Role of vasopressin in regulation of renal kinin excretion in Long-Evans and diabetes insipidus rats.

To study the relationship between vasopressin and the renal kallikrein-kinin system we measured the rate of excretion of kinins into the urine of anesthetized rats during conditions of increased and decreased vasopressin level. The excretion of immunoreactive kinins in Brattleboro rats with hereditary diabetes insipidus (DI) (24 +/- 3 pg min-1 kg-1) was lower than in the control Long Evans (LE) rats (182 +/- 22 pg min-1 kg-1; P less than 0.05). The DI rats also exhibited negligible urinary excretion of immunoreactive vasopressin, reduced urine osmolality, and increased urine flow and kininogenase excretion. In LE rats, volume expansion by infusion of 0.45% NaCl-2.5% dextrose to lower vasopressin secretion reduced (P less than 0.05) kinin excretion, vasopressin excretion, and urine osmolality to 41, 26, and 15% of their respective control values, while increasing (P less than 0.05) urine flow and kininogenase excretion. On the other hand, the infusion of 5% NaCl, which promotes vasopressin secretion, increased (P less than 0.05) the urinary excretion of kinins and vasopressin to 165 and 396% of control, while increasing (P less than 0.05) urine flow and kininogenase excretion. Infusion of vasopressin (1.2 mU/h, intravenous) enhanced (P less than 0.05) kinin excretion by two to threefold in DI rats and in LE rats during volume expansion with 0.45% NaCl-2.5% dextrose, while decreasing urine flow and increasing urine osmolality. This study demonstrates that the urinary excretion of immunoreactive kinins varies in relation to the urinary level of vasopressin, irrespective of urine volume and osmolality and of the urinary excretions of sodium and kininogenase. The study suggests a role for vasopressin in promoting the activity of the renal kallikrein-kinin system in the rat.     

Renal prostaglandins and natriuretic action of oxytocin and vasopressin in rats

The relationship between natriuretic activity of neurohypophysial peptides and renal prostaglandins (PGs) was investigated in anesthetized rats under water diuresis and on kidney homogenates. Over the course of water diuresis, urinary sodium excretion increased steadily, reaching a 3.5-fold increase in 90 min, but there was no significant change in PGE2 and PGF2 alpha excretion. Inhibition of PG synthesis by naproxen sodium abolished the increase in sodium excretion. Oxytocin (OT) and vasopressin, in submaximal antidiuretic doses, produced marked natriuresis to 2139% and 345% of the control rate, respectively, without a concomitant increase in PG excretion. [Leu4]OT, which is devoid of antidiuretic activity, produced natriuresis and diuresis also without a significant effect on PG excretion. Inhibition of PG synthesis by naproxen attenuated the natriuretic response but enhanced the antidiuretic response to OT. Both the natriuretic and diuretic responses to [Leu4]OT were attenuated. Although the possibility that naproxen may have antinatriuretic activity independent of its PG synthesis inhibitory action cannot be excluded, the data obtained are consistent with our postulate that the natriuretic effect of OT-peptides may be mediated in part via a renal PG mechanism. This postulate is strengthened further by our findings that natriuretic peptides, OT, vasopressin and [Leu4]OT stimulated PG synthesis in kidney homogenates in a dose-dependent manner. Their order of potency is in the same order of their relative natriuretic potencies. [Penicillamine1,Phe(Methyl)2,Thr4,Orn8]OT, an OT antagonist and non-natriuretic, had no significant PG synthesis stimulating activity in the kidney homogenates.     

Up-regulation of renal adenylate cyclase-coupled vasopressin receptors after chronic administration of vasopressin antagonists to rats.

