Release of angiostensin in the paraventricular nucleus in response to hyperosmotic stimulation in conscious rats: a microdialysis study

doi:10.1016/0006-8993(94)91215-7

Brain Research

Volume 637, Issues 1–2, 21 February 1994, Pages 45-49

https://doi.org/10.1016/0006-8993(94)91215-7 Get rights and content

Abstract

Angiotensin peptides are thought to act as neurotransmitter or neuromodulators in central osmoregulation. We tested the hypothesis that angiotensin peptides are released in the paraventricular nucleus (PVN) of the hypothalamus upon local osmotic stimulation. Brain microdialysis and radioimmunoassay (RIA) techniques were used to measure the release of immunoreactive angiotensin II (irANG II) in the PVN following direct stimulation of this area with hyperosmotic solutions. In conscious rats, perfusion of the PVN with 0.3 M and 0.6 M NaCl in artificial cerebrospinal fluid (aCSF) elicited concentration-dependent increases in irANG II release to 5.52 + 0.53, (P < 0.01, n = 8)and9.01 ± 1.03pg/100μl, (P < 0.001, n = 7), respectively, from basal values of 3.04 ± 0.46pg/100 μl. Local perfusion of the PVN with 1.2 M glucose in aCSF also resulted in an increased release of irANG II from 3.07 ± 0.87 to 6.24 ± 0.45pg/100μl (P < 0.05, n = 5). Fractionization of angiotensin peptides by HPLC followed by RIA revealed that ANG II (1–8) and ANG III (2–8) were released in similar amounts in the perfusate collected during 0.6 M NaCl stimulation (4.79 ± 0.69and3.45 ± 0.76pg/100 μl, respectively). Our results show that both, ANG II and ANG III are released in the PVN in response to local hyperosmotic stimulation. They support the concept that angiotensin peptides in the PVN are involved as neurotransmitters in central osmotic control.

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Cited by (44)

