Homozygous Brattleboro Rats Research Articles

Modulation of hypothalamic cholecystokinin receptor density with changes in magnocellular activity: A quantitative autoradiographic study

A combination of autoradiographical techniques and computerized image analysis has been used to study the distribution and density of cholecystokinin receptors in the paraventricular and supraoptic nuclei of animals in which the magnocellular-posterior pituitary axis is activated, namely, in salt-loaded (2% sodium chloride) and homozygous Brattleboro rats. [ 125I]cholecystokinin octapeptide binding was greatly elevated in the paraventricular, supraoptic and accessory nuclei of salt-loaded and homozygous Brattleboro rats, compared to the respective control animals. Furthermore, under these conditions [ 125I]cholecystokinin octapeptide binding in the paraventricular nucleus was localized almost exclusively to magnocellular subdivisions, and especially to those containing predominantly oxytocin neurons. Autoradiographical competition studies revealed that the increase in [ 125I]cholecystokinin octapeptide binding in magnocellular nuclei reflected an increase in receptor number (B max) rather than affinity (K d). These results suggest that cholecystokinin receptor density in the paraventricular, supraoptic and accessory magnocellular nuclei is closely linked to magnocellular neurosecretory activity and raises the possibility that cholecystokinin receptors may be involved in oxytocin and vasopressin release processes.

Physiologic Regulation and Distribution of the Renal Vasopressin Receptor

Previous studies suggest that circulating levels of vasopressin (AVP) influence the responsiveness of the kidney to AVP. To determine how changes in renal AVP receptors and adenylate cyclase (AC) contribute to such altered responsiveness, we analyzed AVP receptors and AVP-sensitive AC in kidneys from Sprague-Dawley, Long-Evans and homozygous Brattleboro rats. In autoradiographic studies, the distribution of [3H]AVP binding sites was similar in all groups, corresponding to the location of AVP-sensitive AC: collecting ducts greater than outer medullary collecting ducts greater than medullary thick ascending limb greater than cortical collecting ducts. No differences in AVP receptor affinity or content were observed in kidney medullary membranes from Sprague-Dawley, Long-Evans or Brattleboro rats (KD = 0.8, 0.9, and 0.7 nM; Bmax = 116 +/- 9, 95 +/- 11 and 98 +/- 6 fmol/mg). Basal and AVP-stimulated AC activities were lower in kidney membranes from Brattleboro rats compared with Sprague-Dawley and Long-Evans animals (basal = 28 +/- 4, 40 +/- 4 and 38 +/- 3 pmol cAMP/mg/min; EDmax = 57 +/- 5, 80 +/- 7 and 71 +/- 2 pmol cAMP/mg/min) with no change in ED50. In 48-hour water-deprived Sprague-Dawley rats, AVP receptors were decreased from 116 +/- 9 to 58 +/- 2 fmol/mg, suggesting that AVP receptors are down-regulated by elevated AVP blood levels. The absence of changes in basal or AVP-stimulated AC in dehydrated rats indicates that receptor-AC coupling is normal and that maximum AC activation can occur with partial receptor occupancy. The data also indicate that impaired renal responsiveness to AVP in Brattleboro rats is not due to down-regulation of AVP receptors.

Potential involvement of galanin in the regulation of fluid homeostasis in the rat

A physiological role for galanin, a 29-amino acid neuropeptide, has not been established. However, anatomical studies have demonstrated the presence of galanin in brain regions associated with the control of water balance in the rat, most notably in the paraventricular nucleus (PVN) of the hypothalamus and the neurointermediate lobe of the pituitary gland (NIL). In the PVN, galanin coexists with arginine vasopressin (AVP) in magnocellular neurons. The present study demonstrates that homozygous Brattleboro rats, which lack AVP, produce galanin. Galanin concentrations in the median eminence (ME) of the homozygous Brattleboro rat do not differ from the galanin concentrations in the ME of either heterozygous Brattleboro or Sprague-Dawley rats. However, galanin concentrations in the NIL of the homozygous Brattleboro rat were reduced by 75%. Similarly, dehydration induced by salt-loading reduced galanin concentrations in the NIL and produced transient changes in the ME. These data demonstrate that galanin concentrations are influenced by changes in fluid homeostasis and suggest that galanin may be an important component in the regulation of neurohypophyseal function and AVP secretion.

