Impaired urinary concentration after vasopressin and its gradual correction in hypothalamic diabetes insipidus

This study utilized rates with hereditary hypothalamic diabetes insipidus (D.I.) in order to explore possible mechanisms which prevent full urinary concentration after acute administration of vasopressin in hypothalamic D.I. and which correct this concentrating defect with prolonged therapy.IT WAS FOUND: (a) that the concentrating defect persisted even when the urinary osmolal excretion of D. I. rats was reduced to that of normal animals; (b) that the defect was not corrected more rapidly if larger doses of vasopressin were given; (c) that it persisted even when the D.I. rats were deprived of drinking water after vasopressin was given; (d) that there was osmotic equilibration between urine and renal papilla at a time when the concentrating defect was still evident; and (e) that the correction of the defect was associated with progressive and significant rise of the papillary osmolality.These studies appear to rule out osmotic diuresis, accumulation of exogenous vasopressin, persistent primary polydipsia, or delay in the induction of membrane permeability as causes for the concentrating defect. Rather, subnormal osmolality of the renal papilla, which can be corrected only gradually, accounts for the initial concentrating defect and the long time required for its correction. Reduction of water content and increase of urea content are primarily responsible for restoration of papillary osmolality to normal.     

Effects of centrally administered naloxone on gastrointestinal myoelectrical activity in morphine-dependent rats

The gastrointestinal myoelectrical alterations associated with morphine tolerance and subsequent withdrawal with naloxone were studied before and after treatment with adrenergic blockers, atropine, indomethacin and methysergide administered either i.c.v. or s.c. The rats were prepared chronically with electrodes implanted on the stomach, duodeno-jejunum and colon and two small polyethylene catheters were inserted into the lateral ventricles of the brain. They were rendered physically dependent on morphine by the s.c. administration of a slow-release emulsion containing morphine (75 mg over 48 hr). Morphine treatment was associated with an immediate (15-30 min) inhibition of gastric and colonic spiking activity and intestinal migrating myoelectric complex lasting 6 to 8 hr, followed by a partial recovery of gastric spiking activity while a permanent disorganized motility pattern persisted on the intestine. After 48 hr of morphine treatment the i.c.v. and s.c. administrations of naloxone at doses of 0.03 and 3 mg X kg-1, respectively, promoted typical electrical activity lasting 2 to 3 hr, characterized by the presence of five to seven grouped spike bursts and termed "minute rhythm." Previous central but not peripheral administration of either tolazoline or phentolamine at a dose of 0.3 mg X kg-1 inhibited the i.c.v. naloxone precipitated withdrawal. Neither atropine i.c.v. (30 micrograms X kg-1) nor methysergide i.c.v. (20 micrograms X kg-1) and s.c. (0.2 mg X kg-1) nor indomethacin s.c. (4 mg X kg-1) were found to have any effect on i.c.v. naloxone induced minute rhythm pattern.(ABSTRACT TRUNCATED AT 250 WORDS)     

A vasopressin-mediated diminution of potassium excretion in water-loaded man

Intravenous vasopressin (1-3 mu-units min-1 kg-1) had an antidiuretic effect on water-loaded man and also diminished potassium excretion. As noted by others, aspirin (2.4 g) enhanced the antidiuretic effect of vasopressin, but the fall in potassium excretion was not modified by prior administration of aspirin, which makes it unlikely that the fall was due to the release of endogenous prostaglandins. After terminating the infusion of vasopressin, the fall in potassium output persisted longer than the antidiuresis, which makes it unlikely that the antikaliuretic effect of vasopressin is secondary to its effect on urine flow. The unchanged antikaliuretic effect of vasopressin after aspirin treatment, together with its persistence after terminating the infusion, suggest the possible existence of vasopressin-mediated potassium absorption in the distal nephron in certain circumstances. Aspirin administration had specific effects of its own in water-loaded man. It decreased both the water diuresis and sodium excretion but did not alter potassium excretion or urine osmolality.     

Lithium clearance in dogs: effects of water loading, amiloride and lithium dosage.

