DI Rats Research Articles

Influence of oxytocin on renal hemodynamics and electrolyte and water excretion.

We examined the renal effects of synthetic oxytocin (OT) in the presence and absence of vasopressin in conscious euvolemic rats. Both sexes of the Long-Evans (LE) and Brattleboro homozygous (DI) strains were used. OT infused intravenously at 0.25 and 2.5 ng X min-1 X 100 g body wt (BW)-1 resulted, respectively, in plasma concentrations of 30 +/- 6 and 265 +/- 88 pg/ml in LE rats and 46 +/- 5 and 327 +/- 29 pg/ml in DI rats. Glomerular filtration rate (GFR) was augmented most consistently by the larger dose of hormone in LE rats (P less than 0.05), whereas the low infusion rate of OT enhanced GFR in DI rats (P less than 0.01). Effective renal plasma flow was not changed significantly. OT (both doses) increased the fractional excretion of sodium two- to threefold in each strain of animal (all at least P less than 0.05 from control), whereas the fractional excretion of potassium was largely unaffected. In LE rats, a diuresis was observed with either infusion rate of hormone, accompanied by a rise in osmolar clearance (COsm). In contrast, there was no change of urine flow with the low dose of OT in DI rats, because COsm increased and the clearance of free water (CH2O) decreased proportionately. The higher infusion rate of OT promoted antidiuresis in DI rats, with negative CH2O and little change in COsm. We conclude that oxytocin enhances GFR and is natriuretic regardless of the presence or absence of endogenous vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)

Action of ADH on isolated medullary thick ascending limb of the Brattleboro rat.

Establishment of a maximal corticomedullary osmotic gradient during chronic administration of arginine vasopressin (antidiuretic hormone, ADH) to Brattleboro (diabetes insipidus, DI) rats is a gradual process. The effects of ADH on voltage and radioisotopic chloride efflux (lumen to bath) were investigated in medullary thick ascending limb (mTAL) isolated from DI rats and perfused in vitro. Acute in vitro exposure of mTAL to ADH (250 microU/ml) significantly increased both the voltage (+3.3 +/- 0.3 to +4.5 +/- 0.5 mV) and chloride efflux (192.7 +/- 29.4 to 240.4 +/- 41.5 peq/min X mm). After chronic in vivo treatment with ADH for 10-21 days mTAL expressed substantially higher basal voltage and chloride efflux (+8.4 +/- 0.6 mV and 393.2 +/- 71.6 peq/min X mm). Acute in vitro application of ADH to mTAL from chronically treated animals induced a further small increase in voltage (22%). These results are taken to indicate that ADH may have dual effects on NaCl transport by the mTAL of the DI rat: a small rapid effect, and a larger long-term increase in transport that can be shown only after chronic administration of ADH. These effects may, in part, explain the gradual enhancement of concentrating ability observed in DI rats.

Dehydration-induced changes in the secretion of atrial natriuretic factor in Brattleboro rats: Effect of water-drinking

The secretion of atrial natriuretic factor (ANF) was measured in Brattleboro rats (DI) subjected to 20-h dehydration and in normal Long-Evans rats (LE) subjected to 72-h dehydration and 7 times within the hour following voluntary rehydration by drinking water. In these rats, water deprivation caused a large, significant drop in plasma immunoreactive ANF (IR-ANF). Drinking water did not restore plasma IR-ANF values within one hour, even when indirect indices of intravascular volume such as serum osmolality, sodium and hematocrit returned to normal. The dehydration-induced decrease in plasma IR-ANF and its very low secretion after restoring drinking may be essential for the homeostasis of water conservation in both DI and LE rats.

Role of vasopressin in the cardiovascular response to stimulation of the locus coeruleus.