Role of angiotensin II type 1 receptors in the subfornical organ in the pressor responses to central sodium in rats
2013, Brain Research
Citation Excerpt :
Effects of infusions and/or higher [Na+] were not studied. We hypothesized that SFO neurons are Na+ sensitive and Na+ induced local angiotensin II (Ang II) release (Doris, 1988; Qadri et al.,1994) and AT1 receptor activation causes pressor responses. In the present study, we tested in conscious Wistar rats (1) the BP and heart rate (HR) responses to intra SFO infusion of Na+-rich aCSF and injection of Ang II with and without intra SFO infusion of the AT1 receptor blocker candesartan; (2) the BP and HR responses to intra SFO infusion of mannitol with the same osmolarity as the Na+-rich aCSF; (3) effects of electrolytic lesion of the SFO on the BP and HR responses to icv infusion and injection of Na+-rich aCSF and of Ang II; and (4) the BP and HR responses to icv infusion and injection of Na+-rich aCSF or Ang II before and after intra SFO infusion of candesartan.
Central infusion of Na⁺-rich artificial cerebro-spinal fluid (aCSF) activates the brain renin–angiotensin system and causes sympatho-excitatory and pressor responses. We evaluated the role of the subfornical organ (SFO) and angiotensin II type 1 (AT₁) receptors in the SFO in mediating the central Na⁺-induced pressor response. In conscious Wistar rats, intra SFO infusions of Na⁺-rich aCSF containing 0.45 and 0.6 M Na⁺ at 10 nl/min or injection of angiotensin II (Ang II) at 80 ng increased blood pressure (BP) by 15–22 mmHg, whereas mannitol with the same osmolarity as the Na⁺-rich aCSF had no effects. Intra SFO infusion of the AT₁ receptor blocker candesartan abolished the pressor response induced by intra SFO administration of Na⁺-rich aCSF or Ang II. Intra cerebro-ventricular (icv) infusion of Na⁺-rich aCSF (0.3 M Na⁺) at 3.8 μl/min for 10 min increased BP by 15–20 mmHg. Electrolytic lesion of the SFO attenuated these BP increases by 50–70%. Intra SFO infusion of candesartan also prevented 50% of these pressor responses. These data suggest that SFO neurons are indeed sensitive to Na⁺, the SFO is a major – but not only – site in the brain to sense an increase in CSF [Na⁺], and activation of AT₁ receptors in the SFO mediates the SFO component of the Na⁺-induced pressor response.
Angiotensin III: A physiological relevant peptide of the renin angiotensin system
2013, Peptides
Citation Excerpt :
However, Ang III injected centrally may be less effective than Ang II in promoting dipsogenic responses [30]. Both Ang peptides are equally released in the hypothalamic PVN after hyperosmotic stimulation in conscious rats [59]. Thus, it is plausible that both peptides are produced in cardiovascular centers of the brain and that they both have “pressor” tendencies.
The renin angiotensin system (RAS) is a peptide hormone system that plays an important role in the pathophysiology of various diseases, including congestive heart failure, hypertension, myocardial infarction, and diabetic nephropathy. This has led researchers to focus extensively on this system, leading to the discovery of various peptides, peptidases, receptors and signal transduction mechanisms intrinsic to the RAS. Angiotensinogen (AGT), angiotensin (Ang) II, Ang III, Ang IV, and Ang-(1–7) are the main biologically active peptides of RAS. However, most of the available studies have focused on Ang II as the likely key peptide from the RAS that directly and indirectly regulates physiological functions leading to pathological conditions. However, data from recent studies suggest that Ang III may produce physiologically relevant effects that are similar to those produced by Ang II. Hence, this review focuses on Ang III and the myriad of physiological effects that it produces in the body.
The central role of the brain aldosterone-"ouabain" pathway in salt-sensitive hypertension
2010, Biochimica et Biophysica Acta - Molecular Basis of Disease
Na⁺-transport regulating mechanisms classically considered to reflect renal control of sodium homeostasis and BP, i.e. aldosterone–mineralocorticoid receptors (MR)—epithelial sodium channels (ENaC)—Na⁺/K⁺-ATPase have now been demonstrated to also be present in the central nervous system. This pathway is being regulated independently of the peripheral/renal pathway and contributes to regulation of cerebrospinal fluid [Na⁺] by the choroid plexus, of brain tissue [Na⁺] by the ependyma and to neuronal responses to e.g. Na⁺ or angiotensin II. Increases in CSF [Na⁺] by central infusion of Na⁺-rich aCSF or by high salt intake in Dahl S or SHR cause sympatho-excitation and hypertension. These responses appear to depend on activation of a CNS cascade starting with aldosterone–MR–ENaC–“ouabain,” the latter lowering neuronal membrane potential leading to enhanced angiotensin II release in e.g. the PVN. Specific CNS blockade of any of the steps in this cascade from aldosterone synthase blockade to AT₁-receptor blockade prevents the sympathetic hyperactivity and hypertension on high salt intake, irrespective of the presence of a “salt-sensitive kidney.” We propose that in salt-sensitive hypertension an increase in CSF [Na⁺] causes a local increase in aldosterone biosynthesis which activates an aldosterone dependent neuromodulatory pathway which enhances activity of angiotensinergic sympatho-excitatory pathways leading to hypertension.
Nitric oxide mediates feedback inhibition in angiotensin II-induced upregulation of vasopressin mRNA
2009, Peptides
Angiotensin II (Ang II) stimulates hypothalamic magnocellular neurons to release arginine vasopressin (AVP) via Ang II type 1 (AT1) receptors during chronic hyperosmotic condition. On the other hand, endogenous nitric oxide (NO) tonically inhibits the activity of AVP producing neurons; and system infusion of Ang II elicits the activity of NO producing neurons in the hypothalamus. These studies suggest that NO may mediate feedback inhibition in Ang II modulation of AVP neuronal excitability. To confirm this hypothesis, we first investigated colocalization of neuronal NO synthase (nNOS) and AT1 receptors in the hypothalamic magnocellular nuclei of adult male rats by using double immunofluorescence. We found that 60% and 65% of AT1 receptors immunoreactive neurons coexpressed nNOS in the hypothalamic paraventricular nucleus and supraoptic nucleus, respectively. We then demonstrated that intracerebroventricular administration of nNOS inhibitor N-omega-nitro-l-arginine methyl ester further enhanced upregulation of AVP mRNA level but totally abolished upregulation of nNOS mRNA level in the paraventricular and supraoptic nuclei of anesthetized rats induced by a prior administration of Ang II. Theses morphological and pharmacological data demonstrate that NO mediates negative feedback regulation of Ang II-induced upregulation of AVP mRNA.
Possible involvement of nitric oxide in the central salt-loading-induced cardiovascular responses in conscious rats
2003, Brain Research
Citation Excerpt :
Despite the fact that the PVN appears to be an important regulatory region in the modulation of cardiovascular and behavioral responses during osmotic/sodium challenges, the chemical mediators in the PVN responsible for mediating cardiovascular responses induced by central salt loading are not well understood. Some reports have shown that hypertonic stimulation increased vasopressin (AVP), oxytocin (OXT), angiotensin, amino acids, and dopamine concentration in the PVN region [12,14,24,38] and similarly increased nitric oxide synthase (NOS) levels in the PVN region [36]. The findings raised the possibility of the involvement of these substances in the central osmotic and ionic balance.
The objective of this study was to elucidate the possible involvement of nitric oxide (NO) in the cardiovascular responses induced by central salt loading. Direct perfusion of the hypothalamic paraventricular nucleus (PVN) region with hypertonic saline (0.3 or 0.45 M) was performed in conscious rats by using an in vivo brain microdialysis technique. The extracellular concentration of NO metabolites in the PVN region was measured, as were the blood pressure (BP) and heart rate (HR). Perfusion of 0.45 M saline increased the BP, HR, and NO metabolite levels in the PVN region; however, perfusion of 0.3 M saline enhanced only the level of NO metabolites but did not induce changes in the BP and HR. Next, we determined whether the NO was involved in the cardiovascular responses induced by hypertonic saline. Pretreatment with N^G-methyl-l-arginine (l-NMMA), an inhibitor of NO synthase, attenuated the increases in the BP and HR induced by direct perfusion of 0.45 M saline, while direct infusion of 3-morpholinosyndnonimine (SIN-1, a NO donor) in the PVN region induced increases in the BP and HR. These results suggest that local perfusion of the PVN region with hypertonic saline elicits a local release of NO, which may be carried out by activating nitric oxide synthase to produce cardiovascular responses.
Hypo-osmolarity stimulates and high sodium concentration inhibits thyrotropin-releasing hormone secretion from rat hypothalamus
1999, Neuroscience
The hypothalamic paraventricular nucleus, representing cell bodies in which thyrotropin-releasing hormone is synthesized, and the median eminence, representing nerve terminals, were incubated in vitro. Various hypo- and hyperosmotic solutions were tested to determine osmotic sensitivity of thyrotropin-releasing hormone secretion. High KCl (56 mM) causing membrane depolarization was used as a non-specific control stimulus to induce thyrotropin-releasing hormone secretion. A 30% decrease of medium osmolarity (from 288 to 202 mOsmol/l) increased thyrotropin-releasing hormone secretion from both the paraventricular nucleus and median eminence. A 30% decrease of medium NaCl content by its replacement with choline chloride did not affect basal thyrotropin-releasing hormone secretion. Increasing medium osmolarity with biologically inactive l-glucose did not affect basal or KCl-induced thyrotropin-releasing hormone secretion from either structure. Medium made hyperosmotic (350–450 mOsmol/l) by increasing the NaCl concentration resulted in a dose-dependent decrease of basal thyrotropin-releasing hormone secretion and abolished KCl-induced thyrotropin-releasing hormone secretion. If an osmotically equivalent amount of choline chloride was substituted for NaCl, there was no effect on thyrotropin-releasing hormone secretion, indicating a specific action of Na⁺.
This study indicates a specific sensitivity to high concentrations of Na⁺ ions of both thyrotropin-releasing hormone-producing parvocellular paraventricular neurons and of thyrotropin-releasing hormone-containing nerve terminals in the median eminence.