1. The influences of lithium dosage, urine flow rate and acute administration of amiloride on the renal handling of lithium in normal conscious dogs were investigated. 2. Lithium was administered in the diet at daily doses of 100 mg or 2 mg of lithium carbonate for the 2 days preceding the investigation. Urine flow rate was altered by water loading with and without arginine vasopressin infusion (5 pg min-1 kg-1). Amiloride was administered as an intravenous bolus (130 micrograms/kg) followed by a continuous infusion (1.22 micrograms h-1 kg-1). 3. Glomerular filtration rate (exogenous creatinine clearance) did not change within series and was not different between series; it averaged 3.27 ml min-1 kg-1. Control levels of fractional lithium excretion (12.4 +/- 1.2%, mean +/- SEM) were not influenced by hydration, hydration plus arginine vasopressin administration or the lithium dosage. However, in hydrated dogs having a plasma lithium concentration of 130-140 mumol/l, amiloride administration was associated with a 5% increase in fractional lithium excretion (P less than or equal to 0.01). 4. It is concluded that distal tubular lithium reabsorption may take place in sodium-replete conscious dogs undergoing water diuresis. The low fractional lithium excretion even during amiloride infusion (14.1-16.8%) may well be due to a high fractional reabsorption of lithium in the proximal tubules; however, a significant reabsorption of lithium distal to the proximal straight tubules by amiloride-insensitive pathways cannot be excluded.     

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.     

Corticotropin-releasing factor. Mechanisms to inhibit gastric acid secretion in conscious dogs.

Immunoreactivity similar to that of corticotropin-releasing factor (CRF) is found in regions of the central nervous system that modulate autonomic responses, including gastrointestinal functions. We examined the central nervous system effects of ovine CRF on gastric acid secretion in conscious dogs. Male beagle dogs (11-13 kg) were fitted with chronic intracerebroventricular cannulae and gastric fistulae. Gastric acid secretion in response to intravenously administered gastric secretory stimuli was measured by in vitro titration of gastric juice to pH 7.0 and in response to an intragastric meal by in vivo intragastric titration at pH 5.0. Plasma gastrin was determined by radioimmunoassay. CRF microinjected into the third cerebral ventricle decreased pentagastrin-stimulated gastric acid secretion for 3 h (P less than 0.01) dose-dependently (0.2-6.0 nmol X kg-1). CRF did not inhibit histamine-stimulated gastric secretion but significantly (P less than 0.01) decreased the secretory response after 2-deoxy-D-glucose for 3 h. The gastric inhibitory action of intracerebroventricularly administered CRF on pentagastrin-stimulated gastric acid secretion was completely abolished by ganglionic blockade with chlorisondamine. The opioid antagonist, naloxone, and the vasopressin antagonist, [1-deaminopenicillamine,2-(O-methyl) tyrosine,8-arginine]-vasopressin, significantly suppressed the inhibitory effect of CRF on gastric acid secretion stimulated by pentagastrin. In contrast, truncal vagotomy did not prevent the inhibition of gastric acid secretion induced by CRF. CRF (0.2-2.0 nmol X kg-1) administered intracerebroventricularly decreased gastric acid secretion stimulated by 200-ml liquid meals containing 8% peptone. CRF did not affect plasma gastrin concentrations. These results indicate that CRF microinjected into the third cerebral ventricle inhibits gastric acid secretion in conscious dogs. CRF-induced inhibition of gastric acid secretion appears to be mediated by the sympathetic nervous system and, in part, by opiate and vasopressin-dependent mechanisms.     

Renal action of acute chloroquine and paracetamol administration in the anesthetized,fluid-balanced rat