Hypothalamic vasopressin synthesizing nuclei (paraventricular and supraoptic) send vasopressin-containing projections to a number of neural target areas thought to be involved in cardiovascular regulation. One area known to receive vasopressinergic projections from the paraventricular nucleus is the pontine nucleus locus coeruleus. To examine the possible functional participation of vasopressin in central cardiovascular regulation, we examined mean arterial pressure (millimeters of Hg) and heart rate (beats per min) responses to electrical stimulation of the locus coeruleus in conscious, unrestrained vasopressin-deficient Brattleboro rats homozygous for diabetes insipidus (DI rats) and long Evans (LE) rats. Rats received chronic arterial and venous catheters and bipolar stimulating electrodes 3-5 days before experiment. Stimulation of the locus coeruleus (100 microA, 10-40 Hz) produced frequency-dependent increases in mean arterial pressure and heart rate in LE and DI, but the responses were significantly less in the latter group. The deficiency in mean arterial pressure and heart rate responses to locus coeruleus stimulation in DI rats was found to be centrally mediated in that responses to peripherally administered phenylephrine were the same as those for LE rats. Ganglionic blockade significantly attenuated responses to locus coeruleus stimulation in LE rats but had little effect in DI rats. Pretreatment of DI rats with chronic intracerebroventricular infusion of vasopressin (osmotic minipump) at a dose that had no effect peripherally increased the mean arterial pressure and heart rate responses to locus coeruleus stimulation. Our results suggest that vasopressin acts in the region of the locus coeruleus to exert a central action on sympathetic outflow.

Effects of Extracellular Volume Expansion on Plasma Renin Concentration in Rats with Diabetes Insipidus

The effect of acute and chronic expansion of the extracellular fluid volume on plasma renin concentration (PRC) was studied in normal Long-Evans rats (LE rats) and in rats with hereditary hypothalamic diabetes insipidus (DI rats). Chronic deoxycorticosterone acetate (DOCA) treatment, combined with a high sodium intake, significantly reduced PRC of both DI and LE rats. PRC of DI rats, however, remained higher than that of LE rats. Acute volume expansion, either alone or with DOCA treatment, also significantly diminished PRC of both DI and LE rats. PRC of untreated and DOCA-treated DI rats again remained significantly higher than that of LE rats after acute volume expansion. These findings suggest that the elevated PRC normally observed in DI rats is not due solely to diminished volume of extracellular fluid. Instead, the absence of ADH per se may directly alter renin secretion or the sensitivity of the granular cell to other stimuli.

Increased number of angiotensin II binding sites determined by autoradiography in anterior pituitary of water-deprived and Brattleboro rats.

Pituitary angiotensin II (ANG) binding sites were characterized by autoradiography in individual male Long Evans (LE) rats, heterozygous Brattleboro (HZ) rats, and homozygous Brattleboro (DI) rats which were water satiated or water deprived. An additional group of DI rats was treated with arginine vasopressin for 1 week. The technique utilized 8-micron pituitary sections which were incubated with 125I-[Sar1]-ANG in concentrations ranging from 25 pM to 10 nM. Angiotensin binding in the anterior pituitary of water-satiated LE rats was characterized by a single class of high-affinity, saturable sites with a Bmax of 1.309 +/- 119 fmol/mg of protein and a Ka of 0.51 +/- 0.03 X 10(9) M-1. Compared to LE rats the density of ANG-binding sites in anterior pituitary was higher in DI rats (+84.2%), with HZ having an intermediate concentration (+41.6). Dehydration increased the ANG-binding site density in all groups. Five days of water deprivation increased the number of ANG-binding sites by 86.5% and by 36.9% in LE and HZ rats, respectively, when compared to their water-satiated controls. After 1 day of water deprivation, the ANG-binding site density increased by 19.4% in DI rats. No changes in ANG-binding sites occurred after hormonal replacement with arginine vasopressin in water-satiated DI rats. The binding affinity constant of the agonist for the ANG-binding sites compared with LE rats was decreased in both HZ and DI rats (-27.5 and -19.4%) and was also decreased after 5 days of dehydration in LE rats (-34%) when compared to the water-satiated state.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of arginine vasopressin in alcohol dependence and withdrawal

