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1.
J Neuroendocrinol ; 25(7): 655-67, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23656518

ABSTRACT

Intranasal administration has been widely used to investigate the effects of the neuropeptides vasopressin and oxytocin on human behaviour and neurological disorders, although exactly what happens when these neuropeptides are administered intranasally is far from clear. In particular, it is not clear whether a physiological significant amount of peptide enters the brain to account for the observed effects. In the present study, we investigated whether the intranasal administration of vasopressin and oxytocin to rats induces the expression of the immediate-early gene product Fos in brain areas that are sensitive to centrally-administered peptide, whether it alters neuronal activity in the way that centrally-administered peptide does, and whether it affects behaviour in the ways that are expected from studies of centrally-administered peptide. We found that, whereas i.c.v. injection of very low doses of vasopressin or oxytocin increased Fos expression in several distinct brain regions, intranasal administration of large doses of the peptides had no significant effect. By contrast to the effects of vasopressin applied topically to the main olfactory bulb, we saw no changes in the electrical activity of olfactory bulb mitral cells after intranasal vasopressin administration. In addition, vasopressin given intranasally had no significant effects on social recognition or short-term recognition memory. Finally, intranasal infusions of vasopressin had no significant effects on the parameters monitored on the elevated plus maze, a rodent model of anxiety. Our data obtained in rats suggest that, after intranasal administration, significant amounts of vasopressin and oxytocin do not reach areas in the brain at levels sufficient to change immediate early gene expression, neural activity or behaviour in the ways described for central administration of the peptides.


Subject(s)
Behavior, Animal/drug effects , Gene Expression Regulation/drug effects , Genes, Immediate-Early , Vasopressins/administration & dosage , Administration, Intranasal , Animals , Male , Rats , Rats, Sprague-Dawley , Vasopressins/pharmacology
2.
Osteoarthritis Cartilage ; 20(8): 949-56, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22595226

ABSTRACT

OBJECTIVE: The morphology of lesions in mouse models of osteoarthritis (OA) has not been comprehensively characterized, in part because current histological assessments of OA focus primarily on articular cartilage (AC). In the present study, sections of murine stifle joints with naturally occurring (aged animals) and surgically induced (destabilized medial meniscus, DMM) OA were examined using a newly developed histological grading scheme that includes quantitative measurements and semiquantitative grades to evaluate multiple joint tissues. DESIGN: The data collected was analyzed using Principal Components Analysis (PCA); factor scores for each joint were generated. Individual parameters and factor scores were compared between surgical groups and among age groups. For comparison, the original Mankin Histological-Histochemical Grading System (HHGS) also was applied. RESULTS: Overall, lesions were most severe in the medial tibial plateaus. Significant changes in AC and neighboring bone were identified in surgically induced models and in naturally occurring disease. Mean factor scores provided a comprehensive evaluation of joint changes. An important new finding was that chondrocyte cell death within the AC was a commonly identified lesion and its extent significantly increased with age. While the Mankin HHGS detected significant overall differences in OA severity between surgical groups, it was not sensitive in detecting age-related differences, nor did it provide information regarding changes in individual tissues. CONCLUSION: These results demonstrate the utility of this newly developed murine OA grading scheme in identifying lesions in AC and in other joint tissues. Surgically induced changes were similar to those occurring naturally with aging.


Subject(s)
Arthritis, Experimental/pathology , Cartilage, Articular/pathology , Chondrocytes/pathology , Osteoarthritis/pathology , Aging/pathology , Animals , Male , Menisci, Tibial/pathology , Mice , Mice, Inbred C57BL , Osteoarthritis/diagnosis , Stifle/pathology
3.
Am J Physiol Regul Integr Comp Physiol ; 279(5): R1944-8, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11049880

ABSTRACT

Glycyl-glutamine (Gly-Gln; beta-endorphin(30-31)) is an endogenous dipeptide that is synthesized through the posttranslational processing of beta-endorphin in brain stem regions that control respiration and autonomic function. This study tested the hypothesis that Gly-Gln administration to conscious rats will prevent the respiratory depression caused by morphine without affecting morphine antinociception. Rats were administered Gly-Gln (1-100 nmol) or saline (10 microl) intracerebroventricularly followed, 5 min later, by morphine (40 nmol icv). Arterial blood gases and pH were measured immediately before Gly-Gln and 30 min after morphine injection. Gly-Gln pretreatment inhibited morphine-induced hypercapnia, hypoxia, and acidosis significantly. The response was dose dependent and significant at Gly-Gln doses as low as 1 nmol. In contrast, Gly-Gln (1-300 nmol) had no effect on morphine-evoked antinociception in the paw withdrawal test. When given alone to otherwise untreated animals, Gly-Gln did not affect nociceptive latencies or blood gas values. These data indicate that Gly-Gln inhibits morphine-induced respiratory depression without compromising morphine antinociception.