Chloroquine induces diuresis, natriuresis, and an increase in glomerular filtration rate (GFR) in the rat. These responses are modified in rats with analgesic nephropathy induced by long-term paracetamol (acetaminophen) administration. Here, the effects of acute paracetamol treatment on renal function and the response to chloroquine are reported. Under intraval anesthesia (100 mg kg-1) male Sprague-Dawley rats (n = 6/group) were infused with 2.5% dextrose for 3 h. After a control hour, they received either vehicle, chloroquine (0.04 mg h-1), paracetamol (priming dose of 210 mg kg-1 followed by 110 mg kg-1h-1) or chloroquine and paracetamol over the next hour. Compared with vehicle, chloroquine infusion resulted in increases in GFR (2.4 +/- 0.3 versus 4.8 +/- 0.6 ml min-1), urine flow (4.2 +/- 0.3 versus 10.4 +/- 0.7 ml h-1), and sodium excretion (47.7 +/- 4.1 versus 171.2 +/- 18.6 micromol h-1) and a reduction in urine osmolality (223.2 +/- 5.9 versus 121.7 +/- 23.9 mOsM kg-1). Paracetamol reduced sodium excretion but had no effect on urine flow, GFR, or urine osmolality. When combined, paracetamol blocked the chloroquine-induced diuresis (3.9 +/- 0.7 ml h-1) and natriuresis (22.6 +/- 8.5 micromol h-1), attenuated the increase in glomerular filtration rate (3.5 +/- 0.2 ml min-1), and raised urine osmolality (280.0 +/- 22.8 mOsM kg-1). The differing effects of acute and long-term paracetamol treatment on basal and chloroquine-mediated renal function suggest that the length of prior exposure to paracetamol, and thus the presence of analgesic nephropathy, is an important determinant of the renal response to chloroquine.     

On the Mechanism of Lithium-Induced Diabetes Insipidus in Man and the Rat

The mechanism of lithium-induced diabetes insipidus was investigated in 96 patients and in a rat model. Polydipsia was reported by 40% and polyuria (more than 3 liter/day) by 12% of patients receiving lithium. Maximum concentrating ability after dehydration and vasopressin was markedly impaired in 10 polyuric patients and was reduced in 7 of 10 nonpolyuric patients studied before and during lithium therapy. Severe polyuria (more than 6 liter/day) was unresponsive to trials of vasopressin and chlorpropamide, but improved on chlorothiazide. Rats receiving lithium (3-4 meq/kg/day) developed massive polyuria that was resistant to vasopressin, in comparison to rats with comparable polyuria induced by drinking glucose. Analysis of renal tissue in rats with lithium polyuria showed progressive increase in the concentration of lithium from cortex to papilla with a 2.9-fold corticopapillary gradient for lithium. The normal corticopapillary gradient for sodium was not reduced by lithium treatment. The polyuria was not interrupted by brief intravenous doses of vasopressin (5-10 mU/kg) or dibutyryl cyclic AMP (10-15 mg/kg) capable of reversing water diuresis in normal and hypothalamic diabetes insipidus rats (Brattleboro strain). The present studies suggest that nephrogenic diabetes insipidus is a common finding after lithium treatment and results in part from interference with the mediation of vasopressin at a step distal to the formation of 3',5' cyclic AMP.     

Studies on the nature and mechanism of the diuretic activity of the opioid analgesic ethylketocyclazocine

Subcutaneous injection (0.1 - 3.0 mg/kg) of ethylketocyclazocine (EKC; a prototype kappa agonist) resulted in a dose-dependent increase in urine formation in conscious rats. The increase in urine volume was unaccompanied by a corresponding increase in electrolyte excretion; thus, EKC behaved like a "water diuretic." The diuretic activity was completely abolished by naltrexone, an opiate antagonist. Water loading (10 ml/kg) and EKC (0.5 mg/kg) diminished plasma vasopressin levels equally 60 min after treatment. However, urine formation during the 1 st hr was greater in EKC-treated rats than in water-loaded rats. These results suggested that more than one component was responsible for the diuretic activity of EKC. A central effect of EKC on plasma vasopressin and urine volume was not evident. EKC (10 micrograms/rat) when injected s.c. caused diuresis, but was ineffective as a diuretic when injected into the lateral ventricle. EKC was effective in blocking stimulation of vasopressin secretion caused by volume contraction. EKC also blocked vasopressin-stimulated water flow in the toad bladder, a model of the renal distal tubule and collecting duct. We propose that EKC is diuretic by virtue of inhibition of vasopressin secretion and attenuation of the ADH response in the kidney. Both of these actions may be mediated via opioid receptors responsive to kappa agonists and inaccessible from the cerebroventricle.     

