Kappa-opioid-induced changes in renal water and electrolyte management and endocrine secretion.

1. Subcutaneous injection of the kappa-opioid agonist U50,488 into conscious, saline-loaded rats was associated with a diuresis, antinatriuresis and antikaliuresis which lasted for up to 3 h. Plasma renin activity and corticosterone levels were elevated but plasma vasopressin (AVP) and aldosterone levels were unaltered in similarly treated rats. 2. U50,488 administration to adrenal demeddulated rats was not associated with a diuresis but produced an antinatriuresis, though sodium excretion rates were higher in demedullated than in sham-operated animals. Plasma AVP and corticosterone levels were not affected by demeddulation or subsequent U50,488 treatment. Sham-operated, U50-488-treated rats showed the expected increase in plasma corticosterone levels. 3. U50,488 administration resulted in an antidiuresis and an antinatriuresis in AVP-deficient Brattleboro DI rats. 4. When coupled with fasting stress U50,488 administration resulted in similar but attenuated renal responses compared with those observed in unfasted rats. Basal plasma corticosterone levels were elevated in fasted animals and were further increased by U50,488. 5. Both water and electrolyte handling by the kidney are altered by U50,488. The diuretic effects of U50,488 were reversed by adrenal demedullation and in the absence of endogenous AVP, but the antinatriuretic actions were not altered, suggesting that the effects upon renal water and electrolyte excretion may be mediated by separate mechanisms.     

The diuretic action of 8-cyclopentyl-1,3-dipropylxanthine, a selective A1 adenosine receptor antagonist.

1. The diuretic effect of the selective A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), was investigated in anaesthetized rats. 2. CPX (0.1 mg kg-1, i.v.) produced significant increases in urine flow, and the excretion rate and fractional excretion of both sodium and chloride. By contrast, CPX administration did not result in any significant change in the excretion of potassium. 3. The diuretic effect of CPX was accompanied by a transient increase in inulin clearance although p-amino-hippurate clearance was unaffected, indicating the CPX induced a temporary elevation of glomerular filtration rate but no change in renal blood flow. 4. The fractional excretion of lithium (a marker of delivery of fluid out of the proximal tubule) was also significantly increased by CPX. However, other measures of tubular function derived from lithium clearance indicated that there were no changes in the handling of sodium or water in the distal regions of the nephron. 5. CPX did not significantly alter the relationship between either free water reabsorption or free water clearance and the distal delivery of sodium, which suggests that CPX does not affect the renal concentration/dilution mechanism. 6. The results of this study show that the diuresis and increased excretion of sodium and chloride induced by CPX (0.1 mg kg-1) in the rat, occurs with only transient elevation in glomerular filtration rate and no change in renal blood flow. The primary reason for the diuresis appears to be inhibition of sodium reabsorption in the proximal tubule.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absence of a losartan interaction with renal lithium excretion in the rat.

1. The interaction of losartan, a non-peptide specific AT1 receptor antagonist with the renal handling of lithium was analysed in conscious normotensive Wistar rats and compared with the known increase in renal tubular lithium reabsorption induced by the non-steroidal anti-inflammatory drug, indomethacin. 2. The rats were treated for five days with losartan (10 mg kg-1 day-1, orally), indomethacin (2.5 mg kg-1 day-1, intramuscularly) or their solvents. Lithium chloride (16.7 mg kg-1, i.p.) was given as a single dose on the fifth day; renal functions were then measured. 3. Indomethacin, in the absence of any effect on creatinine clearance, increased renal fractional lithium reabsorption and led to an increase in plasma lithium levels. 4. Losartan did not modify renal lithium handling and its plasma level. No change was observed in renal lithium clearance, the quantity of filtered lithium or the fractional reabsorption of the metal. As expected, losartan had no effect on systolic blood pressure in normotensive rats. 5. In conclusion, our results indicate that losartan, when given orally in the rat at a dose of 10 mg kg-1 day-1 over five days, does not modify renal lithium handling. They suggest that blockade of the angiotensin II receptors does not interfere with renal lithium reabsorption, which occurs mainly at a proximal tubular site.     