Subject(s)
Analgesia , Dipeptides/pharmacology , Morphine/pharmacology , Respiration/drug effects , Acidosis/chemically induced , Animals , Carbon Dioxide/blood , Dipeptides/administration & dosage , Hydrogen-Ion Concentration , Hypercapnia/chemically induced , Hypoxia/chemically induced , Injections, Intraventricular , Male , Morphine/administration & dosage , Oxygen/blood , Pain Measurement , Rats , Rats, Sprague-Dawley
4.
Am J Physiol Renal Physiol ; 278(1): F75-82, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10644657

ABSTRACT

Mice lacking AT(1A) receptors for ANG II have a defect in urinary concentration manifested by an inability to increase urinary osmolality to levels seen in controls after thirsting. This defect results in extreme serum hypertonicity during water deprivation. In the basal state, plasma vasopressin levels are similar in wild-type controls and Agtr1a -/- mice. Plasma vasopressin levels increase normally in the AT(1A) receptor-deficient mice after 24 h of water deprivation, suggesting that the defect in urine concentration is intrinsic to the kidney. Using magnetic resonance microscopy, we find that the absence of AT(1A) receptors is associated with a modest reduction in the distance from the kidney surface to the tip of the papilla. However, this structural abnormality seems to play little role in the urinary concentrating defect in Agtr1a -/- mice since the impairment is largely reproduced in wild-type mice by treatment with an AT(1)-receptor antagonist. These studies demonstrate a critical role for the AT(1A) receptor in maintaining inner medullary structures in the kidney and in regulating renal water excretion.


Subject(s)
Kidney Concentrating Ability/physiology , Kidney/metabolism , Receptors, Angiotensin/deficiency , Water/metabolism , Angiotensin Receptor Antagonists , Animals , Body Weight , Deamino Arginine Vasopressin/pharmacology , Female , Genotype , Kidney/anatomy & histology , Kidney Concentrating Ability/drug effects , Losartan/pharmacology , Male , Mice , Osmolar Concentration , Receptor, Angiotensin, Type 1 , Receptors, Angiotensin/genetics , Urine/chemistry , Urodynamics , Vasopressins/blood , Water/pharmacology , Water Deprivation
5.
Hypertension ; 33(1 Pt 2): 385-8, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9931134

ABSTRACT

We previously demonstrated that the Ren-2 transgenic (TG) rat is sensitive to salt, showing a sodium-induced pressor response. The present studies determined the effect of central stimulation with hypertonic saline (HS) and angiotensin II (Ang II) on mean arterial pressure (MAP), heart rate (HR), and plasma vasopressin. HS (1 mol/L NaCl, 5 microL) or Ang II (100 ng, 5 microL) was injected into the lateral ventricle of conscious male TG and control rats. The pressor responses to HS and Ang were greater in TG than in control rats, increases of 42+/-4 and 41+/-4 mm Hg versus 25+/-3 and 18+/-2 mm Hg (HS and Ang II and TG and control rats, respectively). The TG rats also showed an increased vasopressin response to Ang II, peak levels of 14+/-3 versus 28+/-3 pg/mL (control versus TG rats). HS increased plasma vasopressin levels, although the group responses were not different. HR was not significantly altered by either stimulus. Results demonstrate an increased responsiveness to intraventricular HS and Ang II in Ren-2 transgenic rats, suggesting a relationship between the enhanced angiotensinergic drive and central cardiovascular and vasopressin responses.


Subject(s)
Angiotensin II/pharmacology , Blood Pressure/physiology , Heart Rate/physiology , Hypertension/genetics , Analysis of Variance , Angiotensin II/administration & dosage , Angiotensin II/physiology , Animals , Animals, Genetically Modified , Blood Pressure/drug effects , Cerebral Ventricles/drug effects , Cerebral Ventricles/physiology , Cerebral Ventricles/physiopathology , Heart Rate/drug effects , Heterozygote , Hypertension/physiopathology , Injections, Intraventricular , Male , Rats , Rats, Sprague-Dawley , Saline Solution, Hypertonic/administration & dosage , Saline Solution, Hypertonic/pharmacology , Vasopressins/blood
6.
Hypertension ; 33(1 Pt 2): 482-6, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9931152