Enhanced phosphoinositol hydrolysis in response to vasopressin in the septum of the homozygous brattleboro rat

Arginine 8-vasopressin (AVP) receptors in the septum of the Long-Evans rat have been shown to be both pharmacologically (displacement profiles) and functionally (ability to stimulate phosphoinositide hydrolysis) similar to the peripheral V 1-type receptor for AVP. Previous binding studies of AVP receptors in the septum of heterozygous (HE) and homozygous (vasopressin-deficient, HO) Brattleboro (BB) rats revealed an increased number of receptors with a lower affinity for AVP in the HO-BB rat when compared to the HE-BB rat. To determine the effect of these receptor changes in the HO-BB rat septum on the postreceptor response of the tissue to AVP, concentration-response relationships for AVP-stimulated phosphoinositide hydrolysis were examined in septal slices from age-matched, adult male HE- and HO-BB rats. AVP-stimulated accumulation of [ 3H]inositol-1-phosphate (IP 1) was significantly greater in the HO-BB (43.7%) than in the HE-BB (13.7%) at AVP concentrations of 10 −08 to 10 −05 M. The two groups did not, however, differ in their ability to stimulate [ 3H]IP 1 accumulation in response to 2.0 nM carbochol. When the AVP-stimulated phosphoinositide response in both genotypes was compared to that obtained for the Long-Evans (LE) rat (the parent strain of the Brattleboro rat) septum under the same assay conditions, it was found that the response in the HE-BB was much lower in the LE, AVP receptor binding capacity ( B max correlated ( r = 0.975) with release of IP 1 [ 3H]P 1 accumulation) for all 3 groups studied (LE, HE, HO). These results indicate that Brattleboro rats do posses functional receptors for AVP in the septum, and that the postreceptor response in the septum of the HO-BB rat is much larger than in the HE-BB rat.

Differential distribution of acetylcholinesterase activity among vasopressin- and oxytocin-containing supraoptic magnocellular neurons

Acetylcholinesterase activity was demonstrated histochemically at light- and electron-microscopic levels, in Vibratome sections of the supraoptic nucleus of fixed hypothalami derived from osmotically stimulated and unstimulated Long-Evans rats, from homozygous Brattleboro rats with hypothalamic diabetes insipidus, from lactating rats, from normal adult male house mice ( Mus musculus) and from mice with hereditary nephrogenic diabetes insipidus ( di/di). Reaction product was located in supraoptic magnocellular neurons; in dorsal and rostral aspects of the supraoptic nuclei lightly stained cells predominate, whereas in ventral and caudal regions densely staining perikarya predominate. Pre- and post-embedding immunocytochemical detection of oxytocin-neurophysin or vasopressin-neurophysin, combined with acetylcholinesterase histochemistry, showed that the lightly staining cells are oxytocinergic, and the densely staining cells vasopressinergic. Osmotic stimulation of the animals, either by substitution of drinking water for 3 days with 2.5% saline or by reason of genetic defects which result in diabetes insipidus, enhanced the acetylcholinesterase activity of the vasopressin neurons but had little effect on the weakly acetylcholinesterase-reactive oxytocin cells. Acetylcholinesterase activity was particularly marked in the hypertrophied abnormal magnocellular neurons of homozygous Brattleboro rats which do not release significant amounts of vasopressin. The increased acetylcholinesterase activity in osmotically stimulated animals cannot, therefore, be a function of vasopressin. Acetylcholinesterase activity was also detected in large multipolar neurons lying dorsolateral to the supraoptic nucleus, and in their fine axonal processes which project towards the supraoptic nucleus. A very few synaptic boutons surrounded by acetylcholinesterase reaction product were found in contact with magnocellular neuron basal dendrites. However, much of the punctate acetylcholinesterase reactivity observed at the light microscopic level and previously interpreted as representing the loci of cholinergic synaptic boutons was shown to be intracellular, and probably caused by acetylcholinesterase activity in some large, secondary lysosomes.

Anterior neocortical kindling in vasopressin-deficient rats

Kindling of seizures with stimulation of anterior neocortex was examined in control rats and in Brattleboro rats deficient in arginine-vasopressin (AVP). There were no significant differences between control rats, homozygous Brattleboro rats, and heterozygous Brattleboro rats in the rate and pattern of kindling of generalized seizures. Thus AVP is not critically involved in anterior neocortical kindling.