Insulin action in insulin-dependent diabetics after short-term thiazide therapy

The influence of short-term thiazide treatment on peripheral tissue and liver sensitivity to insulin in insulin-dependent diabetes mellitus was determined by the euglycemic insulin clamp technique. A sequential three-step hyperinsulinemic clamp was performed in six insulin-dependent diabetics before and after 2 wk of hydroflumethiazide (HFT) administration in a daily dose of 75 mg. Insulin was infused at rates of 0.5, 2.0, and 4.0 mU X kg-1 X min-1, and each dose was given for at least 120 min. Glucose uptake during the last 30 min of each step was almost identical in the two situations (2.7 +/- 0.6 vs. 2.4 +/- 0.5 mg X kg-1 X min-1, 9.6 +/- 0.9 vs. 9.7 +/- 1.2 mg X kg-1 X min-1, and 12.0 +/- 1.3 vs. 12.6 +/- 1.5 mg X kg-1 X min-1). Serum insulin levels were also similar, and blood glucose was kept at 100 +/- 3, 99 +/- 4, and 97 +/- 3 mg/dl before thiazides and at 93 +/- 6, 93 +/- 6, and 94 +/- 6 mg/dl after thiazides. Another five insulin-dependent diabetics were infused with tritiated glucose followed by insulin infusion at two rates: 0.45 and 1.0 mU X kg-1 X min-1. Basal glucose output was comparable before and after thiazides (3.63 +/- 0.24 vs. 2.97 +/- 0.26 mg X kg-1 X min-1), as was the liver response to increasing insulin concentrations. The metabolic state as assessed by HbA1c and fasting blood glucose did not differ in the two experiments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nicotine-induced release of vasopressin in the conscious rat: role of opioid peptides and hemodynamic effects

Nicotine has been shown to stimulate the release of vasopressin and to cause significant hemodynamic changes. The mechanisms leading to enhanced vasopressin secretion and the vascular consequences of the high plasma vasopressin levels during nicotine infusion have not yet been determined. Therefore, the purposes of the present study were 1) to examine in normal conscious rats the role of opioid peptides in the nicotine-induced increase in plasma vasopressin levels and 2) to assess the role of vasopressin in the hemodynamic effects of nicotine (20 micrograms/min for 15 min) using a specific V1 antagonist of the vascular actions of vasopressin. Plasma vasopressin levels were significantly increased in the nicotine-treated animals (39.5 +/- 10 vs. 3.7 +/- 0.6 pg/ml in the controls, P less than .01). Pretreatment with naloxone, an antagonist of opioids at their receptors, did not reduce the vasopressin levels (47.7 +/- 9 pg/ml). Nicotine also increased mean blood pressure (122.5 +/- 2.5 to 145.2 +/- 3.3 mm Hg, P less than .01) and decreased heart rate (461 +/- 6 to 386 +/- 14.5 beats/min, P less than .05). Administration of the vasopressin V1 antagonist before the nicotine infusion did not affect the systemic hemodynamics or the regional blood flow distribution, as assessed by radiolabeled microspheres. Thus, these results suggest that the nicotine-induced secretion of vasopressin is not mediated by opioid receptors and that the high plasma vasopressin levels do not exert any significant hemodynamic effect on cardiac output or blood flow distribution.     

Mechanisms underlying the pressor responses to acute and chronic intraventricular administration of carbachol in the rat

Infusions of carbachol into the posterior region of the 3rd ventricle of rats for 7 days produced a sustained elevation of blood pressure and heart rate at doses of 0.6 and 1.2 microgram/hr, but only transient rises in blood pressure were obtained at 2.4 microgram/hr. Carbachol, at 0.6 microgram/hr, increased water consumption. At 1.2 microgram/hr, the dipsogenic effect was observed in 50% of the animals and at 2.4 microgram/hr there was no significant change in drinking. Plasma vasopressin levels, measured by radioimmunoassay, were increased by 19-fold 3 min after acute i.c.v. administration of carbachol (0.5 microgram/rat). However, in rats infused with carbachol for 2 or 5 days, the vasopressin levels were not significantly different from controls. The pressor responses to acute and chronic administration of carbachol could be ascribed to the stimulation of periventricular muscarinic receptors because the effects were blocked by atropine, but not by hexamethonium. In carbachol-infused animals, the pressor responsiveness to i.v. norepinephrine and vasopressin were unchanged. From studies using phentolamine, chlorisondamine and a specific vasopressin vasopressor antagonist, it could be inferred that the pressor responses to acute i.c.v. injections of carbachol were due to increased sympathetic activity and vasopressin release. However, the sustained hypertension produced by chronic infusion of carbachol was due primarily to increased sympathetic activity and not to increased plasma levels of vasopressin.     