ABSTRACT

Angiotensin (Ang) type 1a (AT1a) receptors are critical in the control of blood pressure and water balance. Experiments were performed to determine the influence of dehydration on brain Ang receptors and plasma vasopressin (VP) in mice lacking this receptor. Control or AT1a knockout (AT1aKO) male mice were give water ad libitum or deprived of water for 48 hours. Animals were anesthetized with halothane, blood samples were collected by heart puncture, and brains were processed for Ang-receptor autoradiography with 125I-sarthran (0.4 nmol/L). Dehydration produced an increase in AT1 receptors in the paraventricular nucleus (PVN) and anterior pituitary (AP) in control mice (PVN: 70+/-16 versus 146+/-10 fmol/mg protein; AP: 41+/-7 versus 86+/-15 fmol/mg protein). No changes were noted in the median preoptic nucleus. The majority of the brain receptors were of the AT1 subtype. There was little or no specific Ang binding in AT1aKO mice and no effect of dehydration. Plasma VP levels were elevated in the halothane-anesthetized animals (>200 pg/mL) with no significant effect of dehydration. A separate experiment was performed with decapitated mice anesthetized with pentobarbital. Dehydration increased plasma VP in control mice, from 3.3+/-0.6 to 13.3+/-4.7 pg/mL, whereas no change was noted in the AT1aKO mice, 5.1+/-0.3 versus 6.1+/-0.7 pg/mL (water versus dehydration). These results demonstrate a differential response to dehydration in mice lacking AT1a receptors. There was no evidence for AT1 receptors of any subtype in the brain regions examined and no effect of dehydration on VP secretion or brain Ang receptors.


Subject(s)
Brain/metabolism , Dehydration/physiopathology , Receptors, Angiotensin/physiology , Angiotensin II/analogs & derivatives , Angiotensin II/pharmacokinetics , Animals , Autoradiography , Dehydration/genetics , Iodine Radioisotopes , Losartan/pharmacology , Male , Mice , Mice, Knockout , Paraventricular Hypothalamic Nucleus/metabolism , Pituitary Gland, Anterior/metabolism , Preoptic Area/metabolism , Receptor, Angiotensin, Type 1 , Receptors, Angiotensin/deficiency , Receptors, Angiotensin/genetics , Reference Values , Vasopressins/blood , Water Deprivation
7.
Am J Physiol ; 275(4): H1130-7, 1998 10.
Article in English | MEDLINE | ID: mdl-9746459

ABSTRACT

We previously demonstrated that mRen-2 transgenic [Tg(+)] rats are sensitive to chronic high NaCl intake, showing increased arterial pressure and vasopressin (VP) secretion. In this study, we determined the effect of a chronic osmotic challenge, 4 days of drinking 2% NaCl, on direct arterial blood pressure, heart rate, fluid-electrolyte balance, circadian rhythm of mean arterial pressure (MAP), and changes in plasma VP and catecholamines. Under baseline conditions, male Tg(+) rats showed a significant shift in the peak in circadian MAP into the light portion of the day-night cycle. Substitution of 2% NaCl for drinking water caused a rapid increase in MAP, 20 +/- 5 mmHg in Tg(+) rats within 6 h. Whereas the amplitude of circadian MAP fluctuations increased in salt-loaded Tg(+) rats, there was no significant change in the circadian timing of peak MAP with salt loading. Tg(+) rats showed exaggerated osmotic-induced increases in plasma VP, norepinephrine (NE), and epinephrine (Epi) compared with Tg(-) rats. Plasma NE and Epi were increased two- and fourfold, respectively, in the hypertensive rats with no significant change in the Tg(-) rats. Intravenous administration of a VP antagonist did not alter arterial pressure in either Tg(+) or Tg(-) rats. Tg(+) and Tg(-) rats showed a positive sodium balance with no significant difference observed between the groups. Tg(+) rats showed a significant increase in salt consumption, plasma sodium, osmolality, and hematocrit, accompanied by a negative water balance. We conclude that Tg(+) rats are sensitive to acute and chronic osmotic stimuli in terms of blood pressure, fluid-electrolyte balance, and plasma VP and catecholamines. Whereas elevated plasma VP does not contribute to the hypertensive response, increased sympathetic drive may mediate the salt-induced blood pressure changes in this model.


Subject(s)
Blood Pressure/physiology , Renin/physiology , Sodium, Dietary/pharmacology , Water-Electrolyte Balance/physiology , Animals , Animals, Genetically Modified , Arginine Vasopressin/analogs & derivatives , Arginine Vasopressin/pharmacology , Blood Pressure/drug effects , Circadian Rhythm/physiology , Epinephrine/blood , Female , Heterozygote , Male , Norepinephrine/blood , Rats , Rats, Mutant Strains , Rats, Sprague-Dawley , Renin/deficiency , Renin/genetics , Sodium/metabolism , Vasopressins/blood , Vasopressins/metabolism , Water-Electrolyte Balance/drug effects
8.
Brain Res ; 781(1-2): 57-61, 1998 Jan 19.
Article in English | MEDLINE | ID: mdl-9507065

