Showing papers on "Vasopressin published in 1999"
TL;DR: It is shown that centrally administered arginine vasopressin increases affiliative behaviour in the highly social, monogamous prairie vole, but not in the relatively asocial, promiscuous montane vole.
Abstract: Arginine vasopressin influences male reproductive and social behaviours in several vertebrate taxa1 through its actions at the V1a receptor in the brain. The neuroanatomical distribution of vasopressin V1a receptors varies greatly between species with different forms of social organization2,3. Here we show that centrally administered arginine vasopressin increases affiliative behaviour in the highly social, monogamous prairie vole, but not in the relatively asocial, promiscuous montane vole. Molecular analyses indicate that gene duplication and/or changes in promoter structure of the prairie vole receptor gene may contribute to the species differences in vasopressin-receptor expression. We further show that mice that are transgenic for the prairie vole receptor gene have a neuroanatomical pattern of receptor binding that is similar to that of the prairie vole, and exhibit increased affiliative behaviour after injection with arginine vasopressin. These data indicate that the pattern of V1a-receptor gene expression in the brain may be functionally associated with species-typical social behaviours in male vertebrates.
466 citations
TL;DR: It is proposed that the SCN utilizes neuronal pathways to spread its time of the day message, not only to the pineal, but also to other organs, including the adrenal, utilizing the autonomic nervous system.
Abstract: In view of mounting evidence that the suprachiasmatic nucleus (SCN) is directly involved in the setting of sensitivity of the adrenal cortex to ACTH, the present study investigated possible anatomical and functional connections between SCN and adrenal. Transneuronal virus tracing from the adrenal revealed first order labelling in neurons in the intermedio-lateral column of the spinal cord that were shown to receive an input from oxytocin fibres and subsequently second-order labelling in neurons of the autonomic division of the paraventricular nucleus. The latter neurons were shown to receive an input from vasopressin or vasoactive intestinal peptide (VIP) containing SCN efferents. The true character of this SCN input to second-order neurons was also demonstrated by the fact that third-order labelling was present within the SCN, vasopressin or VIP neurons. The functional presence of the SCN-adrenal connection was demonstrated by a light-induced fast decrease in plasma corticosterone that could not be attributed to a decrease in ACTH. Using intact and SCN-lesioned animals, the immediate decrease in plasma corticosterone was only observed in intact animals and only at the beginning of the dark period. This fast decrease of corticosterone was accompanied by constant basal levels of blood adrenaline and noradrenaline, and is proposed to be due to a direct inhibition of the neuronal output to the adrenal cortex by light-mediated activation of SCN neurons. As a consequence, it is proposed that the SCN utilizes neuronal pathways to spread its time of the day message, not only to the pineal, but also to other organs, including the adrenal, utilizing the autonomic nervous system.
465 citations
TL;DR: Investigation of the aquaporins is providing detailed molecular insight into the fundamental physiology and pathophysiology of water balance and water balance disorders, suggesting a role for AQP2 in the development of water retention.
Abstract: The discovery of aquaporin membrane water channels by Agre and coworkers answered a long-standing biophysical question of how water specifically crosses biologic membranes, and provided insight, at the molecular level, into the fundamental physiology of water balance and the pathophysiology of water balance disorders. Of nine aquaporin isoforms, at least six are known to be present in the kidney at distinct sites along the nephron and collecting duct. Aquaporin-1 (AQP1) is extremely abundant in the proximal tubule and descending thin limb, where it appears to provide the chief route for proximal nephron water reabsorption. AQP2 is abundant in the collecting duct principal cells and is the chief target for vasopressin to regulate collecting duct water reabsorption. Acute regulation involves vasopressin-regulated trafficking of AQP2 between an intracellular reservoir and the apical plasma membrane. In addition, AQP2 is involved in chronic/adaptational regulation of body water balance achieved through regulation of AQP2 expression. Importantly, multiple studies have now identified a critical role of AQP2 in several inherited and acquired water balance disorders. This concerns inherited forms of nephrogenic diabetes insipidus and several, much more common acquired types of nephrogenic diabetes insipidus where AQP2 expression and/or targeting are affected. Conversely, AQP2 expression and targeting appear to be increased in some conditions with water retention such as pregnancy and congestive heart failure. AQP3 and AQP4 are basolateral water channels located in the kidney collecting duct, and AQP6 and AQP7 appear to be expressed at lower abundance at several sites including the proximal tubule. This review focuses mainly on the role of AQP2 in water balance regulation and in the pathophysiology of water balance disorders.