Pharmacology of DuP 532, a selective and noncompetitive AT1 receptor antagonist

DuP 532 (2-propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl- 4-yl)methyl]imidazole-5-carboxylic acid) inhibited the specific binding of [125I]angiotensin II (AII) for the subtype receptor AT1 in rat adrenal cortical membranes with an IC50 of 3.1 X 10(-9) M, but not the [125I]AII binding for the subtype AT2 sites in rat adrenal medulla tissues. It inhibited the contractile response to AII selectively and noncompetitively in the isolated rabbit aorta with a KB value of 1.1 X 10(-10) M. The selective AII antagonism was confirmed in the guinea pig ileum and the pithed rat. In conscious rats, DuP 532 inhibited the AII-induced pressor effect, aldosterone secretion, and water drinking induced by AII. In conscious renal hypertensive rats, DuP 532 decreased blood pressure with i.v. and p.o. ED30 of 0.02 and 0.21 mg/kg, respectively. The antihypertensive effect of DuP 532 at 0.3 to 3 mg/kg p.o. lasted for at least 24 hr. In conscious spontaneously hypertensive rats, DuP 532 given i.v. or p.o. at 0.3 to 3 mg/kg reduced blood pressure dose-dependently. DuP 532, at doses up to 100 mg/kg i.v., did not cause a pressor response in conscious normotensive rats, suggesting lack of agonism. DuP 532 exerted selective AII antagonism in conscious dogs. In conscious furosemide-treated dogs, DuP 532 given either at 0.3 and 1 mg/kg i.v. or at 1 to 10 mg/kg p.o. decreased blood pressure. As the AT1 receptors are responsible for AII-induced vasoconstriction, aldosterone secretion, and water drinking, our study indicates that DuP 532 is a potent, orally active, selective, and noncompetitive AT1 receptor antagonist and antihypertensive agent.     

Arginine vasopressin dissociates the diuresis and natriuresis due to atrial natriuretic factor in man

The possible interaction between arginine vasopressin (AVP) and atrial natriuretic factor (ANF) in the control of urinary sodium and water excretion was investigated in man. Nine healthy male volunteers undergoing stable maximal water diuresis were studied on four separate occasions. Atrial natriuretic factor 15 pmol kg-1 min-1 or placebo (P) was concomitantly administered against a background infusion of either AVP 0.003 pmol kg-1 min-1 or P; thus the combinations P + P, AVP + P, P + ANF and AVP + ANF were studied. Atrial natriuretic factor caused a significant increase in sodium excretion (UNaV) [+56%], urinary flow rate (V) [+17%] and free water clearance (CH2O) [+23%]; creatinine clearance (Ccr) did not change. Arginine vasopressin reduced V (-58%) and CH2O (-68%) but did not alter UNaV or Ccr. On the AVP + ANF study day, UNaV increased (+64%) as with P + ANF, but V (-44%) and CH2O (-52%) continued to decrease below baseline levels; analysis of variance showed this antidiuresis reflected the prevalent effect of AVP rather than any specific interaction. These results show that AVP is able to dissociate the natriuretic and diuretic effects of ANF.     

