Exogenous Arginine Vasopressin Research Articles

Therapy for vasodilatory shock: Arginine vasopressin

V ASODILATORY SHOCK is a condition of hypotension with end-organ hypoperfusion resulting from a decrease in systemic vascular resistance. This vasodilatory state is a well-known characteristic of septic shock, but it is also observed in the late phase of hemorrhagic shock and as a complication of cardiopulmonary bypass. 1-3 Catecholamine vasopressors, the only clinically used vasoconstrictors, can be effective, but their action is frequently diminished in vasodilatory shock, and side effects are prominent at increased doses. ~-4 Thus, the morbidity and mortality from catecholamine-resistant hypotension in vasodilatory shock remains high, and alternative treatments could be useful. The mechanisms responsible for vasodilation in the various syndromes associated with vasodilatory shock continues to be elucidated. We and others have shown that the vasodilatory shock of sepsis is mediated in part by vasodilatory mechanisms such as the inappropriate release of nitric oxide (NO) and the opening of adenosine triphosphate (ATP)-sensitive potassium channels (K+ATP) on vascular smooth muscle. 56 The possibility that vasoconstrictor mechanisms, such as arginine vasopressin (AVP), might be defective and thus contribute to vasodilatory shock has not been as well studied. Our incidental observation of a marked vasopressor response to exogenous AVP in a patient with vasodilatory septic shock contrasted with the decreased effectiveness of catecholamine vasoconstrictors in this patient. This led us to examine the role of AVP in the hypotension of vasodilatory shock. We discovered that the baroreflex-mediated secretion of vasopressin is defective not only in septic shock but in a variety of vasodilatory shock

Hypothalamo–pituitary–adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration: sex differences between major depressives and matched control subjects

Of heuristic value in understanding the neurochemistry of major depression is whether the hypothalamo–pituitary–adrenocortical (HPA) axis hyperactivity that occurs in this illness can be related to putative neurotransmitter dysfunction(s). Cholinergic neurotransmission stimulates hypothalamic corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) secretion, both of which stimulate pituitary corticotropin (ACTH) secretion, but whether the HPA axis in humans is activated only by doses of cholinergic agonists that produce noxious side effects remains controversial. To test the hypothesis of increased cholinergic sensitivity in major depression, physostigmine (PHYSO), a reversible cholinesterase inhibitor, was administered to patients and control subjects at a dose that elevated plasma ACTH, cortisol, and AVP concentrations but produced few or no side effects. Exogenous AVP also was administered to determine if it would augment the effect of low-dose PHYSO on the HPA axis. Twelve premenopausal or estrogen-replaced female major depressives, 12 individually matched female control subjects, eight male major depressives, and eight matched male control subjects underwent four test sessions 5–7 days apart: PHYSO (8 μg/kg IV), AVP (0.08 U/kg IM), PHYSO+AVP, and saline control. Serial blood samples were taken before and after pharmacologic challenge and analyzed for ACTH 1–39, cortisol, and AVP. Estradiol and testosterone were also measured at each test session. PHYSO (8 μg/kg) significantly increased plasma ACTH, cortisol, and AVP, while producing no side effects in approximately half the subjects and predominantly mild side effects in the other half. These hormone increases following PHYSO occurred primarily in the female depressives and the male control subjects and were not significantly related to the presence or absence of side effects. The greater the ACTH and AVP responses to PHYSO, the stronger their correlation, suggesting that AVP may have been acting as a secretagogue for ACTH. Administered AVP significantly increased the secretion of ACTH in the patients and control subjects to a similar degree, and AVP given after PHYSO did not augment the HPA axis response to a greater degree in the depressives than in the control subjects. Plasma estradiol and testosterone were within the normal range for all four groups of subjects and were not significantly related to their HPA axis hormone responses. The study results support the hypothesis of heightened cholinergic sensitivity in premenopausal female, but not in male, patients with major depression. The low dose of PHYSO used may represent a useful paradigm for central cholinergic stimulation of the HPA axis.

Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery.

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. 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 (n=7), and dopamine (n=4) before receiving AVP. Five patients received AVP intraoperatively immediately after cardiopulmonary bypass, 5 in the intensive care unit within 12 hours of surgery, and 1 on postoperative day 2 for hypotension associated with sepsis. The dose of AVP was adjusted for patient size and ranged from 0.0003 to 0.002 U. kg(-1). min(-1). During the first hour of treatment with AVP, systolic blood pressure rose from 65+/-14 to 87+/-17 mm Hg (P<0. 0001; n=11), and epinephrine administration was decreased in 5 of 8 patients and increased in 1. Plasma AVP levels before treatment were available in 3 patients and demonstrated AVP depletion (median, 4.4 pg/mL; n=3). All 9 children with vasodilatory shock survived their intensive care unit stay. The 2 patients who received AVP in the setting of poor cardiac function died, despite transient improvement in blood pressure. Infants and children with low blood pressure and adequate cardiac function after cardiac surgery respond to the pressor action of exogenous AVP. AVP deficiency may contribute to this hypotensive condition.

Intravenous Arginine-Vasopressin in Children With Vasodilatory Shock After Cardiac Surgery

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 (n=7), and dopamine (n=4) before receiving AVP. Five patients received AVP intraoperatively immediately after cardiopulmonary bypass, 5 in the intensive care unit within 12 hours of surgery, and 1 on postoperative day 2 for hypotension associated with sepsis. The dose of AVP was adjusted for patient size and ranged from 0.0003 to 0.002 U · kg −1 · min −1 . During the first hour of treatment with AVP, systolic blood pressure rose from 65±14 to 87±17 mm Hg ( P &lt;0.0001; n=11), and epinephrine administration was decreased in 5 of 8 patients and increased in 1. Plasma AVP levels before treatment were available in 3 patients and demonstrated AVP depletion (median, 4.4 pg/mL; n=3). All 9 children with vasodilatory shock survived their intensive care unit stay. The 2 patients who received AVP in the setting of poor cardiac function died, despite transient improvement in blood pressure. Conclusions —Infants and children with low blood pressure and adequate cardiac function after cardiac surgery respond to the pressor action of exogenous AVP. AVP deficiency may contribute to this hypotensive condition.

Developmental exposure to vasopressin increases aggression in adult prairie voles.

Although the biological roots of aggression have been the source of intense debate, the precise physiological mechanisms responsible for aggression remain poorly understood. In most species, aggression is more common in males than females; thus, gonadal hormones have been a focal point for research in this field. Although gonadal hormones have been shown to influence the expression of aggression, in many cases aggression can continue after castration, indicating that testicular steroids are not completely essential for the expression of aggression. Recently, the mammalian neuropeptide arginine vasopressin (AVP) has been implicated in aggression. AVP plays a particularly important role in social behavior in monogamous mammals, such as prairie voles (Microtus ochrogaster). In turn, the effects of social experiences may be mediated by neuropeptides, including AVP. For example, sexually naïve prairie voles are rarely aggressive. However, 24 h after the onset of mating, males of this species become significantly aggressive toward strangers. Likewise, in adult male prairie voles, central (intracerebroventricular) injections of AVP can significantly increase intermale aggression, suggesting a role for AVP in the expression of postcopulatory aggression in adult male prairie voles. In this paper, we demonstrate that early postnatal exposure to AVP can have long-lasting effects on the tendency to show aggression, producing levels of aggression in sexually naïve, adult male prairie voles that are comparable to those levels observed after mating. Females showed less aggression and were less responsive to exogenous AVP, but the capacity of an AVP V(1a) receptor antagonist to block female aggression also implicates AVP in the development of female aggression.

Altered pituitary sensitivity to corticotropin-releasing factor and arginine vasopressin participates in the stress hyporesponsiveness of lactation in the rat.

