scholarly journals AT1a influences GABAA-mediated inhibition through regulation of KCC2 expression

2018 ◽  
Vol 315 (5) ◽  
pp. R972-R982 ◽  
Author(s):  
George E. Farmer ◽  
Kirthikaa Balapattabi ◽  
Martha E. Bachelor ◽  
Joel T. Little ◽  
J. Thomas Cunningham
Keyword(s):  
Protein Expression ◽  
Body Fluid ◽  
Neuronal Excitability ◽  
Receptor Activation ◽  
Cardiovascular Control ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Fluid Homeostasis ◽  
Body Fluid Homeostasis

The median preoptic nucleus (MnPO) is an integrative site involved in body fluid homeostasis, cardiovascular control, thermoregulation, and sleep homeostasis. Angiotensin II (ANG II), a neuropeptide shown to have excitatory effects on MnPO neurons, is of particular interest with regard to its role in body fluid homeostasis and cardiovascular control. The present study investigated the role of angiotensin type 1a (AT1a) receptor activation on neuronal excitability in the MnPO. Male Sprague-Dawley rats were infused with an adeno-associated virus with an shRNA against the AT1a receptor or a scrambled control. In vitro loose-patch voltage-clamp recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. Additionally, tissue punches from MnPO were taken to asses mRNA and protein expression. AT1a receptor knockdown neurons were insensitive to ANG II and showed a marked reduction in GABAA-mediated inhibition. The reduction in GABAA-mediated inhibition was not associated with reductions in mRNA or protein expression of GABAA β-subunits. Knockdown of the AT1a receptor was associated with a reduction in the potassium-chloride cotransporter KCC2 mRNA as well as a reduction in pS940 KCC2 protein. The impaired GABAA-mediated inhibition in AT1a knockdown neurons was recovered by bath application of phospholipase C and protein kinase C activators. The following study indicates that AT1a receptor activation mediates the excitability of MnPO neurons, in part, through the regulation of KCC2. The regulation of KCC2 influences the intracellular [Cl−] and the subsequent efficacy of GABAA-mediated currents.

Stanniocalcin-1 in the subfornical organ inhibits the dipsogenic response to angiotensin II

2012 ◽  
Vol 303 (9) ◽  
pp. R921-R928 ◽  
Author(s):  
Jason M. Moreau ◽  
Waseem Iqbal ◽  
Jeffrey K. Turner ◽  
Graham F. Wagner ◽  
John Ciriello
Keyword(s):  
Western Blot ◽  
Water Intake ◽  
Body Fluid ◽  
Physiological Role ◽  
Subfornical Organ ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Glycoprotein Hormone ◽  
Fluid Homeostasis ◽  
Body Fluid Homeostasis

Recently, receptors for the calcium-regulating glycoprotein hormone stanniocalcin-1 (STC-1) have been found within subfornical organ (SFO), a central structure involved in the regulation of electrolyte and body fluid homeostasis. However, whether SFO neurons produce STC-1 and how STC-1 may function in fluid homeostasis are not known. Two series of experiments were done in Sprague-Dawley rats to investigate whether STC-1 is expressed within SFO and whether it exerts an effect on water intake. In the first series, experiments were done to determine whether STC-1 was expressed within cells in SFO using immunohistochemistry, and whether protein and gene expression for STC-1 existed in SFO using Western blot and quantitative RT-PCR, respectively. Cells containing STC-1 immunoreactivity were found throughout the rostrocaudal extent of SFO. STC-1 protein expression within SFO was confirmed with Western blot, and SFO was also found to express STC-1 mRNA. In the second series, microinjections (200 nl) of STC-1, ANG II, a combination of the two or the vehicle were made into SFO in conscious, unrestrained rats. Water intake was measured at 0700 for a 1-h period after each injection in animals. Microinjections of STC-1 (17.6 or 176 nM) alone had no effect on water intake compared with controls. However, STC-1 not only attenuated the drinking responses to ANG II for about 30 min, but also decreased the total water intake over the 1-h period. These data suggest that STC-1 within the SFO may act in a paracrine/autocrine manner to modulate the neuronal responses to blood-borne ANG II. These findings also provide the first direct evidence of a physiological role for STC-1 in central regulation of body fluid homeostasis.