Naloxone increases water and electrolyte excretion after water loading in patients with cirrhosis and ascites

Endogenous opioids may be involved in the pathogenesis of ascites and edema in patients with liver cirrhosis. We administered the opioid antagonist naloxone (5 mg bolus followed by a 0.06 mg/min infusion) to eight male patients with alcoholic cirrhosis and ascites and to five healthy age- and sex-matched control subjects and determined the effects of naloxone on water and electrolyte excretion after a nonsustained water load (20 ml/kg). In comparison with saline vehicle infusion carried out in the same subjects, naloxone administration resulted in a 50% increase in urine output and creatinine clearance and twofold increases in sodium and potassium excretion in patients with cirrhosis. Fractional sodium and potassium excretion, minimal urinary osmolality, plasma vasopressin and aldosterone levels, arterial blood pressure, and heart rate were not affected by naloxone treatment. The diuretic effect of naloxone was not observed in control subjects. Plasma naloxone levels were about six times higher in patients with cirrhosis than in control subjects (probably because of impaired metabolism of the drug) but only a weak correlation was found between drug levels and the degree of diuresis observed. The diuretic effect of naloxone may be related to an increase in glomerular filtration rate, possibly in conjunction with altered tubular reabsorption.     

Diuretic effect of bremazocine, a kappa-opioid with central and peripheral sites of action

Intracerebroventricular or i.p. injections of bremazocine produced a dose-dependent diuretic response and increased glomerular filtration rate in hydrated as well as in nonhydrated rats. The potency and magnitude of the bremazocine-induced diuresis were more pronounced in the nonhydrated group of rats. That bremazocine has a central component of action is deduced from the fact that 0.1 microgram of the opioid administered centrally caused a significant increase in urine output; proportionally, larger doses of bremazocine were required to produce the same diuretic effect when the drug was administered parenterally. Bremazocine did not change the total amount of urinary Na+ and K+ as compared to the saline controls; it increased significantly the free water clearance. The bremazocine-induced diuresis was antagonized in a competitive fashion by 10 mg/kg of naloxone giving further support to the notion that the mechanism of action of bremazocine involves activation of kappa-opioid receptors. Bremazocine injected i.v. to nonanesthetized rats increased mean systemic blood pressure in a dose-dependent manner; the pressor action of the opiate was blocked and prevented by 1 mg/kg of naloxone. In contrast, i.c.v. administration of bremazocine did not change mean systemic blood pressure but produced a dose-related increase in urine output. To determine whether in addition to a central site bremazocine also activates a renal mechanism, experiments were performed in the isolated perfused rat kidney. Bremazocine (0.15-2.5 microM) caused a dose-dependent diuretic response and a significant rise in perfusion pressure as well as in glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Kappa agonist-induced diuresis: evidence for stereoselectivity, strain differences, independence of hydration variables and a result of decreased plasma vasopressin levels

Marked diuresis has previously been reported after administration of kappa opioid agonists. The present study shows that this effect is stereospecific; MR-2034 markedly increased urinary output over the dose range 0.08 to 1.25 mg/kg, whereas the opposite isomer, MR-2035, was markedly less potent. Bremazocine increased urinary output in Long-Evans hooded and Sprague-Dawley albino rats as well as lean and fatty Zucker rats. In the lean Zucker and the albino rats, bremazocine produced an inverted U-shaped diuretic dose-effect curve, an effect characteristic of kappa agonists with mu agonist activity. This pattern was not seen with the fatty Zucker rats or the Long-Evans hooded rats. The full kappa agonists bremazocine, ethylketazocine and U-50,488 increased urinary output under three different conditions of hydration: water loaded, normal hydration and water deprived. In contrast, the partial kappa agonists reliably only increase urinary output under the normal hydration condition. The diuretic effects of full and partial kappa agonists correlated with plasma vasopressin levels in water-deprived rats. The full kappa agonists (ethylketazocine, U-50,488, tifluadom and MR-2034) suppressed plasma vasopressin levels below the threshold of detectability of the radioimmunoassay, whereas the partial kappa agonists (nalorphine and butorphanol) suppressed vasopressin levels compared with control values but did not have the efficacy of the full kappa agonists. All these results support the hypothesis that kappa agonists produce their diuretic effect by suppression of plasma vasopressin levels.     