ABSTRACT

Evidence indicates that the hypothalamic paraventricular nucleus (PVN) and oxytocin (OT) neurons in particular play a role in the physiological response to stress. Microdialysis (MD) experiments were performed to determine whether OT is released into the PVN during shaker stress. Male rats were prepared with venous catheters and PVN guide cannulae. OT and vasopressin (VP) release into PVN and peripheral blood were measured under basal conditions and during and after shaker stress (10 min at 110 cycles/min). Stress produced a specific increase in PVN and plasma OT. Dialysate OT levels were 0.3+/-0.1, 2.8+/-1.2 and 1.3+/-0.6 pg/sample (control, stress and recovery, respectively). Plasma OT was significantly increased during stress (3.7+/-1.2 vs. 11.7+/-2.3 pg/ml, basal vs. stress, respectively). When MD probes were located outside the PVN, there was no increase in OT release, demonstrating site specificity. Stress produced no change in VP levels, either in dialysate or plasma. These results show that OT, but not VP, is released into the PVN and peripheral blood in response to shaker stress. The data raise the possibility that local release of OT into the PVN plays a role in the neuroendocrine stress cascade.


Subject(s)
Oxytocin/metabolism , Paraventricular Hypothalamic Nucleus/metabolism , Animals , Male , Microdialysis , Rats , Rats, Sprague-Dawley , Secretory Rate
9.
Am J Hypertens ; 11(3 Pt 1): 357-62, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9544877

ABSTRACT

The (mRen-2)27 transgenic rat (Tg+), a hypertensive model dependent on increased expression of the renin angiotensin system, was used to explore the role of angiotensin AT2 receptors in the control of cardiovascular and renal excretory function. Experiments tested the effect of blockade of AT2 receptors on basal blood pressure and the pressor, renal excretory, and vasopressin (VP) responses to intravenous hypertonic saline (HS). Chronically catheterized male Tg+ and normotensive Sprague-Dawley rats (Tg-) were housed in metabolic cages. PD123319 (AT2 antagonist) or 0.9% NaCl was given by intravenous bolus (3 mg/kg) followed by infusion (50 microg/kg/ min). Blockade of AT2 receptors both in Tg+ and Tg- rats produced no change in basal mean arterial pressure (MAP). The pressor response to intravenous HS (10% NaCl; 325 microL/100 g body weight) was significantly greater in Tg+ than in Tg- rats. PD123319 did not affect the peak rise in MAP but extended the time course of the response only in Tg+ rats. MAP was increased 39+/-4 and 36+/-3 mm Hg in Tg+ rats with and without the antagonist as compared to 20+/-2 and 24+/-2 mm Hg in Tg- rats. In the antagonist-treated Tg+ rats, MAP remained elevated for 60 min as compared to 5 min for Tg+ control or Tg- control or antagonist-treated rats. Hypertonic saline caused similar increases in plasma Na, VP, and in the natriuretic and diuretic responses in both Tg+ and Tg- rats, with no effect of antagonist treatment. These results demonstrate that Tg+ rats are sensitive to the effects of peripheral osmotic stimulation showing an increased pressor response, not attributed to greater secretion of VP or diminished natriuresis. These data also suggest that angiotensin AT2 receptors play a depressor role in the sodium-induced pressor response in this model.


Subject(s)
Animals, Genetically Modified/genetics , Blood Pressure/physiology , Receptors, Angiotensin/physiology , Renin/genetics , Angiotensin Receptor Antagonists , Animals , Diuresis/drug effects , Hypertension/blood , Hypertension/genetics , Hypertension/physiopathology , Imidazoles/pharmacology , Infusions, Intravenous , Male , Natriuresis/drug effects , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Reference Values , Saline Solution, Hypertonic/pharmacology , Vasopressins/blood
10.
Neuroendocrinology ; 65(4): 238-45, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9142995