The regulation of the activity of the hypothalamic-pituitary-adrenal (HPA) axis is modified during lactation, wherein a blunted stress-induced adrenocorticotropic hormone (ACTH) and glucocorticoid secretion is coupled with elevated basal secretion of these hormones. The involvement of pituitary modifications in lactation-induced stress hyporesponsiveness has yet to be established. In this study we tested the hypothesis that the pituitary sensitivity to corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) is altered in lactation in the rat. We examined the effect of exogenous CRF (0.1-5 microg/rat), AVP (0.01-0.5 microg/rat), and AVP (0.01-0.5 microg/rat)+CRF (0.1 microg/rat) on the ACTH response of virgin, mid-lactating (lactation day 10-12) females, as well as nursing females separated from their pups for 48 h. Additionally, to determine if changes in CRF- or AVP-receptor densities might mediate alterations in pituitary sensitivity, we compared pituitary CRF- and AVP-receptor binding by autoradiography in pregnant, mid-lactating, and virgin female rats. While both virgin and lactating female rats exhibited significant ACTH responses to CRF, the responses to the highest doses of CRF (2.0 and 5.0 microg/rat) were greater in virgin than in lactating females. Separation of the litter for 48 h partially restored pituitary responsiveness to 2.0 microg of CRF. Conversely, whereas lactating females displayed robust ACTH secretion following a high dose of AVP or following a combination of AVP+CRF, the response of virgin females was much smaller. These modifications in pituitary responsiveness were not accompanied by significant differences in pituitary CRF-and AVP-receptors levels between female groups. Our results demonstrate that a reduction in pituitary sensitivity to CRF, but not to AVP occur during lactation in the rat which mediates, at least in part, the stress hyporesponsiveness of lactation.

Pituitary-Adrenal Cortical Responses to Low-Dose Physostigmine and Arginine Vasopressin Administration in Normal Women and Men

Animal studies indicate that central cholinergic neurotransmission stimulates CRH secretion, but several human studies suggest that the hypothalamo-pituitary-adrenal cortical (HPA) axis may be activated only by doses of cholinergic agonists that produce noxious side effects and, by inference, a nonspecific stress response. Physostigmine (PHYSO), a reversible cholinesterase inhibitor, was administered to normal women and men at a dose that elevated plasma ACTH1-39, cortisol, and arginine vasopressin (AVP) concentrations but produced few or no side effects. Exogenous AVP also was administered alone and following PHYSO, to determine if it would augment the effect of PHYSO on the HPA axis. Fourteen normal women and 14 normal men matched to the women on age and race underwent four test sessions 5 to 7 days apart: PHYSO (8 μg/kg IV), AVP (0.08 U/kg IM), PHYSO plus AVP, and saline control. Serial blood samples taken before and after pharmacologic challenge were analyzed for ACTH1-39, cortisol, and AVP. PHYSO and AVP administration produced no side effects in about half the subjects and mild side effects in the other half, with no significant female-male differences overall. There also were no significant female-male differences in ACTH1-39 or cortisol responses to AVP. In contrast, the men had significantly greater ACTH1-39 responses to PHYSO administration than did the women. The endogenous AVP response to PHYSO also was significantly greater in the men than in the women, and the ACTH1-39 and AVP responses to PHYSO were significantly correlated in the men (both = +0.70) but not in the women. None of the hormone responses was significantly correlated with the presence or absence of side effects in either group of subjects. These results indicate a greater sensitivity of the HPA axis to low-dose PHYSO in normal men than in normal women, which likely is mediated by increased secretion of AVP. The lack of difference in side effects between the two groups of subjects and the lack of significant correlations between presence or absence of side effects and hormone responses in either group suggest that the increased hormone responses in the men were due to increased responsivity of central cholinergic systems and not to a nonspecific stress response.