The development and maintenance of tolerance to the physiological and behavioral effects of repeated exposure to ethanol can be altered markedly by the presence of arginine vasopressin (AVP). In addition, AVP has been implicated in the etiology of convulsions, including those induced by exposure to high ambient temperatures. In light of these findings, experiments were conducted to determine the role, if any, that AVP might play in the pathogenesis of alcohol-withdrawal convulsions. Thirty-two male Long Evans (LE) rats and 32 age-matched male homozygous Brattleboro (DI) rats (genetically deficient in AVP) were exposed to ethanol vapor concentrations adjusted to maintain blood alcohol levels of each rat at 150–350 mg/dl. Following at least 5 days of ethanol exposure, the animals were withdrawn. From 3–24 hr after cessation of ethanol administration, withdrawal severity was assessed by observing the response of each animal to a 60–120 sec period of auditory stimulation. No significant differences were observed in either latency to onset or severity of the convulsions in LE and DI rats upon ethanol withdrawal. Thus, alcohol-withdrawal convulsions, unlike hyperthermia-induced convulsions, may be mediated by a neurochemical substrate other than AVP.

Hypothalamo-pituitary regulation of thyrotrophin secretion in chronically catheterized Brattleboro rats.

Plasma TSH rhythms were measured in Brattleboro (DI) and control Long-Evans (LE) rats with an intracardiac catheter allowing repeated sampling in conscious unstressed animals. The TSH response to thyrotrophin-releasing hormone (TRH; 500 ng/100 g body weight) was also determined. Finally, hypothalamic and pancreatic TRH concentrations and TRH-degrading activity (TRH-DA) were measured by specific radioimmunoassay. Long-Evans rats had a 24-h rhythm with a major modulatory 8-h component. In DI rats, only the 24-h rhythm was detected. The mean 24-h rhythm-adjusted mean TSH level was higher in DI than in LE rats (1.38 +/- 0.05 and 1.14 +/- 0.06 micrograms/l respectively, P less than 0.01). The peak TSH response to TRH was significantly increased in DI rats while the pituitary concentration of TSH was also higher (0.93 +/- 0.09 vs 0.39 +/- 0.06 micrograms/mg wet weight in LE, P less than 0.001). Hypothalamic TRH and TRH-DA were similar in both strains. The response to propylthiouracil-induced hypothyroidism was identical in both strains. We conclude that DI rats have a normal pituitary sensitivity to tri-iodothyronine but a central dysfunction in the pituitary environment leading to some alterations of TSH secretion.

Supraoptic neurones in Brattleboro rats respond normally to changes in plasma osmotic pressure.

Brattleboro rats homozygous for hypothalamic diabetes insipidus (DI rats) were anaesthetized with urethane. Extracellular recordings were made from antidromically identified neurones of the supraoptic nucleus. About half (77 out of 153) of the neurones recorded in DI rats showed phasic patterns of discharge activity similar to those which are characteristic of vasopressin-secreting neurones in normal rats during hyperosmotic stimulation. Significantly fewer neurones showed phasic activity in DI rats which had been pretreated with vasopressin tannate at a dose which significantly reduced urine volume, water intake and plasma osmolality. Acute systemic hyperosmotic stimulation, induced by an i.p. injection of 1 ml 1.5 M-NaCl, increased the discharge rate of each of 14 neurones from DI rats by 1-5 spikes/s. Hypo-osmotic stimulation, induced by an intragastric injection of 10 ml tap water, reduced the discharge rate of each of four neurones from DI rats by 50% or more. We conclude that supraoptic neurones in DI rats respond normally to acute systemic osmotic stimuli despite the total absence of vasopressin in these rats and despite their chronically disturbed water balance. This implies that the osmoreceptor mechanism which drives the supraoptic nucleus does not adapt substantially during prolonged disturbance of water balance and functions outside the normal physiological range of plasma osmolality, and that the reported alteration of noradrenergic innervation of the neurones in DI rats does not affect their osmotic responsiveness.