ABSTRACT

Sinoaortic baroreceptor denervation (SAD) results in increased osmotically induced secretion of vasopressin (VP) and oxytocin (OT) and increased cardiovascular responses to many centrally acting pressor agents. Studies were conducted to determine whether SAD increases the cardiovascular and endocrine responses to direct and peripheral osmotic stimulation of the supraoptic nucleus (SON). SON microdialysis was performed in urethane-anesthetized male rats with measurement of dialysate peptides, mean arterial pressure (MAP) and heart rate. Experiment 1 tested the effect of direct stimulation of the SON with hypertonic NaCl in SAD, sham-operated (control) and intake-matched (matched) rats. Osmotically induced VP release into the SON was significantly greater in SAD than in control or matched groups. VP release peaked at 36 +/- 13 and 15 +/- 7 pg in SAD and controls, respectively, with no increase observed in the matched group. Plasma VP was significantly elevated after SON osmotic stimulation with no differences observed among the groups. The pressor response to osmotic stimulation was greater in SAD (29 +/- 4 mm Hg) than in control (20 +/- 3 mm Hg) and matched animals (15 +/- 3 mm Hg). Experiment 2 tested the effect of intraperitoneal injection of hypertonic NaCl on SON VP and OT release. SAD rats showed an increased central VP response to peripheral osmotic stimulation, a 64-fold increase in SAD as compared to a 4-fold one in controls. Central OT release was not significantly altered (peak of 22 +/- 6 vs. 11 +/- 4 pg, SAD vs. control). A direct SON osmotic challenge given 3.5 h after the intraperitoneal test confirmed an increased VP responsiveness in the SAD group. Plasma VP and OT were significantly increased after intraperitoneal hypertonic saline with no difference observed between groups. The MAP response to intraperitoneal hypertonic saline was greater in the SAD group with an elevation of 37 +/- 4 versus 18 +/- 3 mm Hg observed in SAD versus control subjects. These results demonstrate that baroreceptor denervation produces a state of heightened osmotic sensitivity for VP neurons, with evidence for increased central VP release to both direct and peripheral hypertonic NaCl stimulation.


Subject(s)
Pressoreceptors/drug effects , Sodium Chloride/pharmacology , Supraoptic Nucleus/drug effects , Vasopressins/metabolism , Animals , Male , Osmolar Concentration , Rats , Rats, Sprague-Dawley , Supraoptic Nucleus/metabolism
11.
Brain Res Bull ; 42(2): 147-51, 1997.
Article in English | MEDLINE | ID: mdl-8971420

ABSTRACT

Baroreceptor input plays a critical role in body fluid balance and the endocrine response to NaCl consumption [25]. Experiments were performed to characterize the alterations in salt intake that are seen after baroreceptor denervation. Using chronically baroreceptor denervated (SAD) or control (CON) male Sprague-Dawley rats, we determined: 1) concentration-dependent consumption of NaCl, 2) time course of saline intake, 3) effect of food access on saline intake, 4) intake of sucrose vs. saline, and 5) water vs. saline intake using a choice paradigm. In protocols 1-4 the rats were given a single bottle containing saline or sucrose for a 2-h period during the early dark period. A comparison of the intake of varying concentrations of NaCl (0.3 to 2.0% NaCl, six concentrations) demonstrated that the SAD consumed significantly less NaCl than the CON (from 0.9 to 2% NaCl), Saline Intake in SAD was 14-56% of the CON (significant group, salt concentration and interaction effects). Regression analysis demonstrated that in the SAD there was an inverse relationship between concentration and the amount of NaCl consumed (p < 0.02), an effect not seen in the CON. There were also differences in the pattern of saline intake with the CON showing the highest consumption in the early dark period with a gradual decrease as compared to the SAD, which demonstrated a uniformly lower pattern of consumption. The reduction in intake in the SAD appeared to be specific for NaCl because there was no difference in water or sucrose intake. The deficit could not be attributed to alterations in food intake, nor was there any difference in the amount of water consumed after the saline challenge.


Subject(s)
Drinking , Pressoreceptors/physiology , Sodium Chloride/administration & dosage , Animals , Denervation , Drinking Behavior , Eating , Male , Osmolar Concentration , Rats , Rats, Sprague-Dawley , Sinus of Valsalva/innervation , Sucrose/administration & dosage , Time Factors
12.
Neurosci Lett ; 215(1): 1-4, 1996 Aug 30.
Article in English | MEDLINE | ID: mdl-8880739

ABSTRACT

Central and systemic osmotic stimulation increase vasopressin (VP) release within the supraoptic nucleus (SON) and into the general circulation. We examined whether changes in water/electrolyte balance affect the neurosecretory responses to these stimuli. Urethane-anesthetized control, salt-loaded (2% NaCl for 2 days) or water-deprived (for 2 days) male rats were implanted with an arterial catheter and bilateral microdialysis probes into the SON. Plasma and SON VP levels were measured before and after acute osmotic stimuli were administered intraperitoneally (i.p.) and then directly into the SON. Water deprivation resulted in elevated basal intranuclear and plasma VP levels. Intraperitoneal hypertonic saline (HS) and direct osmotic stimulation of the SON increased VP release into the SON in both the control and water-deprived groups. Salt loading abolished the intranuclear VP response to both stimuli. Osmotically induced release of VP into plasma was not different between the three groups. These data demonstrate that salt loading, but not water deprivation, alters the central neurosecretory VP response to acute osmotic stimulation.