Chronic administration of vasopressin [antidiuretic hormone (ADH)] antagonists has been shown to produce a paradoxical antidiuresis in both ADH-replete and ADH-deplete (diabetes insipidus) rats. The antidiuretic effect is progressive, reaching maximal levels in 4 to 5 days, and sustained, persisting for at least 24 hr after cessation of treatment. The antidiuretic profiles associated with these antagonists do not coincide with the profiles of potent ADH agonists, arginine vasopressin and 1-deamino-8-D-arginine vasopressin. To investigate the mechanism of the antidiuretic effect of ADH antagonists, male diabetes insipidus rats were administered antagonists selective for the renal [adenylate cyclase-coupled (V2)] or pressor (phosphytidyl inositol-coupled) vasopressin receptor and urine output (volume and osmolality) and renal vasopressin receptor properties (concentration and affinity) were determined and compared to rats treated with arginine vasopressin or 1-deamino-8-D-arginine vasopressin. After acute administration, only the V2-acting antagonists were antidiuretic, but were 3 orders of magnitude less potent than 1-deamino-8-D-arginine vasopressin. Following chronic administration, all of the antagonists were antidiuretic, but the level of antidiuresis achieved with the phosphytidyl inositol-coupled vasopressin receptor-selective antagonist was 2- to 3-fold lower than for analogs with V2 activity. Maximal antidiuretic effects were realized in 5 days and were apparent at 24 hr after cessation of treatment. The antidiuretic activities and potencies of the ADH antagonists appeared to be increased following chronic antagonist administration. Finally, renal vasopressin receptor concentration was significantly elevated 24 hr after cessation of antagonist treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the pharmacologic properties of a vasopressin antagonist in Brattleboro rats

The arginine vasopressin (AVP) analog d-(CH2)5-D-Tyr(Et)VAVP is a potent competitive antagonist of AVP at renal tubular AVP receptors. In Sprague-Dawley rats, this compound induces diuresis after single injections but only a transient diabetes insipidus-like state during continuous infusion. To further evaluate the pharmacologic profile of d-(CH2)5-D-Tyr(Et)VAVP, the present experiments were performed in Brattleboro rats homozygous for hereditary hypothalamic diabetes insipidus. In these rats, acute and chronic administration of the antagonist induced significant antidiuretic effects. These agonistic effects persisted for up to 4 days after single injections and for more than 2 weeks after stopping continuous infusions. The antidiuretic effects of the antagonist during chronic administration were indistinguishable from those of AVP replacement. When the renal tubular AVP receptor antagonist was infused into diabetes insipidus rats that had received AVP for 1 week, it induced a transient rise in water intake. However, the peak values after administration of the antagonist were much lower than after AVP withdrawal. These observations suggest that d-(CH2)5-D-Tyr(Et)VAVP has substantial agonistic properties that are not detectable in Sprague-Dawley rats except for limiting the compound's maximum anti-antidiuretic efficacy. These agonistic effects together with endogenous compensatory mechanisms may allow Sprague-Dawley rats to maintain a normal water balance during the continuous administration of d-(CH2)5-D-Tyr(Et)VAVP.     

Prostaglandin-vasopressin interactions on the renal handling of calcium and magnesium

The role of prostaglandins in the regulation of sodium and water excretion has been widely studied, but little is known about the influence of prostaglandins (PGs) on the tubular handling of calcium, magnesium or phosphorus. Recent observations have suggested that PGE2 and vasopressin may interact and influence reabsorption of calcium and phosphorus in the cortical collecting duct. The present study investigated the effect of meclofenamate (2 mg/kg), and inhibitor of PG synthesis, on the excretion of calcium, magnesium and phosphorus. Experiments were performed in antidiuretic and water diuretic rats to examine potential PG-vasopressin interactions on the reabsorption of these ions by renal tubules. In antidiuretic rats given meclofenamate, urine osmolality increased whereas urine flow and the fractional excretion of water, urea, sodium, calcium and magnesium decreased by 30 to 50%. In water diuretic animals, urine osmolality and urea excretion were unaltered after meclofenamate administration. Fractional excretion of sodium, water, calcium and magnesium declined approximately 50% in water diuretic rats given meclofenamate. Urinary excretion of PGE2 was not significantly different in water diuretic and antidiuretic rats averaging 262 +/- 78 vs. 167 +/- 35 pg/min, respectively. Meclofenamate significantly reduced urinary excretion of PGE2 in both groups. The results indicate that renal PGs modulate renal tubular reabsorption of calcium and magnesium, as well as sodium and water.     

