Insulin in the Brain Increases Gain of Baroreflex Control of Heart Rate and Lumbar Sympathetic Nerve Activity

Pricher, Mollie P.; Freeman, Kurt A.; Brooks, Virginia L.

doi:10.1161/hypertensionaha.107.102608

Cited by 51 publications

(78 citation statements)

References 45 publications

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“…This observation confirms previous studies from several laboratories in which intravenous or intracerebroventricular administration of insulin does not alter ABP or produces a small pressor response (ϳ5 mmHg) in rodents (Bardgett et al 2010;Cassaglia et al 2011;Luckett et al 2013;Morgan et al 1993;Muntzel et al 1994;Pricher et al 2008;Rahmouni et al 2004;Steiner et al 2014;Ward et al 2011). However, it is noteworthy that chronic infusion of insulin has been reported to raise ABP in rodents (Brands et al 1996).…”

Section: Discussionsupporting

confidence: 91%

Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

Stocker

Gordon

2015

Journal of Neurophysiology

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Stocker SD, Gordon KW. Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation. J Neurophysiol 113: 1302-1309, 2015. First published December 4, 2014 doi:10.1152/jn.00764.2014.-The sympathoexcitatory response to insulin is mediated by neurons in the arcuate nucleus (ARC) and hypothalamic paraventricular nucleus (PVH). Previous studies have reported that stimulation of ARC neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through glutamate receptor activation in the PVH. Therefore, the purpose of the present study was to determine whether glutamatergic neurotransmission in the PVH contributes to insulin-induced sympathoexcitation. Male Sprague-Dawley rats (275-400 g) were infused with isotonic saline or insulin (3.75 mU·kg Ϫ1 ·min Ϫ1 ) plus 50% dextrose to maintain euglycemia. Intravenous infusion of insulin significantly increased lumbar SNA without a significant change in mean ABP, renal SNA, heart rate, or blood glucose. Bilateral PVH injection of the excitatory amino acid antagonist kynurenic acid (KYN) lowered lumbar SNA and ABP of animals infused with insulin. Similarly, a cocktail of the NMDA antagonist DL-2-amino-5-phosphonopentanoic acid (AP5) and non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced lumbar SNA and mean ABP during infusion of insulin. In a final experiment, bilateral PVH injection of AP5 only, but not CNQX, lowered lumbar SNA and mean ABP of animals infused with insulin. The peak changes in lumbar SNA and mean ABP of insulin-treated animals were not different between KYN, AP5 plus CNQX, or AP5 alone. These drug treatments did not alter any variable in animals infused with saline. Altogether, these findings suggest that glutamatergic NMDA neurotransmission in the PVH contributes to insulin-induced sympathoexcitation.hypothalamus; lumbar; sympathetic nerve activity; NMDA; blood pressure ACCUMULATING EVIDENCE INDICATES insulin acts within the hypothalamic arcuate nucleus (ARC) to activate downstream pathways including neurons of the hypothalamic paraventricular nucleus (PVH) and rostral ventrolateral medulla (RVLM) to increase sympathetic nerve activity (SNA) and alter baroreflex function (Bardgett et al.

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Section: Discussionsupporting

confidence: 91%

Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

Stocker

Gordon

2015

Journal of Neurophysiology

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“…Second, pregnancy decreases brain insulin, which contributes to the fall in BRG (1,9). Insulin normally increases baroreflex gain via an action in the hypothalamus (26) and the PVN is involved (3). Insulin is an inhibitory neurotransmitter (31,33); therefore, insulin would be expected to excite preautonomic neurons by disinhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Baroreflex function curves were produced and recorded as previously described (26). Briefly, mean arterial pressure (MAP) was first rapidly decreased to ϳ50 mmHg by intravenous infusion of nitroprusside (1 mg/ml; 20 l/min).…”

Section: Methodsmentioning

confidence: 99%

GABA in the paraventricular nucleus tonically suppresses baroreflex function: alterations during pregnancy

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Cassaglia

Brooks

2011

American Journal of Physiology-Regulatory, Integrative and Comp

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It is well established that GABAergic inputs to the paraventricular nucleus of the hypothalamus (PVN) tonically suppress heart rate and the activity of several sympathetic nerves. However, whether GABA similarly inhibits PVN control of baroreflex function has not been previously investigated. To test this hypothesis, it was determined whether microinjection of the GABA A antagonist, bicuculline, into the PVN enhances the baroreflex in anesthetized female virgin rats. In addition, because GABAergic inhibition of PVN preautonomic neurons is decreased during pregnancy, it was also determined whether the effects of PVN bicuculline administration on baroreflex function were less in pregnant animals. In virgin rats, PVN microinjection of bicuculline increased (P Ͻ 0.05) baroreflex gain and maximum levels of heart rate (gain, from 1.6 Ϯ 0.6 to 3.8 Ϯ 1.3 bpm/mmHg; maximum, from 406 Ϯ 18 to 475 Ϯ 14 bpm) and of lumbar sympathetic nerve activity (gain from 2.6 Ϯ 0.7 to 4.8 Ϯ 1.6%/ mmHg; maximum, 149 Ϯ 32 to 273 Ϯ 48%), indicating that PVN GABA normally suppresses baroreflex function. Pregnancy decreased heart rate baroreflex gain (pregnant, 0.9 Ϯ 0.3 bpm/mmHg; virgin, 1.9 Ϯ 0.2 bpm/mmHg; P Ͻ 0.05). Following PVN bicuculline administration in pregnant rats, smaller (P Ͻ 0.01) increments in baroreflex gain (pregnant, 0.6 Ϯ 0.1 bpm/mmHg; virgin, 2.4 Ϯ 0.9 bpm/mmHg) and maximum (pregnant, 33 Ϯ 7 bpm; virgin, 75 Ϯ 12 bpm; P Ͻ 0.05) were produced. Collectively, these data suggest that the PVN normally inhibits the baroreflex via tonic GABAergic inputs and that this inhibition is less during pregnancy. heart rate; baroreceptor reflex; lumbar sympathetic nervous system; ␥-aminobutyric acid THE PARAVENTRICULAR NUCLEUS (PVN) of the hypothalamus integrates multiple forebrain and brain stem inputs to regulate the autonomic nervous system via outputs that ultimately converge with focal brain stem nuclei, such as the rostral ventrolateral medulla, as well as preganglionic sympathetic neurons in the spinal cord (7,27,29,32). While the contribution of the PVN and its connections to basal sympathetic tone at rest in normal animals is minimal, it appears to drive increased sympathetic activity in such pathophysiological states as hypertension, heart failure, and water deprivation (7,27). Moreover, the PVN mediates, in part, autonomic responses to diverse homeostatic challenges, such as changes in food intake, blood volume, stress, and body temperature (29). However, whether and how the PVN can also influence the regulation of the baroreceptor reflex is currently unclear.Of the PVN neurotransmitters and neuromodulators that effect these many functions, the tonically active inhibitory GABAergic inputs to preautonomic neurons are dominant (10, 28). Indeed, local pharmacological blockade of PVN GABA A receptors elicits profound increases in arterial pressure, heart rate (HR), and sympathetic activity and excites neurons that project to the brain stem or spinal cord (15,18,20,22). Therefore, one aim of the present study was to test the hypothes...