365 citations
TL;DR: A VP infusion improved arterial pressure and permitted the withdrawal of catecholamine vasopressors and is a useful agent in the treatment of refractory septic shock.
Abstract: BackgroundDespite appropriate therapy, refractory hypotension often occurs in septic shock. A double-blinded placebo controlled clinical trial was performed to assess the role of low-dose vasopressin (VP) as a pressor agent in septic shock.MethodsPatients admitted to a trauma intensive care unit wit
354 citations
TL;DR: This review considers the rôle played by particular afferent pathways in the regulation of the activity of oxytocin and vasopressin cells.
307 citations
TL;DR: It is concluded that vasopressin strongly upregulates the expression of the Na-K-2Cl cotransporter of the TAL and that it is likely to play an important role in the long-term regulation of the countercurrent multiplication system.
Abstract: To investigate whether the enhancement of thick ascending limb (TAL) NaCl transport in response to long-term increases in circulating vasopressin concentration is associated with increased expressi...
272 citations
TL;DR: Human vascular ECs express OT receptors that are structurally identical to the uterine and mammary OT receptors, and these endothelial OT receptors produce a calcium-dependent vasodilatory response via stimulation of the nitric oxide pathway and have a trophic action.
Abstract: Pharmacological studies in humans and animals suggest the existence of vascular endothelial vasopressin (AVP)/oxytocin (OT) receptors that mediate a vasodilatory effect However, the nature of the receptor subtype(s) involved in this vasodilatory response remains controversial, and its coupled intracellular pathways are unknown Thus, we set out to determine the type and signaling pathways of the AVP/OT receptor(s) expressed in human vascular endothelial cells (ECs) Saturation binding experiments with purified membranes of primary cultures of ECs from human umbilical vein (HUVEC), aorta (HAEC), and pulmonary artery (HPAEC) and [3H]AVP or[ 3H]OT revealed the existence of specific binding sites with a greater affinity for OT than AVP (Kd = 175 vs 1658 nm) Competition binding experiments in intact HUVECs (ECV304 cell line) with the AVP antagonist[ 125I]4-hydroxyphenacetyl-d-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-NH2 or the OT antagonist[ 125I]d(CH2)5[O-Me-Tyr-Thr-Orn-Tyr-NH2]vasotocin, and various AVP/OT analo
258 citations
TL;DR: Preclinical evidence with oxytocin and vasopressin recommends the need for clinical studies using gene scanning, pharmacological and neurobiological approaches, and recent gene targeting studies that alter expression of either the peptides or their receptors in the rodent brain partially support the autism hypothesis.
249 citations
TL;DR: Infants and children with low blood pressure and adequate cardiac function after cardiac surgery respond to the pressor action of exogenous AVP.
Abstract: Background—Recent investigations at our institution have studied a variety of vasodilatory shock states that are characterized by vasopressin deficiency and pressor hypersensitivity to the exogenous hormone. Our experience in adults prompted the use of arginine-vasopressin (AVP) in a similar group of critically ill children. Methods and Results—This report describes our early experience (from February 1997 through April 1998) in 11 profoundly ill infants and children (5 male, 6 female) ages 3 days to 15 years (median, 35 days) treated with AVP for hypotension after cardiac surgery which was refractory to standard cardiopressors. Although underlying heart disease was present (congenital heart defects in 10 and dilated cardiomyopathy in 1), only 2 patients had severely depressed cardiac function as demonstrated by 2D echocardiogram before administration of AVP. All patients were intubated and receiving multiple catecholamine pressors and inotropes, including dobutamine (n=10), epinephrine (n=8), milrinone (...
