerebroventricular (icv) insulin infusion increases baroreflex gain in normal rats, and insulin resistance is associated with impaired transport of insulin into the brain. Insulin receptors are expressed in brain regions that participate in regulation of the autonomic nervous system, in particular, a hypothalamic site known to influence baroreflex gain, the paraventricular nucleus (PVN). Therefore, the proposed experiments will test the general hypothesis that, during pregnancy, insulin resistance impairs baroreflex control of heart rate and sympathetic activity by decreasing transport of insulin into the brain, leading to reduced levels and actions of insulin in PVN to increase gain. We will test this hypothesis by determining if pregnancy reduces insulin transport and insulin levels in the cerebrospinal fluid (CSF) and if the insulin sensitizing drug, rosiglitazone, increases insulin sensitivity, insulin transport, CSF levels of insulin, and baroreflex gain in pregnant rats. We will also determine if icv insulin infusion normalizes baroreflex function in late pregnant rats. Finally, complementary neuroanatomical, in vivo electrophysiological and pharmacological studies of PVN neurons will test the hypothesis that the PVN is necessary and sufficient for insulin's action to increase baroreflex gain. Project Narrative: Resistance to the actions of the pancreatic hormone, insulin, develops in several states, including type II diabetes mellitus and pregnancy. One of the consequences of insulin resistance (besides altered regulation of blood glucose levels) appears to be impairment of a critical blood pressure regulating mechanism, the baroreflex;however, the mechanism is unknown. Our studies of pregnancy will mechanistically link insulin resistance and baroreflex function, thereby increasing our understanding of this baroreflex impairment, as well as of the normal changes in energy balance that occur during pregnancy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088552-03
Application #
7846860
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Mitchell, Megan S
Project Start
2008-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$384,300
Indirect Cost
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Shi, Zhigang; Madden, Christopher J; Brooks, Virginia L (2017) Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways. J Clin Invest 127:2868-2880
Brooks, Virginia L; Shi, Zhigang; Holwerda, Seth W et al. (2015) Obesity-induced increases in sympathetic nerve activity: sex matters. Auton Neurosci 187:18-26
Shi, Zhigang; Brooks, Virginia L (2015) Leptin differentially increases sympathetic nerve activity and its baroreflex regulation in female rats: role of oestrogen. J Physiol 593:1633-47
Shi, Zhigang; Li, Baoxin; Brooks, Virginia L (2015) Role of the Paraventricular Nucleus of the Hypothalamus in the Sympathoexcitatory Effects of Leptin. Hypertension 66:1034-41
Shi, Zhigang; Cassaglia, Priscila A; Gotthardt, Laura C et al. (2015) Hypothalamic Paraventricular and Arcuate Nuclei Contribute to Elevated Sympathetic Nerve Activity in Pregnant Rats: Roles of Neuropeptide Y and ?-Melanocyte-Stimulating Hormone. Hypertension 66:1191-8
Vermehren-Schmaedick, Anke; Jenkins, Victoria K; Hsieh, Hui-ya et al. (2013) Upregulation of brain-derived neurotrophic factor expression in nodose ganglia and the lower brainstem of hypertensive rats. J Neurosci Res 91:220-9
McCully, Belinda H; Hasan, Wohaib; Streiff, Cole T et al. (2013) Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias. Am J Physiol Heart Circ Physiol 305:H1530-7
Li, Baoxin; Shi, Zhigang; Cassaglia, Priscila A et al. (2013) Leptin acts in the forebrain to differentially influence baroreflex control of lumbar, renal, and splanchnic sympathetic nerve activity and heart rate. Hypertension 61:812-9
Zhao, Ding; McCully, Belinda H; Brooks, Virginia L (2012) Rosiglitazone improves insulin sensitivity and baroreflex gain in rats with diet-induced obesity. J Pharmacol Exp Ther 343:206-13
Brooks, Virginia L; Cassaglia, Priscila A; Zhao, Ding et al. (2012) Baroreflex function in females: changes with the reproductive cycle and pregnancy. Gend Med 9:61-7

Showing the most recent 10 out of 17 publications