Mutant vasopressin precursor in the endoplasmic reticulum of the Brattleboro rat. Ultrastructural evidence from individual "vasopressin" cells localized with the light microscope by use of a new gold/silver method for immunostain enhancement.

This ultrastructural study demonstrates that the vasopressin immunoreactivity found in the occasional, densely stained cells in the hypothalamus of the homozygous Brattleboro rat is localized in the rough endoplasmic reticulum. 50-micron Vibratome sections were stained with anti-vasopressin serum by use of a peroxidase method with 3,3-diaminobenzidine as chromogen. The diaminobenzidine end-product has a specific capability to bind gold particles from a chloroauric acid solution and the bound gold was used to precipitate silver grains from a silver developer. The stained sections were flat embedded in resin and ultrathin sections were cut of areas containing the immuno-identified occasional cells. In these densely stained, vasopressin-immunoreactive cells of homozygous Brattleboro rats the rough endoplasmic reticulum was dilated. The lumen of the reticulum contained both end-products of diaminobenzidine and gold/silver grains, but some parts of the reticulum appeared unstained. No other cell organelles were immunostained and no secretory granules were found. In control rats, gold/silver deposits were found throughout the cytoplasm of vasopressin-immunoreactive cells. In these immunostained cells secretory granules were seen.

Plasma osmolality predicts extracellular fluid catechol concentrations in the lateral hypothalamus.

The lateral hypothalamus has an important role in regulating food and water intake. We have investigated the endogenous release of monoamines from the lateral hypothalamus during manipulations of plasma osmolality and circulating volume. Adult male Sprague-Dawley rats implanted with carbon paste in vivo electrochemical (EC) electrodes in the lateral hypothalamus were placed on a 72-h water deprivation schedule. Although the carbon paste EC electrode has an intrinsically ambiguous signal in which changes in ascorbic acid may appear as changes in catechol concentrations, pharmacologic studies in lateral hypothalamus indicated that the electrode most likely measured norepinephrine and possibly epinephrine. On the test day, the EC electrodes were scanned with linear sweep voltammetry from -0.2 to +0.4 V at a rate of 5 mV/s. Semiderivative signal processing showed catechol and hydroxyindole peaks at +0.11 and +0.23 V, respectively. Baseline recordings were made prior to rats drinking distilled water, 10% sucrose, 5% dextrose, 0.30% NaCl, 0.90% NaCl, or 10% d-mannitol. To control for the act of drinking, other implanted dehydrated rats were intraperitoneally injected with 5% dextrose, 0.30% NaCl, or 0.90% NaCl. To dissociate the effects of osmolality and circulating volume on the EC response, hydrated rats implanted with EC electrodes were subcutaneously injected with 12% NaCl or intraperitoneally injected with 35% polyethylene glycol. Other rats subjected to water deprivation and osmotic challenges were decapitated and trunk blood was collected for measurements of plasma osmolality and hematocrit. Similar experiments were conducted using homozygous Brattleboro rats which lack arginine vasopressin (AVP) but which preserve normal plasma osmolality with prodigious drinking.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of alpha 2-adrenoceptor agonist-induced diuresis

In vivo and in vitro studies were performed to assess the mechanism of the diuretic effect of B-HT 933, a selective alpha 2-adrenoceptor agonist. In conscious Sprague-Dawley rats whose plasma vasopressin (AVP) levels were increased by infusion of hypertonic NaCl, B-HT 933 had no effect on AVP secretion. In Brattleboro homozygous (DI) rats, the antidiuretic dose response to AVP was shifted to the right by B-HT 933. In addition, a sustained antidiuresis induced in rats by infusion of 10 pg/min AVP was attenuated by B-HT 933 in a concentration-dependent manner. Pretreatment of DI rats with pertussis toxin (2 micrograms/kg iv) 4-5 days before testing abolished the inhibitory effect of B-HT 933 on AVP-induced antidiuresis. In outer medullary collecting ducts of DI rats, norepinephrine and B-HT 933 produced significant inhibition of AVP-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation. In contrast, the selective alpha 1-adrenoceptor agonist cirazoline had no effect on AVP-induced cAMP formation. The inhibitory effect of norepinephrine was antagonized by the selective alpha 2-adrenoceptor antagonist rauwolscine but not by prazosin, a selective alpha 1-antagonist. In outer medullary collecting ducts dissected from the pertussis toxin-treated DI rats used in the in vivo studies, the inhibitory effect of norepinephrine and B-HT 933 on AVP-stimulated cAMP accumulation was abolished. The results indicate that the hydrosmotic action of AVP is inhibited by alpha 2-agonists via a pertussis toxin-sensitive mechanism.

