Pregnancy increases baroreflex-independent GABAergic inhibition of the RVLM in rats

Kvochina, Lyudmyla; Hasser, Eileen M.; Heesch, Cheryl M.

doi:10.1152/ajpregu.00365.2007

Cited by 17 publications

(20 citation statements)

References 70 publications

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“…Prior blockade of AT 1 receptors in the RVLM decreased responses to disinhibition, but the difference in responses to bicuculline between pregnant and nonpregnant rats persisted. Thus, although ANG II likely contributes to elevated baseline sympathetic outflow in pregnancy (21,149), within the RVLM other underlying excitatory influences must contribute to observed differences between pregnant and nonpregnant rats (110).…”

Section: Neurosteroid Metabolite Of Progesterone: a Contributor To Atmentioning

confidence: 97%

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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Section: Neurosteroid Metabolite Of Progesterone: a Contributor To Atmentioning

confidence: 97%

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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“…A bipolar silver recording electrode was implanted on the left LSNA (Kwik-Sil; World Precision Instruments, Sarasota, FL), a ground wire secured in adjacent muscle, and the LSNA signal amplified (5,000 -10,000ϫ) and filtered (30 Hz-3 kHz; RPS 107; Grass Instruments, Quincy, MA). Pulsatile AP, mean AP (MAP), heart rate (HR), and LSNA were monitored (LabChart 7 ProV 7.1.2; ADInstruments, Colorado Springs, CO) (27). Surgical sinoaortic denervation (SAD) was performed to eliminate arterial baroreceptor afferent fibers and prevent baroreflex compensatory responses, as described previously (27,50).…”

Section: Study 1: Contribution Of Sympathetic Nervous System and Vasomentioning

confidence: 99%

“…Pulsatile AP, mean AP (MAP), heart rate (HR), and LSNA were monitored (LabChart 7 ProV 7.1.2; ADInstruments, Colorado Springs, CO) (27). Surgical sinoaortic denervation (SAD) was performed to eliminate arterial baroreceptor afferent fibers and prevent baroreflex compensatory responses, as described previously (27,50). Absence of baroreflex-mediated decreases in LSNA, in response to increased MAP [phenylephrine (PE), 5 g iv], verified successful SAD.…”

Section: Study 1: Contribution Of Sympathetic Nervous System and Vasomentioning

confidence: 99%

“…Absence of baroreflex-mediated decreases in LSNA, in response to increased MAP [phenylephrine (PE), 5 g iv], verified successful SAD. With the use of a custom-built micropressure injection system (27), a triple-barreled injection pipette (ϳ10 m/barrel), and stereotaxic coordinates (midline, Ϫ0.9 mm caudal to bregma; 4.7 mm ventral to dura), the SFO was first functionally identified by a transient increase in MAP (Ն10 mmHg) and LSNA (Ն10%) due to microinjection of ANG II (20 M; 50 nl ϭ 1 pmol) in the SFO. After recovery (ϳ20 min), RLX (gift from Dr. C. Samuel, Florey Institute, Melbourne, Australia) was microinjected (15.4 M; 50 nl ϭ 0.77 pmol) into the SFO.…”

Section: Study 1: Contribution Of Sympathetic Nervous System and Vasomentioning

confidence: 99%

“…In pregnant (P) rats, the operating pressure range for arterial baroreflex control of sympathetic nerve activity (SNA) shifts toward the lower baseline arterial pressure (AP) of pregnancy, and baroreflex-mediated sympathoexcitation is attenuated (31), likely due to increased baroreflex-independent GABAergic inhibition of the rostral ventrolateral medulla (RVLM) in the brain stem (27). These adaptations are consistent with increased orthostatic hypotension in P women and greater sensitivity to the hypotensive effects of hemorrhage in pregnancy (3).…”

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confidence: 99%

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Relaxin increases sympathetic nerve activity and activates spinally projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats

Coldren

Brown

Hasser

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Coldren KM, Brown R, Hasser EM, Heesch CM. Relaxin increases sympathetic nerve activity and activates spinally projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats. Am J Physiol Regul Integr Comp Physiol 309: R1553-R1568, 2015. First published September 23, 2015; doi:10.1152/ajpregu.00186.2015.-Pregnancy is characterized by increased blood volume and baseline sympathetic nerve activity (SNA), vasodilation, and tachycardia. Relaxin (RLX), an ovarian hormone elevated in pregnancy, activates forebrain sites involved in control of blood volume and SNA through ANG II-dependent mechanisms and contributes to adaptations during pregnancy. In anesthetized, arterial baroreceptordenervated nonpregnant (NP) rats, RLX microinjected into the subfornical organ (SFO; 0.77 pmol in 50 nl) produced sustained increases in lumbar SNA (8 Ϯ 3%) and mean arterial pressure (MAP; 26 Ϯ 4 mmHg). Low-dose intracarotid artery infusion of RLX (155 pmol·ml Ϫ1 ·h Ϫ1 ; 1.5 h) had minor transient effects on AP and activated neurons [increased Fos-immunoreactivity (IR)] in the SFO and in spinally projecting (19 Ϯ 2%) and arginine-vasopressin (AVP)-IR (21 Ϯ 5%) cells in the paraventricular nucleus of the hypothalamus of NP, but not pregnant (P), rats. However, mRNA for RLX and ANG II type 1a receptors in the SFO was preserved in pregnancy. RLX receptor-IR is present in the region of the SFO in NP and P rats and is localized in astrocytes, the major source of angiotensinogen in the SFO. These data provide an anatomical substrate for a role of RLX in the resetting of AVP secretion and increased baseline SNA in pregnancy. Since RLX and ANG II receptor expression was preserved in the SFO of P rats, we speculate that the lack of response to exogenous RLX may be due to maximal activation by elevated endogenous levels of RLX in near-term pregnancy.Fos; paraventricular nucleus; subfornical organ; circumventricular organs; ANG II; arginine-vasopressin WITH ITS HIGHEST CIRCULATING levels achieved during pregnancy, relaxin (RLX) is a 6-kDa peptide hormone secreted primarily by the corpus luteum of the ovary. RLX-2 in humans is functionally equivalent to RLX-1 in all other mammals, and often both are called simply "relaxin" (2, 4, 21). Although best known for its role in growth and remodeling of the female reproductive tract during pregnancy, RLX peptide and RLX binding sites are present in male reproductive tissue and the heart, vasculature, kidney, and brain of both males and females. In regards to the cardiovascular system, in both male and female humans and rats, chronic administration of RLX causes vascular remodeling, angiogenesis, and systemic vasodilation (8). Endogenous RLX is a major contributor to peripheral vasodilation and augmented renal function seen in pregnancy, and recent clinical trials suggest that exogenously administered RLX may have therapeutic value in treating heart-failure patients (2,8,14).In addition to peripheral vascular effects, circulating RLX plays an important role in the central nervous sys...

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Subregional differences in GABA_A receptor subunit expression in the rostral ventrolateral medulla of sedentary versus physically active rats

Mueller

Fyk‐Kolodziej

Azar

et al. 2019

J of Comparative Neurology

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Neurons in the rostral ventrolateral medulla (RVLM) regulate blood pressure through direct projections to spinal sympathetic preganglionic neurons. Only some RVLM neurons are active under resting conditions due to significant, tonic inhibition by gammaaminobutyric acid (GABA). Withdrawal of GABA A receptor-mediated inhibition of the RVLM increases sympathetic outflow and blood pressure substantially, providing a mechanism by which the RVLM could contribute chronically to cardiovascular disease (CVD). Here, we tested the hypothesis that sedentary conditions, a major risk factor for CVD, increase GABA A receptors in RVLM, including its rostral extension (RVLM RE ), both of which contain bulbospinal catecholamine (C1) and non-C1 neurons. We examined GABA A receptor subunits GABA Aα1 and GABA Aα2 in the RVLM/RVLM RE of sedentary or physically active (10-12 weeks of wheel running) rats. Western blot analyses indicated that sedentary rats had lower expression of GABA Aα1 and GABA Aα2 subunits in RVLM but only GABA Aα2 was lower in the RVLM RE of sedentary rats. Sedentary rats had significantly reduced expression of the chloride transporter, KCC2, suggesting less effective GABA-mediated inhibition compared to active rats. Retrograde tracing plus triple-label immunofluorescence identified fewer bulbospinal non-C1 neurons immunoreactive for GABA Aα1 but a higher percentage of bulbospinal C1 neurons immunoreactive for GABA Aα1 in sedentary animals. Sedentary conditions did not significantly affect the number of bulbospinal C1 or non-C1 neurons immunoreactive for GABA Aα2 .These results suggest a complex interplay between GABA A receptor expression by spinally projecting C1 and non-C1 neurons and sedentary versus physically active conditions. They also provide plausible mechanisms for both enhanced sympathoexcitatory and sympathoinhibitory responses following sedentary conditions.

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Pregnancy increases baroreflex-independent GABAergic inhibition of the RVLM in rats

Cited by 17 publications

References 70 publications

Pregnancy and the endocrine regulation of the baroreceptor reflex

Pregnancy and the endocrine regulation of the baroreceptor reflex

Relaxin increases sympathetic nerve activity and activates spinally projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats

Subregional differences in GABA_A receptor subunit expression in the rostral ventrolateral medulla of sedentary versus physically active rats

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Pregnancy increases baroreflex-independent GABAergic inhibition of the RVLM in rats

Cited by 17 publications

References 70 publications

Pregnancy and the endocrine regulation of the baroreceptor reflex

Pregnancy and the endocrine regulation of the baroreceptor reflex

Relaxin increases sympathetic nerve activity and activates spinally projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats

Subregional differences in GABAA receptor subunit expression in the rostral ventrolateral medulla of sedentary versus physically active rats

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Subregional differences in GABA_A receptor subunit expression in the rostral ventrolateral medulla of sedentary versus physically active rats