233 citations
TL;DR: Vasopressin is a uniquely effective pressor in the irreversible phase of hemorrhagic shock unresponsive to volume replacement and catecholamine vasopressors and may contribute to the pathogenesis of this condition.
Abstract: Background—Hypovolemic shock of marked severity and duration may progress to cardiovascular collapse unresponsive to volume replacement and drug intervention. On the basis of clinical observations, we investigated the action of vasopressin in an animal model of this condition. Methods and Results—In 7 dogs, prolonged hemorrhagic shock (mean arterial pressure [MAP] of ≈40 mm Hg) was induced by exsanguination into a reservoir. After ≈30 minutes, progressive reinfusion was needed to maintain MAP at ≈40 mm Hg, and by ≈1 hour, despite complete restoration of blood volume, the administration of norepinephrine ≈3 μg · kg−1 · min−1 was required to maintain this pressure. At this moment, administration of vasopressin 1 to 4 mU · kg−1 · min−1 increased MAP from 39±6 to 128±9 mm Hg (P<0.001), primarily because of peripheral vasoconstriction. In 3 dogs subjected to similar prolonged hemorrhagic shock, angiotensin II 180 ng · kg−1 · min−1 had only a marginal effect on MAP (45±12 to 49±15 mm Hg). Plasma vasopressin was...
212 citations
TL;DR: The idea that OT and AVP receptor systems are phylogenetically plastic, perhaps facilitating the evolution of species-typical social behavior patterns is discussed.
TL;DR: In this article, the HPA axis reactivity of high (HAB) and low (LAB) anxiety-related behavior on the elevated plus-maze was investigated. And the results showed that HAB rats showed higher plasma concentrations at 5 and 15 min following stressor exposure (both hormones and both time points: P<0.01 vs LAB).
Abstract: Psychiatric patients suffering from anxiety disorders or endogenous depression exhibit increased activity in their hypothalamo-pituitary-adrenocortical (HPA) axis. Recently, two Wistar rat lines, bred for high (HAB) and low (LAB) anxiety-related behaviour on the elevated plus-maze, were described as a unique psychopathological animal model (1). The present study focused on the HPA axis reactivity of HAB and LAB animals to an emotional stressor. Thus, adult male HAB and LAB animals, fitted with jugular vein catheters 5 days prior to the experiment, were exposed to an open arm of the elevated plus-maze for 5 min. Whereas basal levels of ACTH and corticosterone were similar in both lines, HAB rats showed higher plasma concentrations at 5 and 15 min following stressor exposure (both hormones and both time points: P<0.01 vs LAB). Furthermore, increased basal (P<0.05 vs LAB) and stimulated (P<0.01 vs LAB) prolactin concentrations in HAB rats were found. In contrast to ACTH, corticosterone and prolactin, plasma oxytocin and vasopressin levels did not differ between HAB and LAB animals; oxytocin, but not vasopressin, responding to open arm exposure with a significant increase in both lines (P<0.05). In conclusion, particularly due to the association between inborn anxiety and HPA axis hyper-reactivity, the HAB rat represents a promising animal model for further investigation of the relationship between emotional disturbance and neuroendocrine activity.
TL;DR: The data provide evidence that Otp and Sim1, a bHLH-PAS transcription factor that directs terminal differentiation of the PVN, SON, and aPV, act in parallel and are both required to maintain Brn2 expression which, in turn, is required for neuronal cell lineages secreting oxytocin (OT), arginine vasopressin (AVP), and corticotropin-releasing hormone (CRH).
Abstract: Development of the neuroendocrine hypothalamus is characterized by a precise series of morphogenetic milestones culminating in terminal differentiation of neurosecretory cell lineages. The homeobox-containing gene Orthopedia (Otp) is expressed in neurons giving rise to the paraventricular (PVN), supraoptic (SON), anterior periventricular (aPV), and arcuate (ARN) nuclei throughout their development. Homozygous Otp(-/-) mice die soon after birth and display progressive impairment of crucial neuroendocrine developmental events such as reduced cell proliferation, abnormal cell migration, and failure in terminal differentiation of the parvocellular and magnocellular neurons of the aPV, PVN, SON, and ARN. Moreover, our data provide evidence that Otp and Sim1, a bHLH-PAS transcription factor that directs terminal differentiation of the PVN, SON, and aPV, act in parallel and are both required to maintain Brn2 expression which, in turn, is required for neuronal cell lineages secreting oxytocin (OT), arginine vasopressin (AVP), and corticotropin-releasing hormone (CRH).