Subject(s)
Osmotic Pressure/drug effects , Salts/pharmacology , Supraoptic Nucleus/drug effects , Vasopressins/metabolism , Animals , Male , Microdialysis , Rats , Rats, Sprague-Dawley
13.
Am J Physiol ; 270(5 Pt 1): E787-92, 1996 May.
Article in English | MEDLINE | ID: mdl-8967466

ABSTRACT

The effects of lesioning of the anteroventral third ventricle (AV3V) region on vasopressin (VP) release into the supraoptic nucleus (SON) and blood in response to central and systemic osmotic stimulation were determined. Microdialysis probes were implanted bilaterally within the SON of male urethan-anesthetized rats with sham or AV3V lesions. Osmotic stimuli were administered intraperitoneally (3.5 M NaCl, 600 microliters/100 g body wt) and then via the microdialysis probes (1 M NaCl-artificial cerebrospinal fluid). AV3V lesions attenuated the response to systemic osmotic stimulation. The lesioned rats showed no increase in intranuclear VP release and reduced plasma VP (increase of 42.6 +/- 8.4 vs. 78.0 +/- 16.4 pg/ml) and blood pressure responses (7.1 +/- 2.3 vs. 19.6 +/- 3.2 mmHg) to intraperitoneal NaCl. In contrast, the endocrine and cardiovascular responses to direct osmotic stimulation of the nucleus were as seen in previous studies and seemed to be unaffected by the lesion. These results show that lesion of the AV3V region interrupts neuronal inputs which trigger VP secretion from the posterior pituitary as well as release into the extracellular compartment of the SON.


Subject(s)
Nervous System Physiological Phenomena , Supraoptic Nucleus/metabolism , Vasopressins/metabolism , Analysis of Variance , Animals , Blood Pressure/drug effects , Injections, Intraperitoneal , Male , Microdialysis , Osmosis , Rats , Rats, Sprague-Dawley , Saline Solution, Hypertonic/pharmacology , Vasopressins/blood
14.
Am J Physiol ; 270(5 Pt 2): R1178-81, 1996 May.
Article in English | MEDLINE | ID: mdl-8928922

ABSTRACT

We have previously demonstrated that mRen-2 transgenic [Tg(+)] rats show a salt-induced exacerbation of hypertension (Callaha, M., P. Li, C. M. Ferrario, D. Ganten, and M. Morris. Hypertension Dallas 27: 573-577, 1996). In this study, we examined the role of paraventricular (PVN) angiotensin type-1 (AT1) receptors in the salt sensitivity of this model. Male Tg(+) and Tg(-) rats were instrumented with PVN cannulas for intracerebral drug administration and carotid catheters for chronic cardiovascular monitoring. Substitution of 2% NaCl for drinking water for 4 days caused a significant elevation (23 mmHg) of mean arterial pressure (MAP) in Tg(+) rats but not in Tg(-) rats. PVN injection of AT1 receptor antisense oligodeoxynucleotides (ASODN), but not scrambled oligodeoxynucleotides (SCODN), produced a rapid decrease in MAP of 24 +/_ 8 mmHg in salt-treated Tg(+) rats. There was no effect of either AT1 ASODN or SCODN on MAP in salt-loaded Tg(-) rats or in Tg(+) rats consuming tap water. Salt loading significantly increased subfornical organ AT1 receptors in Tg(+) rats with no changes produced by ASODN or SCODN. In contrast, there was a 40% decrease in PVN AT1 receptors 20 h after direct PVN injection of AT1 ASODN injection, compared with SCODN in Tg(+) rats. We conclude that PVN AT1 receptors are critical in the expression of salt sensitivity in mRen-2 transgenic rats.


Subject(s)
Hypertension/physiopathology , Paraventricular Hypothalamic Nucleus/metabolism , Receptors, Angiotensin/physiology , Renin-Angiotensin System/physiology , Sodium Chloride/pharmacology , Animals , Animals, Genetically Modified/genetics , Autoradiography , Blood Pressure , Hypertension/etiology , Male , Oligonucleotides, Antisense , Rats
15.
Hypertension ; 27(3 Pt 2): 573-7, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8613206