Kappa opioid partial agonist activity of the enkephalin-like pentapeptide BW942C based on urination and in vitro studies in humans and animals

A diuretic effect of the pentapeptide BW942C [Tyr-D-Met(O)-Gly-pNO2-Phe-Pro-NH2 HCl] was demonstrated in humans and rats; it was characterized pharmacologically using whole animal, isolated tissue and in vitro binding studies. A single 2-mg dose of BW942C increased urine output 5-fold over control values in humans. In Long-Evans rats, BW942C produced a biphasic dose-response curve for urine output with lower doses increasing and higher doses suppressing output. Low doses of naltrexone antagonized the antidiuresis, and high doses antagonized the diuresis produced by BW942C. BW942C was less efficacious in producing diuresis than the full kappa agonists bremazocine and U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate, hydrate). Furthermore, BW942C antagonized the diuretic effects of bremazocine and U50,488H. Rats tolerant to U50,488H-induced diuresis were cross-tolerant to BW942C. In Brattleboro rats, which are unable to synthesize vasopressin, BW942C failed to produce a diuretic effect, demonstrating the necessity of vasopressin for its diuretic response. In the kappa-selective rabbit vas deferens bioassay, BW942C was less efficacious than a full agonist, it was antagonized by naloxone and BW942C in nondepressant doses antagonized a full agonist. In binding studies, BW942C had the highest affinity for mu and delta opioid receptors and an intermediate affinity for kappa opioid receptors. The data suggest that BW942C has the property of a partial kappa opioid agonist in addition to being a mu agonist.     

Pancreatic secretion in the rat influenced by the low molecular weight serine proteinase inhibitor Gabexate mesilate

The effect of intravenous or intragastric administration of the synthetic proteinase inhibitor Gabexate mesilate (GM) on the pancreas of rats was investigated. Infused intravenously at 4 mg kg-1 h-1, GM inhibited both basal or cerulein (0.2 microgram kg-1 h-1)-stimulated pancreatic protein secretion. Intracellular transport and secretion of newly synthesized pancreatic enzymes was not influenced by intravenous infusion of GM. Intragastric administration of GM (400 mg kg-1) on four consecutive days increased pancreatic wet weight, protein and enzyme content of the gland. A preferential increase of proteinases above glucosidases was observed. Pancreatic lobules from inhibitor-treated rats released 30% less amylase in response to cerulein or carbachol when the rate of discharge was expressed in percent of initial content. Expressed in ku amylase/microgram DNA secretion rate was two-fold higher than in controls. In pancreatic duct cannulated rats GM (400 mg kg-1 h-1), introduced intragastrically on five consecutive days, stimulated volume-bicarbonate and protein secretion rate, the secretory response on the fifth day being significantly higher than on the first day. Enzyme pattern in pancreatic juice changed characteristically: mainly the amount of acidic proteinases increased, whereas the amount of the basic isoforms was altered only slightly.     

Experimental gentamicin nephrotoxicity: effect of streptozotocin-induced diabetes

To determine the effect of diabetes mellitus on gentamicin nephrotoxicity we treated male F344 rats with streptozotocin 22 mg/kg (DM rats). DM rats were compared to controls (C) and nondiabetic rats ingesting the osmotic diuretic isosorbide administered to simulate glycosuric diuresis (C/I). Base-line C/I renal function and histology did not differ from C. However, in DM rats base-line inulin clearance (CIN) was 20% lower, and renal cortical slice uptake of p-aminohippurate was reduced compared to C and C/I. DM rats also had foci of renal tubular epithelial dysplasia not seen in C or C/I. Gentamicin was administered at 40 mg/kg-day to C and C/I and 32 mg/kg-day to DM rats to adjust for base-line CIN. Acute tubular necrosis, associated with depression of CIN and renal cortical p-aminohippurate and N-methylnicotinamide uptake, developed in all three groups. There were no differences between C and C/I. However, the degree of acute tubular necrosis and dysfunction was less in DM rats than C and C/I. Renal cortical gentamicin accumulation was also slower in DM than either C or C/I, and changes in renal cortical gentamicin over time followed a different pattern in DM rats. These results indicate that 1) attenuation of gentamicin injury in DM rats may be related to reduced accumulation of gentamicin by the renal cortex, 2) this reduced accumulation may be due to subtle baseline tubular injury mediated by streptozotocin or the diabetic state, and 3) osmotic diuresis does not account for attenuation of renal injury in DM.