Altered emotionality of the vasopressin-deficient Brattleboro rat

Observation of open field behavior of vasopressin-deficient (DI) and normal Long-Evans rats indicated elevated levels of open field activity for the DI rats. Exposure to an acoustic stressor resulted in decreased activity in both groups of animals but with a lesser effect on the DI rat. Handling prior to experimentation diminished the differences between DI and normal rats. Although both groups displayed an equivalent rise in plasma corticosterone in response to the open field, the addition of the acoustic stressor resulted in greater elevation of corticosterone in the normal animals. The behavioral and hormonal data suggest that the DI rat exhibits decreased emotional reactivity. Measurement of brain neurotransmitter levels revealed higher concentrations of serotonin, norepinephrine and dopamine in the limbic regions of the DI rat. These alterations may underlie the behavior reflecting decreased emotionality of the DI rat. In turn, the altered emotional state may be the basis for alteration in performance on learning/memory tasks of these animals. Thus, vasopressin effects on the retrieval and/or consolidation of information may not be direct but rather through its ability to influence the emotional state of the animal.

Antidiuretic effect of endogenous oxytocin in dehydrated Brattleboro homozygous rats.

Despite the absence of vasopressin, Brattleboro homozygous (DI) rats concentrate their urine to hypertonic levels when deprived of drinking water for 24 h. Glomerular filtration rate (GFR) falls concurrently and might contribute to the increased concentrating ability. The present studies concerned the time course of the changes in concentrating ability and GFR during the early hours of dehydration. Experiments were performed in 10 chronically catheterized conscious DI rats in the normally hydrated control state and during 3 h of fluid deprivation. Urine osmolality (Uosmol) increased from 97 +/- 6 (SE) to 325 +/- 11 mosmol/kg H2O at 3 h. Averaged over the 3 h, neither GFR nor effective renal blood flow changed significantly (103 +/- 2 and 106 +/- 4% of control, respectively). Fractional excretion of sodium (FENa) rose markedly from 0.3 +/- 0.1 to 1.3 +/- 0.1% at its peak. Clearly, a fall in GFR cannot explain the rise in Uosmol during the first 3 h. Plasma oxytocin (OT) increased from 5.6 +/- 0.8 to 36.4 +/- 4.5 pg/ml after 3 h of dehydration. In additional experiments, d(CH2)5-D-Phe-VAVP, an antidiuretic antagonist (anti-ADH), was administered to eight DI rats after 3-h dehydration. Control, 3-h dehydration, and post-anti-ADH values were, respectively: for Uosmol, 102 +/- 7, 347 +/- 14, 145 +/- 11 mosmol/kg H2O; for GFR, 1,003 +/- 43, 1,042 +/- 59, 866 +/- 54 microliter X min-1 X 100 g body wt-1; for FENa, 0.4 +/- 0.1, 1.4 +/- 0.1, 0.5 +/- 0.1%. The decreases following anti-ADH were all statistically significant. We conclude that OT is released during the early hours of dehydration in the DI rat and has at least three renal effects. It causes a natriuresis, it maintains renal hemodynamics and GFR during the volume contraction, and it elicits a weak antidiuretic response.

Angiotensin II increases ACTH release in the absence of endogenous arginine-vasopressin

Recent studies from our laboratory indicate a primary central site of action of Angiotensin II (AII) to release ACTH. The present studies were designed to test whether AII is able to release ACTH in vivo in a similar fashion in intact, cannulated, freely moving Long-Evans (LE) or in vasopressin (AVP)-deficient, Brattleboro (DI) female rats. The in vivo response to AII was compared with that elicited by synthetic CRF. All injected i.v. (0.4 or 2 μg/100 g BW) induced a significant, dose-related increase in plasma ACTH values 5 and 15 min after injection, in both LE and DI rats. CRF given to LE and DI rats at 0.4 μg/100 g BW elicited a larger increase in ACTH plasma values than a similar dose of AII, 5 or 15 min after the injection. Moreover, ACTH levels after CRF in DI rats were significantly greater than those obtained in LE controls. In vitro studies using dispersed anterior pituitary cells indicate that the response of cells from either LE or DI rats to AII or AVP (both at 10 −9 and 10 −8) was similar. Cells from DI donors were hyperresponsive to CRF (2×10 −11 and 10 −10M) in terms of ACTH release when compared with the response of cells from LE rats. The present results suggest that the presence of AVP is not essential to mediate the central response to AII and that AII may act centrally to stimulate CRF release from the hypothalamus in vivo , which would then enhance ACTH output. The results in the DI rat indicate that the increased response to CRF may be an important compensatory mechanism involved in the regulation of adrenocortical function in the DI rat.