Renal excretion of antidiuretic hormone in healthy subjects and patients with renal failure

Urinary clearance of antidiuretic hormone (ADH) has been measured under basal conditions and during intravenous administration of arginine vasopressin in ten healthy subjects, and only under basal conditions in 18 patients with chronic renal failure and seven patients with acute renal failure at the polyuric phase of the disease. In healthy subjects studied under conditions of mild water diuresis plasma concentration, urinary excretion rate, urinary clearance and fractional clearance of ADH were 3.3 +/- 0.36 pg/ml, 25.2 +/- 5.5 pg/min, 7.5 +/- 1.2 ml/min and 6.4 +/- 1.0% (means +/- SEM) respectively. When plasma ADH was raised to levels between 7 and 26 pg/ml during intravenous administration of the hormone, urinary excretion rate and urinary clearance of ADH increased. Tubular reabsorption of ADH did not reach a plateau but progressively increased in the range of plasma ADH studied. In patients with chronic renal failure, plasma concentration, urinary excretion rate, urinary clearance and fractional clearance of ADH were 2.8 +/- 0.19 pg/ml, 9.4 +/- 2.0 pg/min, 3.4 +/- 0.6 ml/min and 10.0 +/- 2.9% (means +/- SEM) respectively. Urinary excretion rate and urinary clearance were significantly lower than in healthy subjects. In patients with acute renal failure, plasma concentration, urinary excretion rate, urinary clearance and fractional clearance of ADH were 4.6 +/- 0.47 pg/ml, 52.8 +/- 15.8 pg/min, 9.5 +/- 2.7 ml/min and 24.9 +/- 4.4% (means +/- SEM) respectively. Urinary excretion rate and fractional clearance were higher than in healthy subjects and patients with chronic renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of noradrenaline, vasopressin and angiotensin II on renal prostaglandins in man

To examine the response of renal prostaglandins (PG) to systemic and renal vasoconstriction noradrenaline (NA), arginine vasopressin (AVP) and angiotensin II (ANG II) were each infused into eight healthy female subjects for 3 h on different days. Urinary excretion of PGE2, PGF2 alpha and 6-keto-PGF1 alpha was determined hourly. NA and ANG II stimulated excretion of PGF2 alpha significantly, but not of PGE2 or 6-keto-PGF1 alpha. AVP stimulated renal PGF2 alpha and 6-keto-PGF1 alpha significantly, but not PGE2. A weak correlation was found between urinary PGF2 alpha and diastolic blood pressure during NA and ANG II infusions, but not during AVP infusion. The release of renal PG does not appear to constitute an obligatory and concomitant response to the blood pressure rise induced by the pressor agonists. The greater response of PGF2 alpha than of PGE2 may result from a preferential direct effect on PGF2 alpha secretion or from an increased conversion of PGE2 into F2 alpha.     

The role of sodium depletion in hydrochlorothiazide-induced antidiuresis in Brattleboro rats with diabetes insipidus

1. The mechanism of the antidiuretic effect of hydrochlorothiazide in diabetes insipidus was studied in anaesthetized Brattleboro rats with the hereditary hypothalamic form of the disease. 2. The antidiuresis caused by acute administration of hydrochlorothiazide followed an increase in sodium excretion and was associated with a significant fall in the plasma sodium concentration. There were concomitant falls in effective renal plasma flow and glomerular filtration rate. 3. When sodium depletion was prevented by adjusting the infusion of sodium chloride, the falls in plasma sodium concentration, effective renal plasma flow and glomerular filtration rate were abolished. Under these circumstances there was an increase in urine volume, which suggests that hydrochlorothiazide may inhibit fractional fluid reabsorption in the proximal convoluted tubule. 4. The results indicate that the antidiuresis caused by hydrochlorothiazide in diabetes insipidus results, at least in part, from falls in effective renal plasma flow and glomerular filtration rate. These in turn seem to be entirely secondary to the drug-induced sodium depletion.     

Role of antidiuretic hormone in the attenuated furosemide response observed during indomethacin administration

Recently we demonstrated that increased chloride reabsorption in Henle's loop is a major contributor to the blunted furosemide response observed during prostaglandin synthesis inhibition. Because antidiuretic hormone (ADH) modulates chloride reabsorption in the loop and because prostaglandin synthesis inhibition potentiates ADH-mediated water reabsorption, ADH may be necessary for the attenuated furosemide response observed during prostaglandin synthesis inhibition. If such were the case, then prostaglandin synthesis inhibition should have no effect on furosemide's chloruretic response in the absence of ADH. To test this hypothesis, the effect of indomethacin on furosemide chloruresis was determined in homozygous (ADH-deficient) Brattleboro rats and in homozygous Brattleboro rats receiving ADH (2.4 mU/hr) over a short period of time. Furosemide-induced chloruresis was not different (P was not significant) between indomethacin-treated homozygous Brattleboro rats and homozygous Brattleboro rats receiving the indomethacin vehicle (fractional excretion of chloride: 6.28% +/- 1.08% vs. 6.24% +/- 0.98%). However, in ADH-infused Brattleboro rats, furosemide chloruresis was lower in indomethacin-treated rat groups than in vehicle-treated rat groups (fractional excretion of chloride: 3.09% +/- 0.62% vs. 6.61% +/- 0.88%; P less than 0.02) and lower than in indomethacin-treated ADH-deficient Brattleboro rats as well (P less than 0.05). Mean arterial pressure, inulin clearance, and renal blood flow were not different between any groups. Urinary prostaglandin excretion rates were not different between ADH-deficient Brattleboro rats and ADH-treated Brattleboro rats during furosemide administration and were markedly reduced by indomethacin in both circumstances. Thus, ADH is necessary for the blunted furosemide response observed during prostaglandin synthesis inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of antidiuretic hormone on urinary acidification and on tubular handling of bicarbonate in the rat.