Alternative transcripts of the GABA(A) receptor epsilon subunit in human and rat

The effect of 1,4-dihydropyridine (DHP) calcium channel blockers (CCBs), nimodipine (NIM) and lercanidipine (LDP) on the analgesic response of selective kappa-opioid receptor agonists, U50,488H, PD117,302 and U69,593 was determined in male Sprague-Dawley rats using the tail-flick test. The effect of NIM on development of tolerance to U50,488H-induced analgesia and the status of brain DHP-sensitive Ca(2+) channel (L-type) binding sites in both U50,488H-naive and tolerant rats was determined using the highly selective DHP radioligand, [(3)H]PN200-110. Tolerance was induced by injecting U50,488H (25 mg/kg, i.p.) twice daily for 4 days. Intraperitoneal (i.p.) injection of kappa-opioid receptor agonists produced a dose-dependent acute analgesic response. NIM (1 mg/kg; i.p.) and LDP (0.3 mg/kg; i.p.) used in the study produced no tail-flick analgesia. Administration of NIM and LDP (15 min prior) significantly potentiated the analgesia produced by three kappa-opioid receptor agonists. Tolerance developed completely to the analgesic effect induced by U50,488H (25 mg/kg, i.p.) administered on the 5th day. NIM (1 mg/kg, i.p.) twice daily for 4 days not only completely inhibited the development of tolerance to analgesic response but also significantly potentiated it (supersensitivity). There was a significant up-regulation of DHP binding sites (B(max): +41%) in whole brain membranes of tolerant rats when compared to vehicle treated naive rats, implicating increased influx of Ca(2+) through L-type channels in kappa-opioid tolerance. U50,488H (25 mg/kg, i.p.) and NIM (1 mg/kg, i.p.) twice daily for 4 days also resulted in an equivalent up-regulation of DHP binding sites (+36%) as that of U50,488H alone. These results strongly suggest a functional role of L-type Ca(2+) channels in the regulation of pain sensitivity, mechanism of kappa-opioid analgesia and expression of tolerance.     

Eukaliuric diuresis and natriuresis in response to the KATP channel blocker U37883A: micropuncture studies on the tubular site of action.

1. Systemic application of U37883A, a blocker of ATP sensitive potassium (KATP) channels, elicits diuresis and natriuresis without significantly altering urinary potassium excretion. 2. To elucidate tubular sites of action upstream to the distal nephron, micropuncture experiments were performed in nephrons with superficial glomeruli of anaesthetized Munich-Wistar-Fr?mter rats during systemic application of U37883A (1, 5 or 15 mg kg-1 i.v.). 3. The observed eukaliuric diuresis and natriuresis in response to U37883A at 15 mg kg-1 was accompanied by an increase in early distal tubular flow rate (VED) from 10 - 18 nl min(-1) reflecting a reduction in fractional reabsorption of fluid up to this site (FR-fluid) of 13%. The latter proposed an effect on water-permeable segments such as the proximal tubule which could fully account for the observed reduction in fractional reabsorption of Na+ up to the early distal tubule (FR-Na+) of 8% and the increase in early distal tubular Na+ concentration ([Na+]ED) from 35 - 51 mM whereas [K+]ED was left unaltered. 4. In comparison, furosemide (3 mg kg-1 i.v.), which acts in the water-impermeable thick ascending limb, elicited diuresis, natriuresis and kaliuresis which were associated with a fall in FR-Na+ of 10% with no change in FR-fluid, and a rise in [Na+]ED from 42 - 117 mM and [K+]ED from 1.2 - 5.7 mM with no change in VED. 5. Direct late proximal tubular fluid collections confirmed a significant inhibition of fluid reabsorption in proximal convoluted tubule in response to systemic application of U37883A. 6. These findings suggest that the diuretic and natriuretic effect upstream to the distal tubule in response to systemic application of U37883A involves actions on water-permeable segments such as the proximal convoluted tubule.     

Effects of opioid agonists on urine production in neonatal rats

The modulatory effects of opioids on urine production in adult rats have been well-documented. We report here the first investigation of the effects of these agents on urination in neonatal rats. The kappa-agonists U50,488H (1,10 mg kg-1) and (+)-tifluadom (10 mg kg-1) produced an increase in urine output in 10-day old pups whereas the (-)-isomer of tifluadom was ineffective in this model. The diuretic effects of the highest dose of U50,488H were attenuated by a 10 but not a 1 mg kg-1 dose of the opioid antagonist naltrexone. These findings suggest that kappa-agonists, as in adult animals, produce diuresis in neonates by activity at kappa-opioid receptors and also confirm the stereoselective nature of the response. The increase in urination produced by U50,488H (10 mg kg-1) was also reduced by the alpha-adrenoceptor antagonist phentolamine (1 mg kg -1), an observation which supports the hypothesis that kappa-agonists--in addition to their well-established inhibitory effects on the release of antidiuretic hormone--may increase urination via an adrenergic mechanism at the level of the adrenal medulla. The mu-opioid agonist morphine (0.1-10 mg kg-1), in contrast to its observed effects in older animals, did not produce antidiuresis in either normally-hydrated or water-loaded 10-day old rat pups. The results of this study therefore show that the stimulatory effects of kappa-agonists on urine production appear to be fully-functional at 10-days but the inhibitory effects of opioids on urination lag behind in development.     