Compositional changes of the corticopapillary osmotic gradient during dehydration in the absence of vasopressin.

Despite the absence of vasopressin, Brattleboro homozygous (DI) rats concentrate their urine to hypertonic levels when deprived of drinking water. Ultimately this rise in urine osmolality must follow from increased osmolality of the corticopapillary gradient and/or increased osmotic equilibration across the collecting ducts. In this study we examined the concentrations and contents of total solute, urea, and nonurea solute in tissue from cortex to papillary tip of DI rats before and after dehydration for 12, 24, and 48 h. The greatest increase in osmolality occurred during the first 12 h; both urea and nonurea solute concentrations increased, but urea preferentially. From 12 to 48 h there were only small further increases in these concentrations, largely as a result of decreased tissue water content. Osmotic equilibration (reflected by urine/papillary tip osmolality) increased dramatically during dehydration, presumably because of decreased flow rate, attaining full equilibration by 48 h. The rise in urine osmolality during the first 12 h of dehydration was due to increased osmotic equilibration and to the enhanced corticopapillary gradient; urine became more concentrated from 12 to 48 h largely as a result of increased osmotic equilibration.

CNS-induced natriuresis and renal hemodynamics in conscious rats.

Sodium excretion was studied following experimental elevation of cerebrospinal fluid (CSF) sodium in heterozygous and homozygous (DI) Brattleboro rats given exogeneous antidiuretic hormone. Sodium excretion increased 4.5-fold in heterozygous and 3.5-fold in DI rats. The natriuresis in both groups was rapid in onset and occurred with a simultaneous kaliuresis. Blood pressure increased approximately 10 mmHg in the heterozygous but not in the DI rats. Accordingly, increased blood pressure may contribute to the natriuresis but is not the sole mechanism. Plasma renin concentration did not change in the DI rats during high Na CSF infusion, and chronic bilateral renal denervation did not abolish the natriuresis. Glomerular filtration rate increased during the high Na period in both the intact and renally denervated rats. These data provide evidence that a natriuretic mechanism exists that is not mediated by changes in antidiuretic hormone, renal nerve activity, mean arterial pressure, aldosterone, or angiotensin II, and thus may be due to another circulating substance or natriuretic hormone. This hormone may act totally or in part by increasing glomerular filtration rate.

High, vasopressin-reversible, immunoreactive somatostatin in specific hypothalamic nuclei of rats with diabetes insipidus (Brattleboro rats)

Somatostatin content was studied in brain nuclei and pituitary lobes of homozygous Brattleboro rats lacking vasopressin (DI rats) with and without vasopressin replacement, and their corresponding controls, heterozygous Brattleboro (HZ) rats and Long-Evans (LE) rats. High, vasopressin-reversible, somatostatin levels occurred in DI rats. The changes in somatostatin were localized to the nucleus periventricularis and to brain areas receiving somatostatin projections from this nucleus, including the eminertia mediana. In contrast, vasopressin administration failed to alter somatostatin levels in HZ rats. In brain areas not belonging to the somatostatin periventricular system, the peptide concentration in DI rats was not higher than that of LE controls. High somatostatin levels were present in the intermediate lobe of the pituitary gland. Somatostatin was higher in DI and HZ rats when compared to LE rats. In the posterior pituitary lobe, HZ rats had higher, and DI rats lower, somatostatin than control LE rats. These results suggest that rat brain and pituitary vasopressin and somatostatin systems are interrelated.