Paired micropuncture experiments were carried out in plasma-replete volume-expanded rats to examine the acute effects of 1-desamino-8-D-arginine vasopressin (dDAVP) on urinary acidification and tubular handling of bicarbonate and chloride. No effect was detected on the fractional absorption of water, total CO2, and chloride at end-proximal and early distal sites of superficial nephrons in intact animals; dDAVP, however, inhibited the fractional absorption of total CO2 in Henle's loop while stimulating that of chloride in thyroparathyroidectomized (TPTX) somatostatin-infused rats. In the distal tubule accessible to micropuncture, net total CO2 secretion was observed during hypotonic volume expansion, which reversed to net total CO2 absorption during dDAVP infusion in intact Wistar rats. Marked stimulation of urinary acidification occurred in all animals as attested by a fall in urine pH and bicarbonate excretion. Net acid excretion almost doubled in intact rats. We conclude that (a) antidiuretic hormone (ADH) inhibits fractional bicarbonate absorption in the thick ascending limb while stimulating that of chloride at least in TPTX somatostatin-infused rats, and (b) ADH stimulates proton secretion (or inhibits bicarbonate secretion) in the distal tubule and cortical collecting ducts, which leads to enhanced urinary acidification.     

Biologic response to chronic blockade of vasopressin receptors in Sprague-Dawley rats

The renal tubular arginine vasopressin receptor antagonist, d-(CH2)5-D-Tyr(Et)VAVP, is a potent inhibitor of the vasopressin-induced stimulation of adenylate cyclase in rat renal medullary homogenates in vitro. In acute experiments in vivo, this antagonist increased urine volume and decreased urine osmolality after i.v. or s.c. administration in normally hydrated or dehydrated Sprague-Dawley rats. It did not show any effects in water-loaded rats. The duration of action of the antagonist was between 3 to 4 hr. Chronic i.v. infusion or repeated s.c. injections did not result in a persistent diabetes insipidus. A transient rise in water excretion was followed by a progressive normalization. The marked initial water loss was fully compensated for by an increased water intake so that plasma volume and extracellular fluid volume remained unchanged. After 1 week of treatment with the antagonist, glomerular filtration rate and plasma renin activity were not significantly different from base-line values. Only small functional deficits in renal concentrating capacity became manifest when drinking water was withheld. It is possible that the activation of endogenous compensatory mechanisms restored water balance during chronic arginine vasopressin receptor blockade. An intrinsic agonism of this antagonist, which was not detectable in acute experiments, might have contributed to the normalization of water balance by limiting the maximum anti-antidiuretic effects of renal tubular arginine vasopressin receptor blockade.     

The effect of indomethacin on the renal response to arginine vasopressin in man

The renal response to graded intravenous infusions of arginine vasopressin (AVP) was investigated in a two part study in six volunteers. First, under maximal water diuresis, seven control incremental infusions of AVP were given from zero to 12 fmol min-1 kg-1. Second, the AVP infusions were repeated after pretreatment with indomethacin, 150 mg daily for 36 h. After the AVP infusions, plasma AVP concentrations did not change significantly and remained within the physiological range; in contrast, urinary AVP excretion rate increased steadily. Indomethacin did not alter the plasma or urinary concentrations of AVP. AVP caused a fall in urine flow rate from a state of maximal diuresis to one of maximal antidiuresis. After indomethacin, fractional free water clearance was reduced by an average of 26% at the zero, 2 and 4 fmol min-1 kg-1 infusion rates of AVP. A significant increase in fractional sodium clearance of approximately 50% occurred during the AVP infusions, which was abolished after pretreatment with indomethacin. After indomethacin, urinary prostaglandin E2 (PGE2) excretion rate was reduced by an average of 40% at the zero and 2 fmol min-1 kg-1 infusion rates of AVP. At higher AVP infusion rates, no significant inhibition of PGE2 was observed. Urinary kallikrein excretion rate decreased steadily to one-third of its original value after AVP and this change remained unaltered by indomethacin. The findings show that infusions of AVP, resulting in plasma concentrations in the physiological range, evoke a maximal antidiuretic response, which is accompanied by natriuresis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Arginine vasopressin and cyclic adenosine monophosphate during acute sodium loading in chronic glomerulonephritis