scholarly journals The (pro)renin receptor and body fluid homeostasis

2013 ◽  
Vol 305 (2) ◽  
pp. R104-R106 ◽  
Author(s):  
Theresa Cao ◽  
Yumei Feng
Keyword(s):  
Sympathetic Nerve ◽  
Body Fluid ◽  
Sympathetic Nerve Activity ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Nerve Activity ◽  
Fluid Homeostasis ◽  
Body Fluid Homeostasis ◽  
The Central Nervous System ◽  
Vasopressin Secretion

The renin-angiotensin system (RAS) has long been established as one of the major mechanisms of hypertension through the increased levels of angiotensin (ANG) II and its resulting effect on the sympathetic nerve activity, arterial vasoconstriction, water reabsorption, and retention, etc. In the central nervous system, RAS activation affects body fluid homeostasis through increases in sympathetic nerve activity, water intake, food intake, and arginine vasopressin secretion. Previous studies, however, have shown that ANG II can be made in the brain, and it could possibly be through a new component called the (pro)renin receptor. This review intends to summarize the central and peripheral effects of the PRR on body fluid homeostasis.

scholarly journals Immunosuppression preserves renal autoregulatory function and microvascular P2X1 receptor reactivity in ANG II-hypertensive rats

2013 ◽  
Vol 304 (6) ◽  
pp. F801-F807 ◽  
Author(s):  
Zhengrong Guan ◽  
Matthew I. Giddens ◽  
David A. Osmond ◽  
Anthony K. Cook ◽  
Janet L. Hobbs ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Vascular Dysfunction ◽  
Renal Perfusion ◽  
Receptor Activation ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Activated Lymphocytes

Autoregulation is critical for protecting the kidney against arterial pressure elevation and is compromised in some forms of hypertension. Evidence indicates that activated lymphocytes contribute importantly to cardiovascular injury in hypertension. We hypothesized that activated lymphocytes contribute to renal vascular dysfunction by impairing autoregulation and P2X1 receptor signaling in ANG II-infused hypertensive rats. Male Sprague-Dawley rats receiving ANG II infusion were treated with a lymphocyte proliferation inhibitor, mycophenolate mofetil (MMF) for 2 wk. Autoregulation was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. ANG II-treated rats exhibited impaired autoregulation. At the single vessel level, pressure-mediated afferent arteriolar vasoconstriction was significantly blunted ( P < 0.05 vs. control rats). At the whole kidney level, renal blood flow passively decreased as renal perfusion pressure was reduced. MMF treatment did not alter the ANG II-induced hypertensive state; however, MMF did preserve autoregulation. The autoregulatory profiles in both in vitro or in vivo settings were similar to the responses from control rats despite persistent hypertension. Autoregulatory responses are linked to P2X1 receptor activation. Accordingly, afferent arteriolar responses to ATP and the P2X1 receptor agonist β,γ-methylene ATP were assessed. ATP- or β,γ-methylene ATP-induced vasoconstriction was significantly attenuated in ANG II-infused hypertensive rats but was normalized by MMF treatment. Moreover, MMF prevented elevation of plasma transforming growth factor-β1 concentration and lymphocyte and macrophage infiltration in ANG II-infused kidneys. These results suggest that anti-inflammatory treatment with MMF prevents lymphocyte infiltration and preserves autoregulation in ANG II-infused hypertensive rats, likely by normalizing P2X1 receptor activation.

scholarly journals Apelin and Vasopressin: The Yin and Yang of Water Balance

2021 ◽  
Vol 12 ◽  
Author(s):  
Pierre-Emmanuel Girault-Sotias ◽  
Romain Gerbier ◽  
Adrien Flahault ◽  
Nadia de Mota ◽  
Catherine Llorens-Cortes
Keyword(s):  
Body Fluid ◽  
Collecting Duct ◽  
Plasma Osmolality ◽  
Receptor Activation ◽  
Fluid Homeostasis ◽  
Antidiuretic Effect ◽  
Body Fluid Homeostasis ◽  
Yin And Yang ◽  
Apelin Receptor

Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. Experimental data performed in rodents have shown that apelin has an aquaretic effect via its central and renal actions. In the brain, apelin inhibits the phasic electrical activity of vasopressinergic neurons and the release of vasopressin from the posterior pituitary into the bloodstream and in the kidney, apelin regulates renal microcirculation and counteracts in the collecting duct, the antidiuretic effect of vasopressin occurring via the vasopressin receptor type 2. In humans and rodents, if plasma osmolality is increased by hypertonic saline infusion/water deprivation or decreased by water loading, plasma vasopressin and apelin are conversely regulated to maintain body fluid homeostasis. In patients with the syndrome of inappropriate antidiuresis, in which vasopressin hypersecretion leads to hyponatremia, the balance between apelin and vasopressin is significantly altered. In order to re-establish the correct balance, a metabolically stable apelin-17 analog, LIT01-196, was developed, to overcome the problem of the very short half-life (in the minute range) of apelin in vivo. In a rat experimental model of vasopressin-induced hyponatremia, subcutaneously (s.c.) administered LIT01-196 blocks the antidiuretic effect of vasopressin and the vasopressin-induced increase in urinary osmolality, and induces a progressive improvement in hyponatremia, suggesting that apelin receptor activation constitutes an original approach for hyponatremia treatment.

scholarly journals DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite

2016 ◽  
Vol 115 (6) ◽  
pp. 3123-3129 ◽  
Author(s):  
Haley L. Nation ◽  
Marvin Nicoleau ◽  
Brian J. Kinsman ◽  
Kirsteen N. Browning ◽  
Sean D. Stocker
Keyword(s):  
Water Intake ◽  
Body Fluid ◽  
Subfornical Organ ◽  
Designer Drugs ◽  
Salt Appetite ◽  
Fluid Homeostasis ◽  
Body Fluid Homeostasis ◽  
Acute Injection

The subfornical organ (SFO) plays a pivotal role in body fluid homeostasis through its ability to integrate neurohumoral signals and subsequently alter behavior, neuroendocrine function, and autonomic outflow. The purpose of the present study was to evaluate whether selective activation of SFO neurons using virally mediated expression of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) stimulated thirst and salt appetite. Male C57BL/6 mice (12–15 wk) received an injection of rAAV2-CaMKII-HA-hM3D(Gq)-IRES-mCitrine targeted at the SFO. Two weeks later, acute injection of clozapine N-oxide (CNO) produced dose-dependent increases in water intake of mice with DREADD expression in the SFO. CNO also stimulated the ingestion of 0.3 M NaCl. Acute injection of CNO significantly increased the number of Fos-positive nuclei in the SFO of mice with robust DREADD expression. Furthermore, in vivo single-unit recordings demonstrate that CNO significantly increases the discharge frequency of both ANG II- and NaCl-responsive neurons. In vitro current-clamp recordings confirm that bath application of CNO produces a significant membrane depolarization and increase in action potential frequency. In a final set of experiments, chronic administration of CNO approximately doubled 24-h water intake without an effect on salt appetite. These findings demonstrate that DREADD-induced activation of SFO neurons stimulates thirst and that DREADDs are a useful tool to acutely or chronically manipulate neuronal circuits influencing body fluid homeostasis.

scholarly journals First Report ofEurycoma longifoliaJack Root Extract Causing Relaxation of Aortic Rings in Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Bae Huey Tee ◽  
See Ziau Hoe ◽  
Swee Hung Cheah ◽  
Sau Kuen Lam
Keyword(s):  
Erectile Function ◽  
Receptor Activation ◽  
Root Extract ◽  
Ang Ii ◽  
Angiotensin I ◽  
Eurycoma Longifolia ◽  
Vasodilatory Effect

AlthoughEurycoma longifoliahas been studied for erectile function, the blood pressure- (BP-) lowering effect has yet to be verified. Hence, this study aims at investigating the BP-lowering properties of the plant with a view to develop an antihypertensive agent that could also preserve erectile function. Ethanolic root extract was partitioned by hexane, dichloromethane (DCM), ethyl acetate, butanol, and water. The DCM fraction, found to be potent in relaxing phenylephrine- (PE-) precontracted rat aortic rings, was further purified by column chromatography. Subfraction DCM-II, being the most active in relaxing aortae, was studied for effects on the renin-angiotensin and kallikrein-kinin systems in aortic rings. The effect of DCM-II on angiotensin-converting enzyme (ACE) activity was also evaluatedin vitro. Results showed that DCM-II reduced (p<0.05) the contractions evoked by angiotensin I and angiotensin II (Ang II). In PE-precontracted rings treated with DCM-II, the Ang II-induced contraction was attenuated (p<0.05) while bradykinin- (BK-) induced relaxation enhanced (p<0.001).In vitro, DCM-II inhibited (p<0.001) the activity of ACE. These data demonstrate that the vasodilatory effect of DCM-II appears to be mediatedviainhibition of Ang II type 1 receptor and ACE as well as enhancement of Ang II type 2 receptor activation and BK activity.