High histamine levels in specific hypothalamic nuclei of Brattleboro rats lacking vasopressin

Histamine levels were determined in whole hypothalamus and specific hypothalamic nuclei of male 9-week-old homozygous Brattleboro rats lacking vasopressin and presenting the syndrome of diabetes insipidus (DI rats). These levels were compared to those in heterozygous Brattleboro rats with a partial deficit in vasopressin (HZ rats) and those in Long Evans control rats (LE rats). In whole hypothalamus, histamine levels in DI rats were higher than those found in HZ and LE rats. DI rats showed histamine levels higher than those present in LE rats in the nuclei supraopticus, paraventricularis and suprachiasmatis and in the area retrochiasmatica. Vasopressin replacement produced a selective decrease in histamine levels of DI rats, restricted to the area retrochiasmatica and nuclei supraopticus and paraventricularis. In contrast, vasopressin increased histamine levels in the area retrochiasmatica and eminentia mediana of HZ rats. In other areas normally rich in vasopressin such as the nuclei arcuatus and the eminentia mediana, the histamine content was not different among LE, HZ or DI rats. Our results suggest a physiological interaction between vasopressin and histamine systems in specific hypothalamic areas of the rat and support the hypothesis of a role of brain shitamine on the central control of water balance.

Chlorpropamide action on renal concentrating mechanism in rats with hypothalamic diabetes insipidus.

To determine vasopressin (VP)-potentiating effect of chlorpropamide (CPMD), we studied the effect of CPMD in vivo and in vitro in kidneys and in specific tubule segments of rats with hypothalamic diabetes insipidus, homozygotes of the Brattleboro strain (DI rats). Rats on ad lib. water intake were treated with CPMD (20 mg/100 g body wt s.c. daily) for 7 d. While on ad lib. water intake, the urine flow, urine osmolality, urinary excretion of Na +, K +, creatinine, or total solute excretion did not change. However, corticopapillary gradient of solutes was significantly increased in CPMD-treated rats. Higher tissue osmolality was due to significantly increased concentration of Na +, and to a lesser degree urea, in the medulla and papilla of CPMD-treated rats. Consequently, the osmotic gradient between urine and papillary tissue of CPMD-treated rats (delta = 385 +/- 47 mosM) was significantly (P less than 0.001) higher compared with controls (delta = 150 +/- 26 mosM). Minimum urine osmolality after water loading was higher in CPMD-treated DI rats than in controls. Oxidation of [14C]lactate to 14CO2 coupled to NaCl cotransport was measured in thick medullary ascending limb of Henle's loop (MAL) microdissected from control and CPMD-treated rats. The rate of 14CO2 production was higher (delta + 113% +/- 20; P less than 0.01) in CPMD-treated MAL compared with controls, but 14CO2 production in the presence of 10(-3) M furosemide did not differ between MAL from control and from CPMD-treated rats. These observations suggest that CPMD treatment enhances NaCl transport in MAL. Cyclic AMP metabolism was analyzed in microdissected MAL and in medullary collecting tubule (MCT). MCT from control and from CPMD-treated rats did not differ in the basal or VP-stimulated accumulated of cAMP. The increase in cAMP content elicited by 10(-6) M VP in MAL from CPMD-treated rats (delta + 12.0 +/- 1.8 fmol cAMP/mm) was significantly (P less than 0.02) higher compared with MAL from control rats (delta + 5.1 +/- 1.0 fmol cAMP/mm). Preincubation of MAL dissected from Sprague-Dawley rats with 10(-4) M CPMD in vitro increased cAMP accumulation in the presence of VP, but no such enhancement was found in preincubated MCT. Adenylate cyclase activity, basal or stimulated by VP, 5'guanylimidodiphosphate, or by NaF, assayed in isotonic medium did not differ between MAL or MCT from control rats and MAL or MCT from CPMD-treated rats. When assayed in hypertonic medium (800 mosM), the adenylate cyclase activity in the presence of 10(-6) M VP was significantly higher in MAL of CPMD-treated rats. MAL and MCT from control and CPMD-treated rats did not differ in the activities of cAMP phosphodiesterase. The rate of [(14)C]prostaglandin E2 by medullary and papillary microsomes was not different between the control and CPMD-treated rats; likewise, there was no difference in accumulation of immunoreactive prostaglandin E2 in the medium of in vitro incubated medullary or papillary slices prepared from control and CPMD-treated rats. Based on the findings recounted above, we propose a hypothesis that CPMD administration enhances the antidiuretic effect of VP, primarily by increasing medullary and papillary tonicity dye to increased NaCl reabsorption in MAL. There is no evidence that CPMD sensitizes collecting tubules to the action of VP, at least at the camp-generation step. Therefore, increased antidiuretic response to VP in the kidneys of CPMD-treated DI rats is due to enhanced osmotic driving force for water reabsorption (lumen-to-interstitium osmotic gradient) in collecting tubules, rather than due to increased VP-dependent water permeability of tubular epithelium.