The Use of Naloxone for Investigating Disorders of the Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal (HPA) axis forms an integral and vital part of the stress response system. Pituitary ACTH secretion is regulated by two hypothalamic peptides, corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), with CRH being the primary mediator in humans. Numerous neuronal circuits within the brain influence the activity of the CRH neurons in the paraventricular nuclei of the hypothalamus, including endogenous opioid systems. Opioid receptors are widely distributed in the brain but have a particular association with three major neural networks: the sensory, limbic and neuroendocrine systems. Opioidergic agents affect HPA activity in humans and animals, al though important species differences exist. In vitro and in vivo studies provide considerable evidence for a centrally mediated effect of opioidergic agents on the HPA axis, most likely by direct action on the hypothalamus. Naloxone is a competitive antagonist at multiple opioid receptor subtypes. Clinical investigations utilizing naloxone administration in humans have had three primary aims:1) to elucidate the role of endogenous opioid systems in the normal physiology of the HPA axis; 2) to study the pathophysiology of disorders associated with or caused by dysfunction of the HPA axis; 3) to develop new diagnostic tests. High doses of naloxone stimulate the human HPA ards causing rises in plasma ACTH and cortisol concentrations. Pharmacological stud ies strongly suggest that naloxone blocks a tonic inhibitory effect of endogenous opioids on central alpha-adrenergic pathways, which in turn stimulate ACTH secretion via CRH release from the hypothalamus. Therefore, the naloxone test provides a means of evaluating hypothalamic CRH reserve and assesses the integrity of the entire HPA axis. Several disorders are associated with dysregulation of the HPA axis including major depression, post-traumatic stress disorder, alcoholism, chronic fatigue syndrome, Cushing's syndrome, and obesity. Major depression is a condition often associated with clinical and biochemical evidence of hypercortisolism (pseudo-Cushing's syndrome) and may be very difficult to distinguish from patients with true Cushing's syndrome. Patients with pseudo-Cushing's syndrome are postulated to have hypersecretion of hypothalamic CRH producing an upregulation of an otherwise normal HPA axis. Patients with major depression have an ACTH hyperresponse to naloxone compared with healthy subjects and patients with Cushing's disease. This increased ACTH response is further exaggerated by combining naloxone administration with the direct corticotrope stimulation provided by exogenous AVP. The naloxone test also has potential diagnostic utility-when central adrenal insufficiency is suspected. Naloxone applies a specific pharmacological stimulus at the hypothalamic level, therefore a normal ACTH and cortisol response implies functional integrity of all three components of the HPA axis. Preliminary studies comparing naloxone administration with the insulin hypoglycemia and metyrapone tests are promising. The naloxone test may provide an alternative in patients with suspected central adrenal insufficiency who are unable to undergo an insulin hypoglycemia test or a metyrapone test because of safety issues.

Resistance to vasopressin action on the kidney in patients with Cushing's disease.

To assess the plasma levels and action of arginine vasopressin (AVP) in patients with Cushing's disease. There are many reports that patients with Addison's disease have increased AVP levels associated with hyponatraemia and hypoosmolality, but none on the dynamics of secretion of this neurohormone during osmolality-based stimulation in patients with chronic hypercortisolism. The plasma AVP concentration and the urinary and plasma osmolality after a 7.5-h water deprivation test (WDT) were evaluated in 13 patients with Cushing's disease and 15 normal (control) individuals. In patients with Cushing's disease we also assessed the urinary osmolality in response to 10 micrograms i.v. desmopressin (DDAVP) administered at the end of the WDT. At the end of the WDT, urinary osmolality was significantly lower in patients with Cushing's disease (511.5 +/- 148.5 mOsm/l) than in the normal subjects (981.1 +/- 107.1 mOsm/l, P < 0.001), whereas plasma osmolality did not differ between the two groups. Consequently, the urine/plasma osmolality ratio (Uosm/Posm) was lower in patients with Cushing's disease than in normal individuals (1.8 +/- 0.5 compared with 3.4 +/- 0.4, P < 0.001). The AVP concentration also was greater (7.3 +/- 3.1 pmol/l) in those with Cushing's disease than in the controls (3.9 +/- 2.3 pmol/l, P < 0.005). After administration of DDAVP to the hypercortisolaemic patients, the urinary osmolality attained (718.0 +/- 200.0 mOsm/l) was still lower than that in the normal group at the end of WDT (P < 0.005). Patients with Cushing's disease presented higher AVP levels and smaller Uosm/Posm ratios than normal subjects. After DDAVP, the patients with Cushing's disease were unable to concentrate the urine adequately. These data suggest that the kidney shows resistance to the action of both endogenous and exogenous AVP in patients with Cushing's disease.