TL;DR: Repeated administration of vasopressin but only the first epinephrine dose given early and late during basic life support CPR maintained coronary perfusion pressure above the threshold that is needed for successful defibrillation.
Abstract: Background—It is unknown whether repeated dosages of vasopressin or epinephrine given early or late during basic life support cardiopulmonary resuscitation (CPR) may be able to increase coronary perfusion pressure above a threshold between 20 and 30 mm Hg that renders defibrillation successful. Methods and Results—After 4 minutes of cardiac arrest, followed by 3 minutes of basic life support CPR, 12 animals were randomly assigned to receive, every 5 minutes, either vasopressin (early vasopressin: 0.4, 0.4, and 0.8 U/kg, respectively; n=6) or epinephrine (early epinephrine: 45, 45, and 200 μg/kg, respectively; n=6). Another 12 animals were randomly allocated after 4 minutes of cardiac arrest, followed by 8 minutes of basic life support CPR, to receive, every 5 minutes, either vasopressin (late vasopressin: 0.4 and 0.8 U/kg, respectively; n=6), or epinephrine (late epinephrine: 45 and 200 μg/kg, respectively; n=6). Defibrillation was attempted after 22 minutes of cardiac arrest. Mean±SEM coronary perfusion ...
TL;DR: The data demonstrate VP responses in parvocellular neurons of both control and RR rats, whereas profound inhibition of CRH transcription is selective for the homotypic stressor with CRH responsiveness to the heterotypes preserved or increased.
Abstract: Stress-responsive neurons of the hypothalamic paraventricular nucleus (PVN) show functional plasticity and adapt to repeated restraint (RR) stress. To investigate whether neuronal adaptation to the homotypic stress also affects their response to a heterotypic stressor, we used in situ hybridization with intronic and exonic probes to measure primary transcript (hnRNA) and messenger RNA (mRNA) levels for CRH and vasopressin (VP) in the PVN of control and RR rats after the heterotypic stress of i.p. hypertonic saline injection (ipHS). Two weeks of daily restraint blunted plasma corticosterone and parvocellular CRH, but not VP, transcript responses to a further restraint episode. IpHS increased circulating corticosterone in both groups, but levels were higher in RR rats. CRH hnRNA increased within 15 min and returned to baseline by 1 h in both naive and RR rats. CRH mRNA increased more slowly in both groups, peaking at 2 h, with RR rats showing greater responses at this time. Parvocellular VP hnRNA reached a peak 2 h after ipHS in naive rats, but more rapidly (1 h) and to higher levels in RR rats. The number of parvocellular neurons expressing VP hnRNA increased approximately 5-fold after ipHS in both groups. Basal VP mRNA levels and the number of parvocellular cells expressing VP mRNA were elevated in RR rats. Both ipHS and naive rats showed an increase in VP mRNA transcripts after ipHS, with RR rats showing greater levels at 2 and 4 h. Magnocellular cells in both PVN and supraoptic nuclei showed increases in VP hnRNA within 15 min. The data demonstrate VP responses in parvocellular neurons of both control and RR rats, whereas profound inhibition of CRH transcription is selective for the homotypic stressor with CRH responsiveness to the heterotypic stress preserved or increased.
TL;DR: Data demonstrate that not only the activity of PKA, but also its tethering to subcellular compartments, are prerequisites for cAMP-dependent AQP-2 translocation.
TL;DR: This new animal model presenting long-term and tissue-specific down-regulation of angiotensinogen corroborates the functional significance of local angiotENSin production in the brain for the central regulation of blood pressure and for the pathogenesis of hypertension.