The relationship of arginine vasopressin (AVP) in plasma to cyclic adenosine 3' 5'-monophosphate (cAMP), sodium excretion in urine, and arterial blood pressure were determined during intravenous infusion of hypertonic sodium chloride solution (500 ml of 50 g/l) in 10 normotensive control subjects and in 11 normotensive and 10 hypertensive patients with chronic glomerulonephritis and relatively well preserved kidney function. The concentration of AVP in plasma increased 2-4 fold, osmolality in serum increased 12-16 mosmol/kg, and urinary excretion of cAMP increased 20-40% during sodium loading to the same extent in all three groups. Sodium and water excretion were higher during the sodium loading in the hypertensive patients, but not in the normotensive patients when compared to the control subjects. Neither AVP nor changes in AVP correlated significantly with changes in cAMP excretion, sodium excretion or blood pressure. In the control subjects the level of parathyroid hormone in serum was unchanged during the sodium chloride infusion. Water loading without sodium loading in eight of the control subjects caused a decrease in the excretion of cAMP. In conclusion, the increase in cAMP excretion in urine during the sodium loading might be explained by an AVP-induced stimulation of renal cAMP production. The study does not suggest that AVP plays a role in the increased sodium excretion during sodium loading or in the development of hypertension or chronic glomerulonephritis.     

Effects of adrenalectomy and chronic adrenal corticosteroid replacement on potassium transport in rat kidney

Clearance experiments were carried out in pair-fed rats to examine the long-term effects of adrenalectomy and selective adrenal corticosteroid replacement in physiological amounts on renal potassium transport. To this end, clearance studies were conducted in rats that were sham operated, or adrenalectomized (ADX). ADX animals were given either vehicle, aldosterone (0.5 microgram/100 g body wt per day), dexamethasone (1.2 micrograms/100 g body wt per day), or aldosterone and dexamethasone, by osmotic minipump for 7-9 d whereupon clearance experiments were conducted. After chronic hormone treatment, during basal conditions when only Ringers solution was infused, all groups excreted similar amounts of potassium. However, in all ADX animals without mineralocorticoid replacement, the maintenance of urinary potassium excretion at control levels was associated with hyperkalemia, increased urine flow, and natriuresis; all are factors known to stimulate urinary potassium excretion. During acute potassium infusion, the increase in urinary potassium excretion was less in ADX rats than in controls. This functional deficiency in potassium excretion was partially corrected by dexamethasone and was uniformly associated with a significant increase in urine flow. Aldosterone replacement or aldosterone and dexamethasone given together chronically, sharply increased potassium excretion but did not restore excretion to control levels. Only acute aldosterone infusion (0.2 microgram/100 g body wt bolus plus 0.2 microgram/100 g body wt per hour), superimposed upon chronic aldosterone and dexamethasone treatment, fully restored potassium excretion to control levels. This aldosterone induced enhancement of potassium excretion, both chronic and acute, was not associated with hyperkalemia, and increased urine flow or natriuresis. Thus, physiological levels of both classes of adrenal corticosteroids stimulate renal potassium excretion albeit by different mechanisms. Mineralocorticoids stimulate tubular potassium excretion directly, whereas glucocorticoids augment excretion indirectly by increasing fluid and sodium delivery along the distal nephron.     