ABSTRACT

The (mREN-2)27 transgenic model of hypertension was developed to investigate the effect of genetic over activity of angiotensin II systems as a contributing factor in the development of arterial hypertension. In this model, transgene-positive rats demonstrate elevated renin-angiotensin system activity not only in the circulatory system but also in adrenal gland, reproductive organs, and brain. Since evidence indicates that angiotensin peptides and osmotic stimuli interact synergistically to produce exaggerated behavioral, endocrine, and cardiovascular effects, we examined the effect of salt consumption on arterial pressure, plasma vasopressin, and body fluid balance in male (mREN-2)27 transgene-positive and -negative rats. Four days of drinking 2% NaCl increased mean arterial pressure from 165 +/- 10 to 199 +/- 7 mm Hg in transgene-positive rats. In contrast, transgene-negative rats showed no change in arterial pressure (126 +/- 5 to 128 +/- 3 mm Hg). Plasma vasopressin levels were significantly elevated only in transgene-positive rats, whereas pituitary levels of vasopressin were significantly lower in transgene-positive rats compared with transgene-negative controls (18 +/- 3 and 118 +/- 14 ng, respectively). Although transgene-positive rats consumed significantly more 2% NaCl than did transgene-negative rats, during this period 24-hour sodium balance did not differ between the groups. Since fluid and electrolyte balance is similar between the two groups of rats, the data suggest that transgene-positive rats may be more sensitive to the effects of increased NaCl intake in terms of both endocrine and cardiovascular responses.


Subject(s)
Hypertension/physiopathology , Renin-Angiotensin System/genetics , Sodium, Dietary/metabolism , Animals , Animals, Genetically Modified , Blood Pressure , Hypertension/genetics , Hypertension/metabolism , Male , Rats , Sodium, Dietary/administration & dosage
16.
Neuroendocrinology ; 62(6): 619-27, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8751288

ABSTRACT

Tetrodotoxin (TTX) was used to (1) distinguish between axonal and dendritic/somatic release of vasopressin (VP) and oxytocin (OT) within the supraoptic nucleus (SON) and (2) to determine whether neuronal inputs trigger intranuclear peptide release in the response to osmotic stimulation. Microdialysis was used to administer TTX (10(-6) M or 10(-4)M) bilaterally into the SON with simultaneous monitoring of central and peripheral peptide release and mean arterial pressure in urethane-anesthetized male rats. Osmotic stimuli were given via the microdialysis probe (1 M NaCl-artificial CSF) or injected intraperitoneally (3.5 M NaCl; 600 mu l/100 g b.w.) SON perfusion with TTX did not alter basal intranuclear VP or OT release or the intranuclear peptide response to direct NaCl stimulation of the SON. However, TTX treatment abolished the effect of peripheral osmotic stimulation on central peptide release. Basal plasma peptide levels were significantly reduced by TTX, e.g. decreases of 94.8 and 75.8% for VP and OT, respectively. TTX also blocked the peripheral endocrine and cardiovascular responses to both modes of osmotic stimulation. The TTX insensitivity of directly stimulated intranuclear release suggests nonsynaptic peptide release from dendrites and/or cell bodies. The ability of TTX to abolish the central peptide response to systemic osmotic stimulation demonstrates that intranuclear release is a part of a cascade produced by osmotic activation of multisynaptic pathways.


Subject(s)
Oxytocin/metabolism , Supraoptic Nucleus/drug effects , Tetrodotoxin/pharmacology , Vasopressins/metabolism , Animals , Male , Microdialysis , Osmosis/physiology , Radioimmunoassay , Rats , Rats, Sprague-Dawley , Sodium/metabolism , Supraoptic Nucleus/metabolism , Supraoptic Nucleus/physiopathology
17.
Regul Pept ; 59(2): 261-6, 1995 Oct 20.
Article in English | MEDLINE | ID: mdl-8584763

ABSTRACT

Experiments were performed to evaluate the role of central oxytocin (OT) in the inhibition of salt intake produced by sinoartic denervation (SAD). The effect of OT antisense treatment on 24 h intake of 2% NaCl in SAD and sham-operated (SO) rats was determined. PVN injection of unmodified antisense oligodeoxynucleotides (ODNs) to OT mRNA decreased intake of 2% NaCl in SAD, but not SO rats. Salt consumption was 22 +/- 4 ml after the injection of control ODN as compared to 8 +/- 4 ml after the OT antisense injection (P < 0.05). SAD animals also demonstrated an increased plasma OT response to salt loading, an elevation from 3.2 +/- 0.7 to 6.9 +/- 0.8 pg/ml. In contrast, salt ingestion produced no significant change in plasma OT in the SO group. The increased endocrine response in the SADs occurred even though salt intake was lower in this group. There were no group differences in plasma electrolytes or posterior pituitary OT content. Results show that OT antisense specifically inhibits salt intake in the denervated rat, suggesting that the central oxytocinergic axis stimulates sodium drive in this experimental model.