Abstract: Angiotensin produced systemically or locally in tissues such as the brain plays an important role in the regulation of blood pressure and in the development of hypertension. We have established transgenic rats [TGR(ASrAOGEN)] expressing an antisense RNA against angiotensinogen mRNA specifically in the brain. In these animals, the brain angiotensinogen level is reduced by more than 90% and the drinking response to intracerebroventricular renin infusions is decreased markedly compared with control rats. Blood pressure of transgenic rats is lowered by 8 mmHg (1 mmHg = 133 Pa) compared with control rats. Crossbreeding of TGR(ASrAOGEN) with a hypertensive transgenic rat strain exhibiting elevated angiotensin II levels in tissues results in a marked attenuation of the hypertensive phenotype. Moreover, TGR(ASrAOGEN) exhibit a diabetes insipidus-like syndrome producing an increased amount of urine with decreased osmolarity. The observed reduction in plasma vasopressin by 35% may mediate these phenotypes of TGR(ASrAOGEN). This new animal model presenting long-term and tissue-specific down-regulation of angiotensinogen corroborates the functional significance of local angiotensin production in the brain for the central regulation of blood pressure and for the pathogenesis of hypertension.
TL;DR: The novel concept that heat produced by axonal UCP2 modulates neurotransmission in homeostatic centers, thereby coordinating the activity of those brain circuits that regulate daily energy balance and related autonomic and endocrine processes is suggested.
Abstract: Distinct brain peptidergic circuits govern peripheral energy homeostasis and related behavior. Here we report that mitochondrial uncoupling protein 2 (UCP2) is expressed discretely in neurons involved in homeostatic regulation. UCP2 protein was associated with the mitochondria of neurons, predominantly in axons and axon terminals. UCP2-producing neurons were found to be the targets of peripheral hormones, including leptin and gonadal steroids, and the presence of UCP2 protein in axonal processes predicted increased local brain mitochondrial uncoupling activity and heat production. In the hypothalamus, perikarya producing corticotropin-releasing factor, vasopressin, oxytocin, and neuropeptide Y also expressed UCP2. Furthermore, axon terminals containing UCP2 innervated diverse hypothalamic neuronal populations. These cells included those producing orexin, melanin-concentrating hormone, and luteinizing hormone-releasing hormone. When c-fos-expressing cells were analyzed in the basal brain after either fasting or cold exposure, it was found that all activated neurons received a robust UCP2 input on their perikarya and proximal dendrites. Thus, our data suggest the novel concept that heat produced by axonal UCP2 modulates neurotransmission in homeostatic centers, thereby coordinating the activity of those brain circuits that regulate daily energy balance and related autonomic and endocrine processes.
TL;DR: Data show that vasopressin, by itself, is able to trigger the luteinizing hormone surge in suprachiasmatic nucleus-lesioned rats, and it is proposed that vasipressin is a timing signal from the suprachesmatic nucleus responsible for the activation of the hypothalamo-pituitary-gonadal axis in the female rat.
TL;DR: Hemodynamically unstable organ donors without clinically apparent diabetes insipidus display a defect in the baroreflex-mediated secretion of vasopressin, which significantly increases blood pressure with a pressor response sufficient to reduce catecholamine administration.
Abstract: Background—Solid organ donors often develop hypotension due to vasodilation, and recently we observed that a variety of vasodilatory states are characterized by vasopressin deficiency and hypersensitivity. Thus, we investigated the prevalence of vasopressin deficiency in hypotensive solid organ donors without clinical evidence of diabetes insipidus; we also investigated the vasopressor effect of vasopressin replacement in hypotensive donors. Methods and Results—Fifty organ donors were evaluated for hemodynamic instability, (mean arterial pressure [MAP]≤ 70 mm Hg despite the use of catecholamine vasopressors), and in those unstable donors who were not already receiving exogenous vasopressin, low-dose vasopressin was administered as a continuous infusion (0.04 to 0.1 U/min). MAP, catecholamine requirements, serum vasopressin, and serum osmolality were obtained before and after vasopressin administration. Ten patients meeting the enrollment criteria received vasopressin and MAP increased from 72.2±3.5 to 89....