Facilitation of AVP(4–8) on Gene Expression of BDNF and NGF in Rat Brain

Zhou, A.-W., W.-X. Li, J. Guo and Y.-C. Du. Facilitation of AVP(4–8) on gene expression of BDNF and NGF in rat brain. Peptides 18(8) 1179–1187, 1997.—In situ hybridization and Northern blot assay were used to evaluate the effects of exogenous AVP(4–8) on the transcription of mRNAs for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in the adult rat brain. NGF and BDNF expression was found to be significantly enhanced by AVP(4–8) administration in the cerebral cortex and hippocampus, but NT-3 expression was not changed. In the same conditions, behavior-active arginine-vasopressin (AVP) showed a small effect and its behavior-inactive homologue, oxytocin did not. Our results suggest that selective regulation of neurotrophin gene expression by the peptides may be responsible for its memory-enhancing function.

Urinary concentrating defect in experimental hemochromatosis.

We studied the urinary concentrating capacity in experimental hemochromatosis. Sprague-Dawley rats were randomized into iron (Fe)-loaded (injected sc with 1.2 g elemental iron/kg body weight as iron dextran) and pair-fed control groups. The urinary concentrating ability was studied after 10 months of iron loading. At basal condition, urine osmolality (Uosm) was significantly lower (P < 0.05) in the Fe-loaded rats compared with the control animals despite comparable urinary arginine-vasopressin (AVP) excretion in the two groups. Although 48-h water deprivation resulted in comparable rises in plasma concentration and urinary excretion of AVP in the two groups, maximal Uosm in the Fe-loaded animals was significantly lower than that seen in the control group (P < 0.01). Moreover, the observed urinary concentrating defect could not be corrected by pharmacological doses of exogenous AVP. There was no significant difference in renal chloride, sodium, calcium, or magnesium handling at either basal or sodium depleted states. Histologic studies showed marked iron deposition in the cortex and outer medulla accompanied by mild tubular atrophy particularly in the distal convoluted tubules. Thus, chronic experimental iron overload leads to nephrogenic diabetes insipidus marked by AVP-resistant urinary concentrating defect.

Cortisol feedback in adrenalectomized adult sheep.

These experiments tested the sensitivity of cortisol feedback on adrenocorticotropic hormone (ACTH) secretion in adult sheep. In series I, five bilaterally adrenalectomized (ADX) adult sheep were maintained on "low" (125 micrograms/h) or "high" (500 micrograms/h) intravenous cortisol replacement, and dose-response curves were obtained with corticotropin-releasing factor (CRF) and arginine vasopressin (AVP). CRF caused incremental increases in plasma ACTH at the low but not the high dose of cortisol. AVP was similarly ineffective in stimulating ACTH at the high dose of cortisol. However, in series II, where ADX animals were again maintained on low or high cortisol infusions, a combined infusion of CRF and AVP was able to stimulate a robust ACTH response during both steroid replacement regimens. These studies demonstrate that the pituitary represents a major site of steroid feedback in the sheep, with a relatively small increase in the concentration of cortisol, within the normal unstressed physiological range, being able to inhibit ACTH secretion in response to exogenous CRF and AVP. However, under these conditions, inhibition of ACTH release can be overcome by the combined action of CRF and AVP. Further studies in series III, concerned with the nature of glucocorticoid inhibition of AVP release, demonstrate that whereas exposure to maximal cortisol levels (5,000 micrograms/h) completely abolishes the ACTH response to severe hemorrhage (15 ml/kg over 15 min), AVP release is maintained, suggesting that the system controlling AVP release during hemorrhagic stress is less sensitive to the negative influences of glucocorticoids than is the system controlling ACTH release.