Subject(s)
Drinking/drug effects , Oligonucleotides, Antisense/pharmacology , Oxytocin/physiology , Paraventricular Hypothalamic Nucleus/drug effects , Pressoreceptors/physiology , Sodium Chloride/administration & dosage , Animals , Base Sequence , Evaluation Studies as Topic , Male , Molecular Sequence Data , Muscle Denervation , Oxytocin/genetics , Rats , Rats, Sprague-Dawley
18.
J Neuroendocrinol ; 7(6): 455-9, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7550292

ABSTRACT

To address the role of oxytocin in the control of cardiovascular reactivity, we examined the effect of central injection of oxytocin, vasopressin and mixed base antisense oligodeoxynucleotides on stress-induced cardiovascular and endocrine changes. Antisense oligomers were injected into the paraventricular nucleus (PVN), 4 h prior to the stress test. The oxytocin antisense abolished the tachycardia produced by 5 min of shaker stress. The blood pressure and plasma oxytocin responses were not different between the groups. PVN levels of OT were reduced in the oxytocin antisense-treated group while brain stem levels were increased. These results demonstrate the importance of a specific peptide system, the PVN/oxytocin axis, in stress-induced tachycardia. Further, the data illustrate the effectiveness of short-term treatment with antisense oligomers on physiological responses.


Subject(s)
Oxytocin/physiology , Stress, Physiological/complications , Tachycardia/etiology , Animals , Base Sequence , Brain/drug effects , Brain/metabolism , Male , Molecular Sequence Data , Oligonucleotides, Antisense/pharmacology , Oxytocin/genetics , Oxytocin/pharmacology , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/physiopathology , Rats , Rats, Sprague-Dawley , Tachycardia/prevention & control , Vasopressins/pharmacology
19.
Am J Physiol ; 267(6 Pt 2): R1640-5, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7810775

ABSTRACT

The effect of hypertonic NaCl consumption on vasopressin (VP) and oxytocin (OT) mRNA levels and plasma and pituitary peptides was evaluated in rats with sham or anterior ventral third ventricular (AV3V) lesions. Rats were given tap water or 2% NaCl for 4 days. Because the rats with lesions drank significantly less salt solution than the controls (78.8 +/- 17.4 vs. 205.5 +/- 37.8 ml/4 days), a second control group was included in which saline intake was matched to the lesioned group. AV3V rats showed a deficit in the peptide response to the osmotic stimulus. There was no increase in plasma VP or OT or decrease in posterior pituitary peptide content in the face of an extreme hypernatremia: plasma sodium of 180.1 +/- 4.2 meq/l. Evaluation of mRNA changes by means of in situ hybridization showed that animals with lesions responded to the salt challenge with increases in hypothalamic VP and OT mRNA levels. There were significant increases in paraventricular and supraoptic OT mRNA and paraventricular VP mRNA in the lesioned group. The salt-matched control group showed no changes in peptide mRNA levels. These results demonstrate that AV3V lesions produce an impairment of the salt-neuroendocrine reflex but a persistence of the peptide mRNA response. Differences in control mechanisms must account for this dissociation between peptide mRNA expression and peptide secretion.


Subject(s)
Cerebral Ventricles/physiology , Neuropeptides/metabolism , Oxytocin/genetics , RNA, Messenger/metabolism , Vasopressins/genetics , Animals , Base Sequence , Cerebral Ventricles/surgery , In Situ Hybridization , Male , Molecular Sequence Data , Paraventricular Hypothalamic Nucleus/metabolism , Pituitary Gland, Posterior/metabolism , Rats , Rats, Sprague-Dawley , Sodium/blood , Sodium Chloride/administration & dosage , Supraoptic Nucleus/metabolism
20.
J Neuroendocrinol ; 6(4): 369-73, 1994 Aug.
Article in English | MEDLINE | ID: mdl-7987366

ABSTRACT

Vasopressin (VP) and oxytocin (OT) are released within the hypothalamic nuclear region in response to direct microdialysis with hypertonic solutions. Experiments were performed to determine whether systemic osmotic stimulation causes changes in intranuclear peptide release within the supraoptic nucleus (SON). A hypertonic sodium chloride solution was injected intraperitoneally (i.p.) or intravenously (i.v.) and microdialysis techniques were used to simultaneously monitor central and peripheral peptide release in urethane anesthetized rats. Systemic osmotic stimuli elicited increases in intranuclear peptide release which were delayed and long-lasting, occurring over a 2.5 h period. In contrast, plasma peptide levels peaked at 30-min after the stimulus. The results demonstrate that increased plasma sodium elicits an increase in VP and OT release into the extracellular space of the hypothalamic SON. The different patterns of peptide release in plasma and brain point toward the possibility of independently regulated release into the different compartments.


Subject(s)
Oxytocin/metabolism , Saline Solution, Hypertonic , Supraoptic Nucleus/metabolism , Vasopressins/metabolism , Animals , Dialysis , Injections, Intraperitoneal , Injections, Intravenous , Kinetics , Male , Osmolar Concentration , Rats , Rats, Sprague-Dawley , Saline Solution, Hypertonic/administration & dosage , Sodium/blood , Supraoptic Nucleus/drug effects
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