TL;DR: The results showed that VP receptor antagonism impaired social recognition and reduced open-arm activity in the plus-maze, while it had no effect on spatial learning (Morris maze) and shock-probe burying behavior, indicating a strong task-dependent specificity of lateral septal VP functioning.
TL;DR: Compared with a maximum dose of epinephrine, vasopressin significantly increased left ventricular myocardial and total cerebral blood flow during CPR and return of spontaneous circulation in a porcine model of prolonged cardiac arrest with postcountershock pulseless electrical activity.
Abstract: ObjectiveAlthough a benefit of vasopressin when compared with epinephrine was shown during cardiopulmonary resuscitation (CPR) after a short duration of ventricular fibrillation cardiac arrest, the effect of vasopressin during prolonged cardiac arrest with pulseless electrical activity is currently
TL;DR: Evidence is provided for the influence of circulating sex steroids on pituitary and adrenal activity under some, but not all circumstances.
Abstract: We used two stresses--exposure to mild electrofoot shocks (a neurogenic stress) and acute alcohol injection (a systemic stress)--to investigate the influence of gender and circulating sex steroids on ACTH and corticosterone released by adult rats Both types of stresses significantly increased plasma levels of these hormones Following exposure to shocks, intact females secreted significantly more ACTH than intact males, a difference that was abolished by ovariectomy Gender differences in corticosterone responses were sometimes, but not always, present In contrast, in this series of experiments males released more ACTH when acutely injected with alcohol, while there was no obvious effect of sex on corticosterone secretion Corticotropin-releasing factor (CRF) antagonists were more effective at reducing ACTH compared to corticosterone levels Finally, pituitary response to CRF, but much less so to vasopressin (VP), was larger in intact females compared to intact males Blockade of endogenous nitric oxide formation slightly enhanced the effect of CRF in males, but not in females, and while it produced the expected enhancement of VP-induced ACTH release, this effect was more pronounced in females Collectively, these results provide evidence for an influence of circulating sex steroids on pituitary and adrenal activity under some, but not all circumstances
TL;DR: Knowledge of the involved afferent pathways will suggest therapeutic interventions that may modulate the intensity of the stress response, and concepts as they relate to perioperative medicine are described.
TL;DR: When plasma 17beta-estradiol concentration was high, P(osm) was low throughout rest, exercise, and rehydration, but plasma arginine vasopressin concentration, thirst, and body fluid retention were unchanged, indicating a lowering of the osmotic operating point for body fluid regulation.
Abstract: To test the hypothesis that estrogen reduces the operating point for osmoregulation of arginine vasopressin (AVP), thirst, and body water balance, we studied nine women (25 ± 1 yr) during 150 min o...
TL;DR: The results indicate that AVP stimulates phosphorylation of AQP2 at Ser256 via activation of PKA, supporting the idea that this is one of the first steps leading to increased water permeability in collecting duct cells.
Abstract: Aquaporin-2 (AQP2), the protein that mediates arginine vasopressin (AVP)-regulated apical water transport in the renal collecting duct, possesses a single consensus phosphorylation site for cAMP-dependent protein kinase A (PKA) at Ser256. The aim of this study was to examine whether AVP, and other agents that increase cAMP levels, could stimulate the phosphorylation of AQP2 in intact rat renal tissue. Rat renal papillae were prelabeled with 32P and incubated with vehicle or drugs, and then AQP2 was immunoprecipitated. Two polypeptides corresponding to nonglycosylated (29 kDa) and glycosylated (35-48 kDa) AQP2 were identified by SDS-PAGE. AVP caused a time- and dose-dependent increase in phosphorylation of both glycosylated and nonglycosylated AQP2. The threshold dose for a significant increase in phosphorylation was 10 pM, which corresponds to a physiological serum concentration of AVP. Maximal phosphorylation was reached within 1 min of AVP incubation. This effect on AQP2 phosphorylation was mimicked by the vasopressin (V2) agonist, 1-desamino-[8-D-arginine]vasopressin (DDAVP), or forskolin. Two-dimensional phosphopeptide mapping indicated that AVP and forskolin stimulated the phosphorylation of the same site in AQP2. Immunoblot analysis using a phosphorylation state-specific antiserum revealed an increase in phosphorylation of Ser256 after incubation of papillae with AVP. The results indicate that AVP stimulates phosphorylation of AQP2 at Ser256 via activation of PKA, supporting the idea that this is one of the first steps leading to increased water permeability in collecting duct cells.