Ramipril-induced decrease in renal lithium excretion in the rat.

1. The interaction of ramipril, an inhibitor of angiotensin I converting enzyme, with renal lithium handling was analysed in conscious normotensive Wistar rats and compared with the known increase in renal tubular lithium reabsorption induced by the non-steroidal anti-inflammatory drug, indomethacin. 2. The rats were treated for five days with ramipril (1 mg kg-1 day-1 orally), indomethacin (2.5 mg kg-1 day-1 intramuscularly) or their solvents. Lithium chloride (16.7 mg kg-1 intraperitonealy) was given as a single dose on the fifth day and renal functions were measured. 3. Ramipril induced a decrease in renal lithium clearance which was correlated with the decrease in the quantity of filtered lithium and the increase in the tubular fractional reabsorption of the metal. Ramipril also reduced the systolic blood pressure of the rats by about 15 mmHg. 4. In the absence of any effect on creatinine clearance or systolic blood pressure, indomethacin increased renal fractional lithium reabsorption and led to an increase in plasma lithium levels, as previously reported by our group. 5. In conclusions, our results indicate that ramipril decreases renal lithium excretion in Wistar rats, when given orally at a dose of 1 mg kg-1 day-1 over five days.     

Effects of the kappa-opioid agonist U50,488 on parturition in rats.

1. The effects of the kappa-opioid agonist U50,488 on parturition were studied in the rat. 2. Given directly after the birth of the second pup U50,488 (5 mg or 10 mg kg-1, i.p.) delayed the birth of the subsequent 4 pups by ca. 100 min, acting like morphine (10 mg kg-1, i.p.). In controls given the vehicle i.p., the birth of the 4 pups after treatment took 45.4 +/- 4.6 min. The effects of U50,488 could be prevented by simultaneous naloxone injection (10 mg kg-1). Injection of either U50,488 or morphine at 1 mg kg-1, i.v. also significantly delayed parturition. The effects of U50,488 but not of morphine were fully prevented by preinjection with nor-binaltorphimine (0.5 mg kg-1, i.v.) showing selective kappa-opioid receptor-mediated inhibition by U50,488 of established parturition. 3. In rats with an indwelling jugular venous cannula, i.v. injection of U50,488 (5 mg kg-1) after the birth of the second pup slowed parturition in a similar way to i.p. injection and significantly reduced blood plasma oxytocin concentration measured by radioimmunoassay compared with vehicle-injected controls. 4. Bolus i.v. injections of oxytocin (4 mu once per 5 min) significantly reduced the delay in parturition caused by i.v. U50,488, but continuous i.v. infusion of oxytocin (4 mu 5 min-1) was less effective. 5. Since i.v. oxytocin did not immediately reverse the effects of U50,488 on parturition, direct effects of U50,488 on isometric uterine contractions in vitro were sought.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of changes in perfusion pressure and angiotensin II on the renal excretory responses to atrial natriuretic peptides.

The renal actions of atriopeptin III were examined in anaesthetised rats at differing perfusion pressures before and following blockade of the renin-angiotensin system. At normal perfusion pressure 1000 ng kg-1 atriopeptin III caused reversible increases in glomerular filtration rate, of 20%, urine flow, absolute and fractional sodium excretions of 51-93%. Reduction of left renal perfusion pressure to 80 mm Hg decreased glomerular filtration rate by 30% and urine flow, absolute and fractional sodium excretions by 80% while atriopeptin III administration only minimally changed these variables. Concomitantly, right kidney perfusion pressure rose by 15 mm Hg which significantly increased fluid output, while the atriopeptin III induced diuresis and natriuresis were significantly larger. During infusion of captopril 900 micrograms kg-1 h-1 when pressures at the left and right kidneys had been reduced and elevated, respectively, atriopeptin III caused larger excretory responses in both kidneys which were greater than without captopril. These result suggested that the atriopeptin III mediated natriuresis and diuresis were directly proportional to perfusion pressure and attenuated by angiotensin II.     

Effects of intravenous mu and kappa opioid receptor agonists on sensory responses of convergent neurones in the dorsal horn of spinalized rats.