Arginine vasopressin-induced renal vasodilation mediated by nitric oxide.

The vasoconstrictor vasopressin has been reported to induce paradoxical local vasodilation in the basilar vasculature through stimulation of the endothelium-derived relaxing factor nitric oxide (NO). We investigated the possibility that at subpressor doses, exogenous arginine vasopressin (AVP) might have a similar effect in the kidney. Ten Inactin-anesthetized rats were infused with sequential doses of AVP from 25 to 6,400 microU/min in 30-min increments. Subpressor infusion resulted in progressive renal vasodilation; renal blood flow (RBF) increased significantly going from 14 +/- 6% above basal at 200 microU/min (p < 0.02) to 27 +/- 5% (p < 0.01) at 1,600 microU/min accompanied by a 24 +/- 5% decrease in renal vascular resistance (RVR). At 6,400 microU/min, blood pressure (BP) increased 29 +/- 6 mm Hg and RVR increased. A second group of 8 rats were first given 10 mg/kg b.w. of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) before infusion of AVP. L-NAME increased BP 22 +/- 3 mm Hg (p < 0.001), and decreased RBF 16 +/- 3% (p < 0.005). After L-NAME, no dose of AVP had any further effect on either BP, RBF, or RVR. Continuous infusion of a single subpressor dose of 100 microU AVP resulted in a 26% increase in RBF (from 7.52 +/- 0.68 to 9.49 +/- 0.54 ml/min/g kidney weight, p < 0.001). AVP doubled urinary cyclic guanosine monophosphate excretion, a marker for renal NO synthesis, from 8.51 +/- 1.01 to 17.48 +/- 4.26 pM/min (p < 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Exogenous Vasopressin on Electrocortical Activity in the Fetal Lamb

We evaluated the effects of exogenous arginine vasopressin on electrocortical activity in the fetal lamb. Eight experiments were conducted on 5 chronically instrumented fetal lambs. Arginine vasopressin was infused at the rate of 1.56-2.27 mlU/min/kg estimated fetal weight for 30 min. Fetal electrocortical activity was obtained by 2 stainless steel screw electrodes implanted bilaterally on the fetal parietal skull. A significant increase was seen in the number of times that electrocortical activity switched from low voltage to high voltage and from high voltage to low voltage. The mean duration of the low voltage state was significantly decreased, while the duration of high voltage remained the same. The percentage of time that fetuses spent in the low voltage state was significantly decreased and in the high voltage state was significantly increased. In conclusion, exogenous AVP affects the regulation of fetal electrocortical activity, including the frequency of switching from one electrocortical activity to another.

Adaptation of inner medullary collecting duct to dehydration involves a paracellular pathway