Selective increase of angiotensin-converting enzyme activity in discrete extrahypothalamic areas of Brattleboro rats

We studied the activity of angiotensin I converting enzyme (ACE, kininase II, E.C. 3.4.15.1) in discrete areas of the brainstem and limbic system, and in circumventricular orugans, pineal gland and choroid plexus of homozygous rats (DI) which are characterized by vasopressin deficiency and diabetes insipidus, with or without vasopressin replacement. We also determined ACE activity in heterozygous Brattleboro (HZ) and Long-Evans (LE) control rats. We found changes in ACE activity in several brain areas and the pineal gland of Brattleboro rats. ACE activity was increased in DI rats with respect to HZ and LE controls in the A1 area of the brainstem, locus coeruleus, and triangular nucleus of the septum. ACE activity in the A2 area of the brainstem, the nucleus tractus spinalis nervi trigeminii and the pineal gland was enhanced in both HZ and DI rats with respect to that of LE controls, but was not different between HZ and DI rats. ACE activity did not change in the other extrahypothalamic areas studied. The elevated ACE activity in extrahypothalamic areas of DI rats was not reversed by vasopressin replacement. These results suggest that a relationship between central vasopressin and angiotensin or bradykinin systems may exist in selective extrahypothalamic areas of the rat brain, and that peripherally administered vasopressin cannot influence this relationship.

Endogenous vasopressin modulates the baroreflex sensitivity in rats.

The effect of endogenous vasopressin on the baroreceptor reflex has been examined by comparing baroreflex function in Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI rat) with that in Long-Evans rats (LE rat). Baroreflex function was assessed in conscious unrestrained rats during increases in blood pressure with phenylephrine. The slope of the baroreflex function line in LE rats [(19.0, s.e.m. = 1.4) X 10(-4), n = 34] was significantly steeper than that in DI rats [(6.9, s.e.m. = 0.6) X 10(-4), n = 44, P less than 0.0001]. A subpressor infusion of arginine8-vasopressin (2 ng/kg per min for 2 h i.v.) and an equidose of DDAVP caused bradycardia and increased the baroreflex function slope significantly. Acute volume expansion in DI rat did not change the baroreflex sensitivity. A specific vasopressin vascular receptor antagonist, d(Ch2)5Tyr(Me)AVP, did not alter the baroreflex sensitivity in LE rats. These results suggest that endogenous vasopressin is an important physiological regulator of the baroreflex sensitivity in normal rats.

Effect of chronic vasopressin treatment on alcohol drinking of Brattleboro HZ and DI rats

Preference for alcohol was determined for three groups of male and female rats, 100–150 days old, comprised of: (1) Long Evans (LE); (2) LE-derived Brattleboro heterozygous (HZ); and (3) Brattleboro homozygous (DI) animals afflicted with diabetes insipidus due to vasopressin deficiency. Each alcohol drinking test was run over 11 days during which food, water and an ethyl alcohol solution, increased in concentration from 3% to 25%, were freely available. Following an initial preference screen, 100 milli-units of vasopressin tannate in oil was administered subcutaneously, during a second preference test, once per day to each animal. This treatment ameliorated the polydipsia-polyuria syndrome characteristic of the DI sub-strain of Brattleboro rat. Administration of the peptide to both the LE or HZ animals exerted no effect on g/kg intake nor on the proportional measure of alcohol to water. However, in the DI rat of either gender, vasopressin reduced the mean absolute gram intake of alcohol over concentrations to resemble that of the other LE and/or HZ groups. These results demonstrate that vasopressin serves to normalize the intake of alcohol in the DI rat by virtue of the elimination of the diabetic condition. However, since vasopressin fails to alter alcohol consumption of the HZ and LE rats, it would appear that this neuroactive peptide may play only a minor role in the CNS mechanisms governing the voluntary selection of alcohol.