1. Electrophysiological experiments have been performed to assess the effects of intravenously administered mu and kappa opioid agonists on the responses to noxious thermal and mechanical and non-noxious tactile stimuli of single convergent neurones in laminae III-VI of the dorsal horn of spinalized rats anaesthetized with alpha-chloralose. 2. The mu receptor agonists tested were fentanyl (1-16 micrograms kg-1) and morphine (0.5-16 mg kg-1) and the kappa-receptor agonists U-50,488 (1-16 mg kg-1) and tifluadom (0.1-1.6 mg kg-1). Multiple drug tests were made on each cell so that compounds could be compared under closely comparable conditions. 3. In one protocol, thermal and mechanical nociceptive responses of matched amplitudes were elicited alternately. Both mu and kappa agonists dose-dependently reduce the neuronal responses. Thermal nociceptive responses were as sensitive to the kappa agents as were the mechanical nociceptive responses; the mu agonists similarly reduced both types of response in parallel. 4. In another protocol, nociceptive and non-nociceptive responses were elicited alternately to permit the degree of selective antinociception to be assessed. The mu agonists were scarcely selective, fentanyl reducing nociceptive only slightly (but significantly at 4-16 micrograms kg-1) more than non-nociceptive responses. The kappa-opioid agonist U50,488 reduced tactile responses somewhat more than nociceptive responses. 5. The spontaneous discharge of these cells with ongoing activity was reduced to a significantly greater degree than the evoked responses; this is likely to have contributed to the non-selectivity of the reduction of the evoked responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antidiuretic effect of bremazocine and U-50,488 in rats after alpha 2-adrenoceptor blockade.

The role of alpha 2-adrenoceptors and kappa-opioid receptors in urination was studied in rats. In water-loaded rats (40 mL kg-1 p.o.) the kappa-opioid agonist bremazocine (0.05 0.2 mg kg-1 i.p.) induced a dose-related diuretic response in the second hour after administration, but had no effect in the first hour. When rats were pretreated with the alpha 2-adrenoceptor antagonist idazoxan (1 mg kg-1 s.c.), bremazocine induced a dose-related antidiuretic response in the first hour; thereafter the rats showed an increase of urination similar to that with bremazocine alone. The antidiuretic effect of bremazocine was dependent on the dose of idazoxan with maximal response after 1-3 mg kg-1. Similar results were obtained with bremazocine in the presence of yohimbine (1 mg kg-1 s.c.). The antidiuretic profile of bremazocine after idazoxan was shared by U-50,488 (2.5-10 mg kg-1 i.p.), although this compound alone at the high dose reduces urine output in the first hour. The antidiuresis induced by bremazocine in the presence of idazoxan in water-loaded rats was completely antagonized by 10 but not 2 mg kg-1 i.p. of the opioid antagonist naloxone. Thus, kappa-opioid agonists, in addition to their diuretic effect, also produce an antidiuretic response which may be mediated by alpha 2-adrenoceptors.     

Mu-opioid component of the ethylketocyclazocine (EKC) discriminative stimulus in the rat

The opioid receptor selectivity of the EKC discriminative stimulus was characterized in Fischer rats trained to discriminate 0.3 mg/kg EKC (SC) from saline in a twochoice discrete-trial avoidance paradigm. The putative kappa-opioid receptor agonists EKC and U50,488H completely generalized with the EKC aue at doses of 0.3 and 10 mg/kg, respectively. The putative mu-opioid receptor agonists morphine (M) and fentanyl also dose-dependently generalized with the EKC stimulus. The generalization of M with EKC was not symmetrical, EKC and U50,488H produced little or no M-appropriate responding in rats trained to discriminate 3.0 mg/kg M (SC) from saline. This generalization pattern may reflect a lack of opioid receptor selectivity of the EKC stimulus. However, distinct muopioid and kappa-opioid components of the EKC cue could be identified using graded doses of naloxone in EKC-trained rats. The discriminative effects of morphine and fentanyl were blocked completely by doses of 0.1–1.0 mg/kg naloxone, whereas doses of naloxone 3–10 times greater were necessary to block the discriminative effects of EKC and U50,488H. These results suggest that EKC produces a complex discriminative stimulus with mu-opiod and kappa-opioid components that can be separated using antagonists such as naloxone.     

Potentiation of kappa-opioid receptor agonist-induced analgesia and hypothermia by fluoxetine.