Prolonged fluid restriction in rats is accompanied by functional modifications of the terminal part of the inner medullary collecting duct (IMCD) revealed by a sustained increase in arginine vasopressin (AVP)-independent transepithelial osmotic water permeability (PTE) in vitro. The cellular basis of this adaptation was explored in isolated and perfused terminal IMCDs of Sprague-Dawley rats using video and fluorescence microscopy. Basolateral membrane osmotic water permeability (Posm), transcellular Posm, and PTE were measured in quick sequence in every tubule. They were expressed per unit area of basolateral membrane corrected for infoldings, based on previous stereological studies and assuming no major change in membrane surface area between hydrated and dehydrated animals. Compared with IMCDs of rats with a high water intake, IMCDs of rats deprived of fluid for 36 h displayed a significantly higher basal PTE (24.9 +/- 5.1 vs. 6.1 +/- 0.6 microns/s), a similar basolateral Posm, and a higher transcellular Posm, implying a higher permeability of the apical membrane, despite the absence of exogenous AVP. However, when IMCDs of thirsted rats were exposed to AVP in vitro, their transcellular Posm (36.0 +/- 2.4 microns/s) was significantly smaller than their PTE determined simultaneously (51.8 +/- 7.1 microns/s), suggesting that part of the water flow may follow a paracellular route. A change in paracellular pathways was supported by higher apparent permeabilities to [14C]sucrose (0.85 +/- 0.27 vs. 0.28 +/- 0.04 x 10(-5) cm/s) and to [methoxy-3H]inulin (0.25 +/- 0.04 vs. 0.14 +/- 0.03 x 10(-5) cm/s) in IMCDs of thirsted rats. The nonelectrolyte permeabilities were affected neither by AVP nor by urea-rich bathing solutions. We conclude that in vivo factors related to dehydration produce a conditioning effect on terminal IMCD, which includes stabilization of the apical membrane in a state of high Posm and opening up of paracellular pathways revealed by a higher permeability to water and nonelectrolytes. The role of these adaptive phenomena remains unclear but may pertain to the sudden transitions between antidiuresis and diuresis.

In vivo diuretic effect of a new non-peptide arginine vasopressin antagonist, OPC-31260, in conscious rats.

The present study was undertaken to determine whether a non-peptide arginine vasopressin (AVP) antagonist (5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetra hydro-1H- benzazepine; OPC-31260) antagonizes the antidiuretic action of endogenous and exogenous AVP in conscious rats. OPC-31260, given orally at a dose of 5 mg/kg or higher, increased urinary volume (UV) and reduced urinary osmolality (Uosm) in a dose-dependent manner, in rats acutely denied access to water. Minimal Uosm was obtained 1-2 h after oral administration of OPC-31260. OPC-31260 caused sustained water diuresis for more than 12 h when water was available ad libitum since OPC-31260 (30 mg/kg) reduced Uosm to less than 230 mOsmol/kg H2O, significantly less than the control value of 600 mOsmol/kg H2O. Water deprivation for 24 h increased plasma AVP levels to 7.2 pmol/l and increased Uosm to 2160 mOsmol/kg H2O. In such water-deprived rats, oral administration of OPC-31260 at 100 mg/kg was diuretic; it markedly increased free water clearance and decreased Uosm to 202 mOsmol/kg H2O. In homozygous Brattleboro rats (with inherited AVP deficiency), given free access to water, subcutaneous infusion of the V2 agonist 1-deamino-8-D-AVP (dDAVP) at a rate of 1 ng/h markedly decreased UV to 12.6 from 148.7 ml/day and increased Uosm to 1762 from 231 mOsmol/kg H2O. OPC-31260 (30 mg/kg) promptly increased UV and reduced Uosm to levels similar to those before the administration of dDAVP; repeated OPC-31260 treatment had sustained effects. These results indicate that OPC-31260 is an orally effective non-peptide AVP antagonist to the antidiuretic action of AVP in the conscious rat.

Exogenous arginine vasopressin does not enhance carotid baroreflex control in the conscious dog

Arginine vasopressin (AVP) has profound effects on the cardiovascular system, yet has minimal pressor activity at physiological levels in intact subjects. We designed an investigation to delineate the effects of AVP on open-loop carotid baroreflex control of mean arterial pressure (MAP), total peripheral resistance (TPR), and cardiac output (CO) in conscious, chronically instrumented dogs. During graded infusions of AVP (0.5-2.0 ng.kg-1.min-1), the open-loop hemodynamic responses to controlled changes in isolated carotid sinus pressure (CSP) were determined. Increasing levels of AVP infusion led to significant increases in plasma AVP levels (P < 0.01). Increasing doses of AVP led to significant increases in TPR at all levels of CSP (P < 0.01). The overall range and gain of the response were not significantly different at any level of AVP infusion. Despite this increase in systemic resistance, there was no significant change in the MAP-CSP relationship. Infusion of AVP led to a dose-dependent depression in CO (P < 0.01) and heart rate (HR; P < 0.05) at all levels of CSP with no significant effect on open-loop baroreflex control. We conclude that although exogenous AVP induces profound changes in cardiovascular function, it does not alter carotid baroreflex control of MAP, TPR, CO, and HR.