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“…It is well established that insulin is sympathoexcitatory, via a central action (117,142). In addition, acute and chronic increases in brain insulin increase the gain of baroreflex control of both heart rate and sympathetic activity (150,161). Interestingly, however, the rate of transport of insulin into brain, and therefore brain insulin levels, can be altered; indeed, insulin resistance is associated with impaired transport of insulin into brain (62,74,198).…”

Section: Insulin Resistance: a Contributor To Pregnancy-induced Decrementioning

confidence: 99%

“…As described above, insulin receptors are concentrated in many forebrain and hindbrain regions known to influence neural control of the circulation. However, infusion of insulin via the fourth cerebral ventricle failed to alter baroreflex control of heart rate or lumbar sympathetic nerve activity, suggesting that insulin initiates its effect at a forebrain site when infused via the lateral ventricles (161). Among potential hypothalamic sites, the PVN is a likely candidate, since this region is enriched with insulin receptors (171,197) (Fig.…”

Section: Insulin Resistance: a Contributor To Pregnancy-induced Decrementioning

confidence: 99%

Pregnancy and the endocrine regulation of the baroreceptor reflex

Brooks

Dampney

Heesch

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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-The purpose of this review is to delineate the general features of endocrine regulation of the baroreceptor reflex, as well as specific contributions during pregnancy. In contrast to the programmed changes in baroreflex function that occur in situations initiated by central command (e.g., exercise or stress), the complex endocrine milieu often associated with physiological and pathophysiological states can influence the central baroreflex neuronal circuitry via multiple sites and mechanisms, thereby producing varied changes in baroreflex function. During pregnancy, baroreflex gain is markedly attenuated, and at least two hormonal mechanisms contribute, each at different brain sites: increased levels of the neurosteroid 3␣-hydroxydihydroprogesterone (3␣-OH-DHP), acting in the rostral ventrolateral medulla (RVLM), and reduced actions of insulin in the forebrain. 3␣-OH-DHP appears to potentiate baroreflex-independent GABAergic inhibition of premotor neurons in the RVLM, which decreases the range of sympathetic nerve activity that can be elicited by changes in arterial pressure. In contrast, reductions in the levels or actions of insulin in the brain blunt baroreflex efferent responses to increments or decrements in arterial pressure. Although plasma levels of angiotensin II are increased in pregnancy, this is not responsible for the reduction in baroreflex gain, although it may contribute to the increased level of sympathetic nerve activity in this condition. How these different hormonal effects are integrated within the brain, as well as possible interactions with additional potential neuromodulators that influence baroreflex function during pregnancy and other physiological and pathophysiological states, remains to be clearly delineated.3␣-hydroxy-dihydroprogesterone; angiotensin II; insulin; paraventricular nucleus of the hypothalamus NORMAL PREGNANCY is characterized by profound changes in fluid and electrolyte balance and blood pressure regulation. Blood volume and cardiac output increase by 30 -50%, but arterial pressure falls due to even greater decreases in systemic vascular resistance (120,138,189). These hemodynamic alterations are evident early in pregnancy, precede the increases in uterine blood flow, and are sustained until parturition (127,138,189). Considerable data implicate increases in relaxin and nitric oxide (NO) in the systemic vasodilation induced by pregnancy (20,127,128,177,196). In addition, peripheral vascular sensitivity to circulating vasoconstrictors including vasopressin, angiotensin II (ANG II), and norepinephrine (NE) is decreased (50,71,154).Unlike the hemodynamic changes, which likely subserve adequate fetal development, an adverse consequence of normal pregnancy is a marked impairment of the arterial baroreceptor reflex. This change was first noted by Humphreys and Joels (97,98) in an extensive series of studies in anesthetized pregnant rabbits, in which reductions in carotid sinus pressure failed to elicit normal increases in arterial pressure and peripheral vascular resistanc...

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Insulin in the Brain Increases Gain of Baroreflex Control of Heart Rate and Lumbar Sympathetic Nerve Activity

Cited by 51 publications

References 45 publications

Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

GABA in the paraventricular nucleus tonically suppresses baroreflex function: alterations during pregnancy

Pregnancy and the endocrine regulation of the baroreceptor reflex

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