Decreased urinary active and inactive kallikrein by chronic infusion of vasopressin in conscious rats

To assess possible interactions of circulating vasopressin with the synthesis or activation of renal kallikrein, we studied the effect of chronic infusion of vasopressin (7.2 U/kg/day i.p.) for 6 days on the urinary excretion of total and active kallikrein in conscious rats. We determined urinary total, active and inactive kallikrein by measuring kallikrein activity using a kininogenase assay before and after the treatment with trypsin (200 micrograms/ml). Chronic infusion of vasopressin induced sustained decreases in urinary total, active and inactive kallikrein excretion, but did not affect the ratio of active to total kallikrein. The infusion of vasopressin induced significant increases in circulating levels of vasopressin (248.1 +/- 35.2 pg/ml in vasopressin-infused rats (n = 7) compared to 95.5 +/- 14.6 pg/ml in vehicle-infused rats (n = 7), p less than 0.001) and in weight gain (39.6 +/- 1.3 g in vasopressin-infused rats (n = 7) compared to 29.1 +/- 3.3 g in vehicle-infused rats (n = 7), p less than 0.05), and also sustained decreases in water intake and urine volume, but it did not induce any change in urinary sodium excretion. Circulating levels of angiotensin II was decreased by chronic infusion of vasopressin. Thus, the present study suggests that the elevation of circulating vasopressin levels induces a decrease in the synthesis of renal kallikrein.     

Clofibrate-Induced Antidiuresis

Normal subjects and patients with antidiuretic hormone (ADH) deficiency were studied to determine the mechanism of the antidiuretic action of clofibrate. Before clofibrate treatment, the patients' ability to concentrate urine with a standardized dehydration procedure correlated with the amount of ADH which was excreted. During clofibrate administration all six patients with ADH deficiency developed an antidiuresis which was like that of ADH, since there was no change in sodium, potassium, total solute, or creatinine excretion. There was a correlation between the patients' ability to concentrate urine during dehydration and the subsequent response to clofibrate, and the excretion of ADH during dehydration correlated with the excretion of ADH on clofibrate therapy. Clofibrate-induced antidiuresis in these patients was partially overcome by ethanol and by water loading. Clofibrate interfered with the ability of patients and subjects to excrete a water load and prevented the water load from inhibiting ADH excretion in the normal subjects. These studies suggested that clofibrate was acting through endogenous ADH and this thesis was supported by the failure of clofibrate to produce an antidiuresis when injected into rats with total ADH deficiency (Brattleboro strain) although an antidiuresis was produced in water-loaded normal rats. When the drug was injected into Brattleboro rats with exogenous ADH, clofibrate either did not alter or it inhibited the action of the ADH. The data demonstrate that clofibrate has a significant ADH-like action. This action appears to be mediated through the release of endogenous ADH.     

Role of vasopressin in response to intrarenal infusions of alpha-2 adrenoceptor agonists

Previous studies have indicated that the effects of renal alpha-2 adrenoceptor stimulation are mediated through the blockade of the renal effects of vasopressin. If this premise is correct then 1) specific antagonists of the antidiuretic effect of vasopressin (V2 antagonists) should mimic alpha-2 adrenoceptor stimulation and 2) in the presence of V2 antagonists, the diuretic and natriuretic effect of clonidine should be attenuated. The renal effects of [d(CH2)5,D-Ile2,Ile4]AVP, a specific V2 antagonist, were studied. On the day of the experiment, uninephrectomized rats were anesthetized, and the carotid artery and jugular vein were cannulated for recording blood pressure and saline infusion, respectively. The left kidney was exposed and the ureter cannulated. A 31-gauge needle was advanced into the renal artery to permit direct i.r. infusion of study drugs. Bolus doses of the V2 antagonist (0, 1, 3, 10, or 30 nmol/kg i.v.) produced a dose-related increase in urine volume and free water clearance at all doses tested. Sodium excretion increased only at the higher doses (10 and 30 nmol/kg). This dose-related dissociation in water and then sodium excretion is similar to that observed after i.r. clonidine infusions. In the presence of the V2 antagonist, clonidine (3 micrograms/kg/min) had no effect on urine volume or free water clearance but significantly decreased the excretion of sodium from control. These results demonstrate that V2 antagonists mimic the effects of i.r. clonidine. As well, in the absence of vasopressin (V2 antagonism), the effects of clonidine are attenuated. Moreover, they are also consistent with not only an antidiuretic role for endogenous vasopressin but also an antinatriuretic one.     

Renal, haemodynamic and hormonal interactions between atrial natriuretic factor and arginine vasopressin in patients with congestive heart failure.