Vasopressin-stimulated turnover of phosphatidylinositol in the decentralised superior cervical ganglion of the rat

Vasopressin (AVP) receptors have been demonstrated in the superior cervical ganglion (SCG) linked to the turnover of phosphatidylinositol (PI). We have investigated the effect of changes in autonomic function on the turnover of PI in the rat SCG in response to AVP and carbachol. Decentralisation of the SCG for 3 days causes a significant decrease in the response to AVP, while the response to carbachol is unaffected. The decrease in response to AVP is still present 21 days after decentralisation. A similar pattern of changes is present in ganglia from the homozygous Brattleboro rat. Pretreatment with reserpine has no effect on the response to AVP. The results suggest that AVP may be involved in ganglionic transmission in the autonomic nervous system, but that full expression of AVP-induced turnover of PI is dependent on an intact preganglionic input.

Immunoreactive vasopressin and oxytocin in hypothalamo-hypophysial portal blood of the Brattleboro and Long-Evans rat: effect of adrenalectomy and dexamethasone.

Immunoreactive vasopressin and oxytocin were measured in the hypothalamo-hypophysial portal blood of both Long-Evans and homozygous Brattleboro rats. Adrenalectomy caused an increase in vasopressin immunoreactivity in portal blood in the Long-Evans strain, whilst administration of dexamethasone to these adrenalectomized animals resulted in a reduction in portal vasopressin immunoreactivity to levels below those seen in sham-operated animals. This vasopressin immunoreactivity co-eluted with synthetic vasopressin on high-pressure liquid chromatography (HPLC), and diluted in parallel in radio-immunoassay. In Brattleboro rats, however, although vasopressin-like immunoreactivity was detected, the portal concentration did not vary with the adrenal status of the animal, nor did it show the characteristics of standard vasopressin on HPLC or in immunoassay. Oxytocin was present in the portal blood of both Long-Evans and Brattleboro rats at similar very high concentrations, but did not vary in response to adrenalectomy. These results are consistent with a role for vasopressin, but not oxytocin, in the hypothalamic response to adrenalectomy and glucocorticoid feedback. Neither vasopressin immunoreactivity nor oxytocin appear to subserve this role in the homozygous Brattleboro rat.

Physiological regulation of neurohypophyseal κ-opiate receptors

Quantitative autoradiography was used to examine the characteristics of κ-opiate receptor binding in neural lobe sections from dehyrated rats and water-sated homozygous Brattleboro rats. The density of κ-sites was decreased by 40% and 44%, respectively, after 5 days of water deprivation or hypertonic saline. Both the density and affinity of κ-receptor sites were lower in homozygous Brattleboro rats. We suggest that κ-receptor down-regulation occurs as a result of elevated release of opioid peptides induced by chronic osmotic stimulation.

Alterations in atrial natriuretic peptide receptors in rat brain nuclei during hypertension and dehydration.

We have studied the localization, kinetics, and regulation of receptors for the circulating form of the atrial natriuretic peptide (99-126) in the rat brain. Atrial natriuretic peptide receptors were discretely localized in the rat brain, with the highest concentrations in circumventricular organs, the choroid plexus, and selected hypothalamic nuclei involved in the production of the antidiuretic hormone vasopressin and in blood pressure control. Spontaneously (genetic) hypertensive rats showed much lower numbers of atrial natriuretic peptide receptors than normotensive controls in the subfornical organ, the area postrema, the nucleus of the solitary tract, and in the choroid plexus. These changes are in contrast with those observed for receptors of angiotensin II, another circulating peptide with actions opposite to those of the atrial natriuretic peptide. In acute dehydration after water deprivation, as well as in chronic dehydration such as that present in homozygous Brattleboro rats, there was an up-regulation of atrial natriuretic peptide receptors in the subfornical organ. Thus, circumventricular organs contain atrial natriuretic peptide receptors that could respond to variations in the concentration of circulating peptide. The localization of atrial natriuretic peptide receptors and the alterations in their regulation present in hypertensive and dehydrated rats indicate that these brain receptors are related to fluid regulation, including the secretion of vasopressin, and to cardiovascular function. Atrial natriuretic peptide receptors in the choroid plexus may be related to the formation of cerebrospinal fluid.