TL;DR: The development of urinary concentration ability correlates with the development of an increased medullary osmotic gradient which is diminished in murine ARPKD, however, CD genes associated with this process are overexpression in vivo but underexpressed in vitro in the cystic kidney.
Abstract: Currently, there is little understanding of what factors regulate the development of urine concentrating capability in normal or polycystic kidney. The present study examined the developmental expression of genes associated with urine concentration in developing mice, including C57BL/6J-cpk/cpk mice with autosomal recessive-infantile (AR) polycystic kidney disease (PKD). Concentration of urine requires: 1) medullary collecting ducts (CD) located within a hypertonic interstitium, 2) CD cell expression of functional arginine vasopressin V2 receptors (AVP-V2R), and 3) the presence of appropriate CD water channels (aquaporins, AQP 2 and 3). An increase in urine osmolarity, normally seen between 1 and 3 weeks of age, was absent in cpk cystic mice. Aldose reductase mRNA expression (a gene upregulated by medullary hyperosmolarity) increased in normal mice, but remained low in the cystic kidney, suggesting the absence of a hypertonic medullary interstitium. AVP-V2R, AQP2, and AQP3 mRNA expression normally increase between 7 and 14 days. However, all were dramatically overexpressed even at 7 days of age in the cpk kidney in vivo, but decreased in vitro. Activation of the AVP-V2 receptor stimulates the production of cAMP, a substance known to promote cyst enlargement. To determine if CD cAMP, generated from increased AVP-V2Rs, was accelerating the PKD, cystic mice and their normal littermates were treated with OPC31260, a relatively specific AVP-V2R antagonist. OPC31260 treatment of cystic mice led to an amelioration of the cystic enlargement and azotemia. Treatment also decreased renal AQP2 mRNA but increased AVP-V2R and AQP3 mRNA expression in vivo. AVP upregulates the expression of AVP-V2R, AQP2, and AQP3 mRNAs in vitro. Renal EGF, known to inhibit AVP-V2R activity, downregulates AVP-V2R mRNA in vitro. Brief in vivo EGF treatment, known to decrease PKD in cpk mice, led to increased expression of AVP-V2R, AQP2, and AQP3 mRNAs at 2 weeks in both normal and cystic mice but no change was evident at 3 weeks of age. In conclusion, the development of urinary concentration ability correlates with the development of an increased medullary osmotic gradient which is diminished in murine ARPKD. However, CD genes associated with this process are overexpressed in vivo but underexpressed in vitro in the cystic kidney. The overexpression and/or overactivity of the AVP-V2R appears to contribute to the progression of PKD since an AVP-V2R antagonist inhibits cystic renal enlargement in the cpk mouse. Dev. Genet. 24:309–318, 1999. © 1999 Wiley-Liss, Inc.
TL;DR: The results suggest that an α1E or “R”-type Ca2+ channel exists in oxytocinergic nerve terminals and, thus, functions in controlling only Oxytocin release from the rat neurohypophysis.