1. Nine patients with compensated heart failure were infused with synthetic arginine vasopressin at a rate of 0.1 m-units min-1 kg-1 for 60 min to increase their plasma arginine vasopressin concentration. Synthetic human atrial natriuretic factor (3 pmol min-1 kg-1) or placebo was co-infused with the arginine vasopressin in random order in a single-blind cross-over design. 2. The resultant plasma concentrations of arginine vasopressin and atrial natriuretic factor fell to within the upper range observed in congestive heart failure. Compared with the infusion of arginine vasopressin alone, atrial natriuretic factor co-infusion enhanced both the urine flow rate and the sodium excretion rate (both P less than 0.05) without significant haemodynamic and hormonal effects. 3. Systematic blood pressure was elevated by arginine vasopressin infusion (P less than 0.05) without any change in heart rate. Co-infusion of atrial natriuretic factor did not affect these haemodynamic parameters. 4. These results suggest that an increased release of atrial natriuretic factor maintains water and sodium excretion in the presence of arginine vasopressin-induced renal modulations, and that the pressor effect of arginine vasopressin is not antagonized by the increased plasma level of atrial natriuretic factor in patients with congestive heart failure.     

Antidiuretic effects of a nonpeptide vasopressin V(2)-receptor agonist, OPC-51803, administered orally to rats

OPC-51803 is the first nonpeptide vasopressin (AVP) V(2)-receptor-selective agonist. Its pharmacological profile, including antidiuretic action and receptor binding, was characterized using conscious Brattleboro rats with hereditary diabetes insipidus and Sprague-Dawley rats. In membrane preparations from the liver and kidney, OPC-51803 displaced the [(3)H]AVP binding to V(2)-receptors (K(i) = 49.8 +/- 8.1 nM) more greatly than that to V(1a)-receptors (K(i) = 1061 +/- 60 nM), showing a 21 times higher affinity for V(2)-receptors. At single oral doses of 0.003 to 0.3 mg/kg in female Brattleboro rats, OPC-51803 decreased urine volume (from 10.8 +/- 1.1 to 0.5 +/- 0.2 ml during 0-2 h postdosing) and increased urinary osmolality (from 114 +/- 9 to 432 +/- 114 mOsm/kg) in a dose-dependent manner. During the period of 4-week treatment with OPC-51803, significant and constant antidiuresis was observed. In male Sprague-Dawley rats with normal plasma AVP levels, OPC-51803 at 0.03 to 0.3 mg/kg also produced a dose-dependent antidiuretic action (urine volume: from 2.6 +/- 0.6 to 1.1 +/- 0.2 ml at 0-4 h postdosing). Few changes in urinary parameters, serum parameters, or plasma hormone levels were observed. OPC-51803 did not change blood pressure or heart rate, or inhibit AVP-induced pressor response even at 30 mg/kg p.o. These results demonstrate that OPC-51803 is a V(2)-selective agonist that produces a significant antidiuretic action after single and multiple oral dosing in AVP-deficient and normal AVP states. The data suggest that OPC-51803 is a useful therapeutic drug in the treatment of hypothalamic diabetes insipidus, nocturnal enuresis, and some kinds of urinary incontinence.     

Effect of an acute oral lithium intake on urinary Aquaporin-2 in healthy humans with and without simultaneous stimulation with hypertonic saline infusion

OBJECTIVE: Animal experiments have shown that lithium interferes with the formation of Aquaporin-2 in the distal renal tubuli. The effect of lithium on formation of renal water channels has not been studied in healthy humans. The aim of this study was to test the hypotheses that a single oral dose of lithium will reduce the formation of water channels both with and without stimulation with hypertonic saline infusion, and that this effect can be detected by measurement of urinary excretion of Aquaporin-2 (u-AQP2). METHODS: In healthy subjects, Study 1 (n = 11) and Study 2 (n = 12), urine was collected in 6 and 7 periods between 08.00 and 14.00, respectively, and blood samples were drawn at 30- to 60-min intervals. The study medication was given at 09.00; u-AQP2 was determined by radioimmunoassay. RESULTS: In Study 1 neither u-AQP2 nor urinary output were significantly changed by lithium. In Study 2, u-AQP2 was increased by hypertonic saline infusion in parallel with an increase in arginine vasopressin. At the end of the study, u-AQP2 was increased by 30% with placebo but only by 13% with the 600 mg lithium dose, and urinary output was significantly higher after 600 mg lithium than after placebo and 300 mg lithium. CONCLUSIONS: U-AQP2 was not significantly changed after a single oral dose of lithium. The antidiuretic response to hypertonic saline infusion was reduced when lithium was given. It is suggested that lithium increases urinary output by inhibiting trafficking of renal water channels in healthy humans.