Specificity of vasopressin binding to the posterior pituitary gland in the rat. An autoradiographic study.

Specific binding sites for vasopressin (AVP) were compared in the kidney and posterior pituitary gland from normal and homozygous Brattleboro rats using autoradiography with [3H]-AVP. The specificity of ligand binding was assessed by displacement with AVP analogues differing in specificity and potency. In the kidney, specific [3H]-AVP binding was found in the medulla, with much less in the cortex, in both normal and Brattleboro rats. Binding of [3H]-AVP was displaced most effectively by dDAVP and least by AVP-OH, in line with their relative antidiuretic potencies. In the pituitary gland, specific AVP binding was much higher in the posterior lobe than in the intermediate or anterior lobes. This posterior lobe AVP binding was greatly reduced in Brattleboro rats, even in animals given exogenous AVP to restore their water balance. It was unlikely that neurophysin binding was responsible since there was no correlation between [3H]-AVP displacement and neurophysin binding in a series of analogues slightly modified at the N or C terminus to affect selectively neurophysin or receptor binding. We suggest that specific AVP receptors may be present in the posterior pituitary gland, possibly on or in the AVP terminals themselves, associated with the normal synthesis, packaging and/or transport of AVP granules to the neural lobe.

Early Development of the Thyroid Axis in the Brattleboro Rat

Plasma concentrations of thyrotrophin (TSH), thyroxine (T4), and triiodothyronine (T3), and pituitary TSH concentrations were determined at weekly intervals during the first 42 days following birth in Brattleboro homozygous (DI), Brattleboro heterozygous (HZ), and Long-Evans (LE) rats. Offspring from matings of Brattleboro rats were divided into DI and HZ animal subgroups on the basis of hypothalamic vasopressin content. In control LE rats, circulating levels of TSH, T4, and T3, and pituitary TSH concentrations increased during the early postnatal period to reach relatively stable levels between 28 and 42 days of age. In DI and HZ rats, the thyroid axis developed in parallel to that of LE rats during initial postnatal weeks. However, by 42 days of age, pituitary TSH concentrations were clearly elevated in Brattleboro rats relative to levels in age-matched LE animals. These data indicate that differences in thyroid axis function between Brattleboro and LE rats occur only after the attainment of a degree of maturity.

Prenatal development of the Brattleboro rat is influenced by genotype and lysine vasopressin treatment of the mother.

Homozygous (Hom) Brattleboro rats suffer from severe diabetes insipidus (DI) as a consequence of the lack of arginine-vasopressin (AVP) in the brain. Compared with heterozygous (Het) AVP-synthesizing Brattleboro rats, Hom rats show disturbed body and brain development. In this study breeding experiments with Het and Hom rats were performed to determine whether prenatal conditions might contribute to the developmental disturbances in Hom pups. For this purpose Het and Hom females were mated with Hom and Het males, respectively. In addition lysine-vasopressin (LVP) was administered to half of the pregnant females, since this has previously been shown to stimulate birth weight of Hom pups. On day 1 postnatally the body and brain weight of Hom pups of nontreated Hom mothers was significantly smaller than that of the Het litter mates, whereas no difference was found between the weight of Het or Hom pups of nontreated or LVP-treated Het mothers. These results indicate an important role of the genotype of the mother in prenatal development of Hom pups. LVP administration failed to diminish the growth deficits, but increased protein and DNA content of the cerebellum of both Het and Hom pups. Notwithstanding the improved prenatal growth of Hom pups from Het mothers, postnatally retarded development was still observed: at 1 month of age there was a significant difference between the body, brain and cerebellar weight of Het and Hom pups from Het mothers. It was therefore concluded that the prenatal situation of the Hom mother, i.e. AVP-deficiency, significantly contributes to the developmental disturbance of the Hom pup, but also that growth impairment is linked to the presence of the mutation in the Hom pups themselves.