Abstract: Multiple types of voltage-dependent Ca(2+) channels are involved in the regulation of neurotransmitter release (Tsien et al., 1991; Dunlap et al., 1995). In the nerve terminals of the neurohypophysis, the roles of L-, N-, and P/Q-type Ca(2+) channels in neuropeptide release have been identified previously (Wang et al., 1997a). Although the L- and N-type Ca(2+) currents play equivalent roles in both vasopressin and oxytocin release, the P/Q-type Ca(2+) current only regulates vasopressin release. An oxytocin-release and Ca(2+) current component is resistant to the L-, N-, and P/Q-type Ca(2+) channel blockers but is inhibited by Ni(2+). A new polypeptide toxin, SNX-482, which is a specific alpha(1E)-type Ca(2+) channel blocker (Newcomb et al., 1998), was used to characterize the biophysical properties of this resistant Ca(2+) current component and its role in neuropeptide release. This resistant component was dose dependently inhibited by SNX-482, with an IC(50) of 4.1 nM. Furthermore, SNX-482 did not affect the other Ca(2+) current types in these CNS terminals. Like the N- and P/Q-type Ca(2+) currents, this SNX-482-sensitive transient Ca(2+) current is high-threshold activated and shows moderate steady-state inactivation. At the same concentrations, SNX-482 blocked the component of oxytocin, but not of vasopressin, release that was resistant to the other channel blockers, indicating a preferential role for this type of Ca(2+) current in oxytocin release from neurohypophysial terminals. Our results suggest that an alpha(1E) or "R"-type Ca(2+) channel exists in oxytocinergic nerve terminals and, thus, functions in controlling only oxytocin release from the rat neurohypophysis.
TL;DR: In rats short‐lasting stressors like defeat induce long‐lasting, temporal dynamic changes in the regulation of the HPA axis and since these changes in time are reflected in GRs and MRs in different brain areas an altered corticosteroid receptor binding might play an important role in the affected HPA activity following defeat.
Abstract: The present study focuses on the long-term changes in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis following two short-lasting episodes of intensive stress in the rat stress model of social defeat and the possible similarities with HPA functioning in human affective disorders. Male Wistar rats experienced social defeats on 2 consecutive days by an aggressive male conspecific. The long-term effect of these defeats on resting and ovine corticotropin-releasing factor (oCRF; intravenous (i.v.) 0. 5 microg/kg) induced levels of plasma ACTH and corticosterone (CORT) were measured 1 and 3 weeks later. In a second experiment the glucocorticoid feedback regulation of HPA function was tested in a combined dexamethasone (DEX)/CRF test (DEX; 25 microg/kg s.c., 90 min before oCRF injection, 0.5 microg/kg). The oCRF challenges were performed between 11.00 and 13.00 h (about three hours after start of the light phase). One week after defeat the ACTH response to CRF was significantly enhanced in defeated rats as compared to controls. Three weeks after defeat the ACTH response was back to control levels. The increased ACTH response 1 week after the stressor was not reflected in higher CORT levels. Neither were baseline ACTH and CORT levels affected by the prior stress exposure. DEX pretreatment inhibited pituitary adrenocortical activity, reflected both in reduced baseline and response values of ACTH and CORT. The ACTH response to CRF following DEX administration was significantly higher in defeated rats as compared to controls both at one and three weeks after defeat. A reduced DEX suppression of baseline secretion of ACTH appeared 3 weeks after defeat. The same tendency was apparent in response and baseline values of CORT. The differences in CORT between socially stressed and control treated rats, however, did not reach significance. The possible role of changes in glucocorticoid-(GR) and mineralocorticoid receptor (MR) binding in the altered regulation of HPA activity following defeat were studied in brain and pituitary of male Wistar rats 1 and 3 weeks after defeat. One week after defeat GR-binding decreased in hippocampus and hypothalamus. No changes were observed in GR-binding in the pituitary nor in MR-binding in any of the regions analysed. Three weeks after defeat GR-binding recovered in hippocampus and hypothalamus but at this time MR-binding in hippocampal tissue was seriously decreased. In a fourth experiment vasopressin (AVP) and CRF stores in the external zone of the median eminence (ZEME) were measured by quantitative immunocytochemistry one and three weeks after defeat and compared with controls. Social defeat failed to induce a change in the immunocytochemical stores of AVP or CRF. The present findings show that in rats short-lasting stressors like defeat induce long-lasting, temporal dynamic changes in the regulation of the HPA axis. Since these changes in time are reflected in GRs and MRs in different brain areas an altered corticosteroid receptor binding might play an important role in the affected HPA activity following defeat.