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Abstract

Reference (27)

Effects of microelectrophoretically applied acetylcholine- and angiotensin-antagonists on the paraventricular neurosecretory cells excited by osmotic stimuli

Neurosci. Lett.

c-fos may code for a common transcription factor within the hypothalamic neural circuits involved in osmoregulation

Brain Res.

Extracellular oxytocin in the paraventricular nucleus, hyperosmotic stimulation by in vivo microdialysis

Brain Res.

Combined high performance liquid chromatography-radioimmunoassay for the characterization and quantitative measurement of neuropeptides

J. Chromatogr.

Does the release of vasopressin within the supraoptic nucleus of the rat brain depend upon changes in osmolality and Ca⁺/K⁺?

Brain Res.

Sensors of antidiuresis and thirst-osmoreceptors or CSF sodium detectors?

Brain Res.

Intravenous hypertonic saline induces Fos immunoreactivity in neurons throughout the lamina terminalis

Brain Res.

Angiotensin II-induced noradrenaline release from anterior hypothalamus in conscious rats: a brain microdialysis study

Brain Res.

Thirst and brain control of water balance

Am. Sci.

The K+-induced increases in noradrenaline and dopamine release are accompanied by reductions in the release of their intraneuronal metabolites from the rat anterior hypothalamus: an in vivo microdialysis study

Naunyn-Schmiedeberg's Arch. Pharmacol.

Characterization of the responses of oxytocin- and vasopressin-secreting neurones in the supraoptic nucleus to osmotic stimulation

J. Physiol.

Intracellular recordings from the paraventricular nucleus in slices of rat hypothalamus

J. Physiol.

In vitro and in vivo characterization of the new ACE inhibitor moexpril: comparison with enalapril

Naunyn-Schmiedeberg's Arch. Pharmacol.

Cited by (44)

Role of angiotensin II type 1 receptors in the subfornical organ in the pressor responses to central sodium in rats

Angiotensin III: A physiological relevant peptide of the renin angiotensin system

The central role of the brain aldosterone-"ouabain" pathway in salt-sensitive hypertension

Nitric oxide mediates feedback inhibition in angiotensin II-induced upregulation of vasopressin mRNA

Possible involvement of nitric oxide in the central salt-loading-induced cardiovascular responses in conscious rats

Hypo-osmolarity stimulates and high sodium concentration inhibits thyrotropin-releasing hormone secretion from rat hypothalamus