Dehydration reduces κ-opiate receptor binding in the neurohypophysis of the rat

Quantitative autoradiography was used to examine the effects of dehydration on κ-opiate receptor binding in the neural lobe of the pituitary in rats. Dehydration was produced by 5 days of water deprivation or ingestion of 2% saline. Brattleboro rats homozygous for diabetes insipidus were used as a model of chronically disturbed water balance. Slide-mounted pituitary sections were incubated with [ 3H]bremazocine using κ-receptor-selective assay conditions. Binding in the neural lobe was quantified by densitometry of film autoradiographs. Specific [ 3H]bremazocine binding in neural lobe sections of control rats was 45.4 fmol/mg wet weight. In contrast, binding in neural lobe sections of water-deprived, saline-treated, and water-sated homozygous Brattleboro rats was lower by 50%, 35% and 37%, respectively. We suggest that chronic dehydration elevates levels of endogenous neurohypophyseal dynorphin and produces a down-regulation of κ-opiate receptors in the neurohypophysis, a change in affinity of the receptors for κ-agonists, or both.

Studies on desglycinamide arginine vasopressin and scopolamine in a modified/lever-touch autoshaping model of learning/memory in rats

Vasopressin administration has been reported to improve acquisition and retard extinction of both conditioned avoidance and food-reinforced behavioral tasks. In the present experiment the effects of a vasopressin analog (DGAVP) and scopolamine (SCOP) were tested in an autoshaped lever-touch model of learning and memory. Rats were food-deprived to 80% of original body weights and tested in modular cages which contained a retractable lever that was presented on a random interval 48 sec schedule. The lever retracted after 15 sec or when it was touched, at which time one 45 mg food pellet was delivered. Subcutaneous injection of 10 μg/kg DGAVP 1 hr prior to acquisition and extinction sessions did not alter responding compared to saline controls. DGAVP at doses of 10, 20, and 30 μg/kg also failed to affect responding in a more difficult task which included an 8 sec delay between lever retraction and reinforcement. Homozygous Brattleboro rats, which are deficient in vasopressin, did not differ from normal heterozygous littermates in the acquisition of the lever-touch response. Intraperitoneal injection of SCOP (0.1–0.8 mg/kg) 30 min prior to testing caused a dose-related impairment of acquisition compared to saline controls, but did not alter responding in animals which had previously acquired the lever-touch response. These data suggest that manipulations of vasopressin do not affect, while SCOP impairs, the acquisition of a positively reinforced lever-touch response in rats.

Defective regulation of vasopressin gene expression in Brattleboro rats.

The Brattleboro rat has severe diabetes insipidus due to an autosomal recessive trait resulting in the inability to synthesize detectable amounts of hypothalamic vasopressin. To determine whether this abnormality is due to a regulatory defect in the Brattleboro rat's vasopressin gene, we studied changes in the hypothalamic content of vasopressin mRNA in normal Long-Evans and homozygous Brattleboro rats subjected to osmotic stress and correlated these changes with systemic responses to water deprivation. We report that the Brattleboro rat does have a marked defect in the regulation of vasopressin gene expression consisting of an inability to increase hypothalamic vasopressin mRNA content in response to severe osmotic stress.

Functional adaptation of thick ascending limb and internephron heterogeneity to urine concentration

The kidney is able to adapt to a variety of chronic changes in excretory needs, for example, to high or low sodium or potassium intake [1] and to acidosis and alkalosis [2]. One of the main functions the mammalian kidney assumes is the concentration of solutes in the urine. The diversity of mammals affords examples of renal adaptation to water conservation. Comparison among animals living in fresh water, in temperate regions, or inhabiting desert areas reveals several differences in kidney morphology and function [3]. Recent experiments have shown, not only among different species but within a given species as well, remarkable functional adaptation of the kidney to chronic variations in urine concentration. Urine concentration can be altered for sustained periods of time by modifying either antidiuretic hormone (ADH) or fluid intake. The Brattleboro rat offers a unique model in which the effects of the total absence of ADH can be studied [4]. By studying homozygous Brattleboro rats with diabetes insipidus (DI) and comparing their kidney function and morphology with that of heterozygous rats of the same strain, normal Long Evans rats (the strain from which the Brattleboro are derived), and DI rats chronically receiving antidiuretic hormone, we were able to demonstrate several features of the renal adaptation to water conservation. Several of these features were also observed in normal rats in response either to an increase or to a decrease in water intake for several weeks. These changes are described in the first part of this paper. The second part will address the mechanisms by which these changes are induced, and how they improve the urine concentrating process.