Neuronal nitric oxide synthase modulates rat renal microvascular function

1998 ◽  
Vol 274 (3) ◽  
pp. F516-F524 ◽  
Author(s):  
Atsuhiro Ichihara ◽  
Edward W. Inscho ◽  
John D. Imig ◽  
L. Gabriel Navar
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Macula Densa ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Vasoconstrictor Response ◽  
Arteriolar Tone ◽  
Oxide Synthase

This study was performed to determine the influence of neuronal nitric oxide synthase (nNOS) on renal arteriolar tone under conditions of normal, interrupted, and increased volume delivery to the macula densa segment and on the microvascular responses to angiotensin II (ANG II). Experiments were performed in vitro on afferent (21.2 ± 0.2 μm) and efferent (18.5 ± 0.2 μm) arterioles of kidneys harvested from male Sprague-Dawley rats, using the blood-perfused juxtamedullary nephron technique. Superfusion with the specific nNOS inhibitor, S-methyl-l-thiocitrulline (l-SMTC), decreased afferent and efferent arteriolar diameters, and these decreases in arteriolar diameters were prevented by interruption of distal volume delivery by papillectomy. When 10 mM acetazolamide was added to the blood perfusate to increase volume delivery to the macula densa segment, afferent arteriolar vasoconstrictor responses tol-SMTC were enhanced, but this effect was again completely prevented after papillectomy. In contrast, the arteriolar diameter responses to the nonselective NOS inhibitor, N ω-nitro-l-arginine (l-NNA) were only attenuated by papillectomy.l-SMTC (10 μM) enhanced the efferent arteriolar vasoconstrictor response to ANG II but did not alter the afferent arteriolar vasoconstrictor responsiveness to ANG II. In contrast, l-NNA (100 μM) enhanced both afferent and efferent arteriolar vasoconstrictor responses to ANG II. These results indicate that the modulating influence of nNOS on afferent arteriolar tone of juxtamedullary nephrons is dependent on distal tubular fluid flow. Furthermore, nNOS exerts a differential modulatory action on the juxtamedullary microvasculature by enhancing efferent, but not afferent, arteriolar responsiveness to ANG II.

Physiological regulation of the renal vasopressin receptor-effector pathway in dogs

1990 ◽  
Vol 258 (3) ◽  
pp. R763-R769
Author(s):  
L. B. Kinter ◽  
N. Caldwell ◽  
S. Caltabiano ◽  
C. Winslow ◽  
D. P. Brooks ◽  
...  
Keyword(s):  
Volume Expansion ◽  
Body Fluid ◽  
Physiological State ◽  
Extracellular Volume ◽  
Conscious Dogs ◽  
Physiological Regulation ◽  
Fluid Homeostasis ◽  
Effector Pathway ◽  
Body Fluid Homeostasis ◽  
V2 Receptor

Physiological regulation of receptor-effector pathways is recognized as a significant factor determining target organ selectivity and sensitivity in several hormonal systems. Whether or not physiological regulation of the renal vasopressin (V2) receptor-effector pathway participates in the control of body fluid homeostasis is unknown. We evaluated four states likely to be associated with altered sensitivities of the renal V2 receptor-effector pathway as follows: dehydration (18-h hydropenia), volume expansion, exogenous arginine vasopressin (AVP) infusion (10 ng/kg + 0.25 ng.kg-1.h-1), and cyclooxygenase blockade (indomethacin, 2 mg/kg + 2 mg.kg-1.h-1) for effects on the antidiuretic efficacies and potencies of putative V2-receptor antagonists in conscious dogs. The antidiuretic efficacies of desGly9[Pmp1-D-Tyr(Et)2Val4]AVP [Smith Kline & French (SK&F) 101926; 0.01-1,000 micrograms/kg] ranged from that of a full agonist to that of an antagonist, depending on the physiological state studied. The vasopressin antagonist potency of SK&F 101926 was increased 150-fold in association with extracellular volume expansion and decreased by blockade of renal cyclooxygenase activity. This spectrum of activities is that anticipated for a partial agonist under conditions where receptor number and/or sensitivity of receptor-effector coupling is increased or decreased, respectively. Thus volume expansion and increased circulating vasopressin concentration are associated with effective decreases, whereas hydropenia and cyclooxygenase blockade are associated with effective increases in sensitivity of the renal V2 receptor-effector pathway in the dog kidney. We conclude that the V2 receptor-effector pathway is a site of integration of physiological mechanisms participating in the control of body fluid homeostasis in conscious dogs.

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