Vasopressin and oxytocin: modulators of neurohypophysial blood flow

We examined the role of arginine vasopressin (AVP) as a mediator of neurohypophysial (NH) blood flow regulation in anesthetized dogs. First, we evaluated the NH hyperemia that occurs during hemorrhagic hypotension in the presence (n = 7) and absence (n = 7) of the selective AVP-V1 receptor antagonist [d(CH2)5Tyr(Me)]AVP. AVP-V1 blockade did not alter NH transient or steady-state flow responses to a standardized decrease to 80 mmHg mean arterial blood pressure. We then determined whether exogenous AVP alters NH and regional cerebral blood flow (CBF) (n = 8). Sequential intracarotid infusions resulted in sagittal sinus blood AVP concentrations ranging from 6.97 +/- 3.3 x 10(3) to 2.45 +/- 0.47 x 10(6) pg/ml. No change in NH blood flow (control 428 +/- 162 vs. 487 +/- 75 ml.min-1.100 g-1) was observed even at the highest blood level. However, CBF at the highest AVP level increased from a control value of 20 +/- 3 to 40 +/- 4 ml.min-1.100 g-1, while cerebral oxygen consumption remained unchanged. Administration of a selective AVP-V1 receptor antagonist, [d(CH2)5Tyr(Me)]AVP, blocked AVP-induced elevation in CBF in a third set of dogs (n = 5). Oxytocin was also given by intracarotid infusion at a constant rate (1-200 micrograms/ml) in a final group (n = 5). NH blood flow was unchanged at all doses, whereas CBF increased from control (24 +/- 2 to 38 +/- 5 ml.min-1.100 g-1) at the highest dose. (ABSTRACT TRUNCATED AT 250 WORDS)

Central administration of senktide, a tachykinin NK-3 agonist, has an antidiuretic action by stimulating AVP release in water-loaded rats

Intracerebroventricular (i.c.v.) injections of senktide (0.01–10 nmol), a tachykinin NK-3 agonist, had an antidiuretic action in water-loaded rats (4.5% body wt.). Pretreatment with OPC-31260 (1 mg/kg, i.v.), a non-peptide vasopressin V 2 antagonist, inhibited the antidiuretic action induced by exogenous arginine vasopressin (AVP, 0.1 μg/kg, i.v.) and senktide (0.1 nmol, i.c.v.). In addition, senktide (11.8 nmol, i.c.v.) caused a marked increased of the plasma AVP level in conscious rats. These results suggest that the central NKB analogue senktide has an antidiuretic effect by stimulating AVP secretion from the pituitary gland through the NK-3 receptor in the hypothalamus.

Detection of a novel arginine vasopressin defect by dideoxy fingerprinting.

Autosomal dominant neurohypophyseal diabetes insipidus is a familial form of diabetes insipidus. This disorder is associated with variable levels of arginine vasopressin (AVP) and diabetes insipidus of varying severity, which responds to exogenous AVP. To determine the molecular basis of autosomal dominant neurohypophyseal diabetes insipidus, the AVP genes of members of a large kindred were analyzed. A new method, called dideoxy fingerprinting, was used to detect an AVP mutation that was characterized by DNA sequencing. The novel defect found changes the last codon of the AVP signal peptide from alanine to threonine, which should perturb cleavage of mature AVP from its precursor protein and inhibit its secretion or action.