The effect of fluoxetine, a selective 5-HT reuptake inhibitor on the analgesic and hypothermic response of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methane sulphonate (U-50,488H) and (+/-)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzo[b] thiophene-4-acetamide (PD 117302), kappa-opioid receptor agonists, was determined in female Sprague-Dawley rats using the tail-flick method and telethermometer, respectively. Intraperitoneal injections of U-50,488H (U50) and PD 117302 (PD117) produced a dose-dependent analgesic and hypothermic response. Fluoxetine (10 mg/kg, i.p.) by itself did not produce an analgesic response. The analgesic response to U50 (10, 20, and 40 mg/kg, i.p.) and PD117 (7.5, 15, and 22.5 mg/kg, i.p.) was potentiated by fluoxetine injected intraperitoneally 60 min prior to the injection of kappa-opioid agonists. Similarly, the hypothermic response of U50 (20 and 40 mg/kg, i.p.) and PD117 (7.5, 15, and 22.5 mg/kg, i.p.) was potentiated by fluoxetine. The results indicate that selective kappa-opioid receptor agonists-induced analgesia and hypothermia is potentiated by fluoxetine, suggesting the role of extracellular 5-HT in the kappa-opioid receptor-mediated analgesia and hypothermia.     

Effects of kappa-opioid receptor agonists and morphine on food intake and urinary output in food-deprived and nondeprived rats

The effects of kappa-opioid receptor agonists, bremazocine, U-50, 488H and tifluadom and of a mu-opioid receptor agonist, morphine, on food intake and urinary output in food-deprived and nondeprived Sprague-Dawley rats was determined. In food-deprived animals, intraperitoneal administration of bremazocine at 0.1 mg/kg increased food intake but at 1.0 and 10.0 mg/kg doses decreased it. Tifluadom (0.1-10.0 mg/kg) had no effect on food intake. U-50,488H at 1.0 mg/kg increased food intake, whereas 10.0 mg/kg dose decreased the food consumption. In nondeprived rats, the kappa-opioid receptor agonists failed to produce any effect on food consumption. In food-deprived rats, all the three kappa-opioid receptor agonists increased the urinary output at the highest dose (10 mg/kg). In nondeprived rats similar effects as in food-deprived rats were observed except bremazocine increased urinary output at all the doses used. These results with kappa-opioid agonists may be related to either the existence of more than one population of kappa-opioid receptors or their differential actions at the opioid receptor types.     

Studies on the adrenomedullary dependence of kappa-opioid agonist-induced diuresis in conscious rats.

1. The dependence of kappa-opioid agonist-induced diuresis, upon an intact and functional adrenal medulla in conscious rats, was investigated in order to test the hypothesis that the diuresis is mediated by a blood-borne 'diuretic factor', of adrenomedullary origin, released by kappa-opioid receptor stimulation. 2. Confirming previous observations, adrenal demedullation significantly attenuated diuretic responses to the kappa-opioid agonists U50488H, ethylketocyclazocine (EKC) and tifluadom, but did not affect basal urine output, furosemide-induced diuresis or the antidiuretic response to the mu-opioid agonist, buprenorphine. Naloxone abolished U50488H-induced diuresis, confirming an involvement of opioid receptors. 3. Transfusion studies established that blood, from intact rats treated with U50488H, induced diuresis in intact and demedullated recipient rats, whether or not the recipients had been pretreated with naloxone. However, blood from demedullated rats treated with U50448H was unable to induce diuresis when administered to intact or demedullated recipients. 4. It is concluded that kappa-opioid agonist-induced diuresis is dependent upon an intact and functional adrenal medulla and appears to be mediated by a blood-borne 'diuretic factor' of adrenomedullary origin.     

Chronic opioid treatment of the mouse thymoma cell lines R1.G1 and R1EGO leads to down-regulation of the kappa opioid receptor without desensitization of adenylyl cyclase activity

Kappa opioid agonists alter some immune functions of macrophages, and T- and B-lymphocytes. The mouse thymoma cell lines R1.G1 and R1EGO express only kappa-opioid receptors and these kappa-opioid receptors are coupled to an inhibitory GTP-binding regulatory protein. Binding of kappa-opioid agonists to the opioid receptor leads to the inhibition of adenylyl cyclase activity in these cells. In this study, an acute (15 min) and chronic (24 h) treatment of R1.G1 and R1EGO cell with a potent kappa-opioid agonist (-)U50,488 (100 nM) was studied to determine if a kappa-opioid agonist altered receptor number and/or desensitization of adenylyl cyclase activity in these two cell lines. Chronic treatment of both R1.G1 and R1EGO cells with (-)U50,488 lead to down-regulation of the kappa-opioid receptor, measured as a decrease of approximately 50% in the Bmax value for the binding of [3H]U69,593. The binding affinity (Kd value) was not affected after chronic treatment either in R1.G1 or R1EGO cells. There was no difference in the magnitude of inhibition of adenylyl cyclase activity by (-)U50,488 between the acute (15 min) and chronic (24-h) treatment in both cell lines R1.G1 and R1EGO. This study indicates that chronic opioid treatment of mouse thymoma R1.G1 and R1EGO cell lines leads to down-regulation of the receptor, without desensitization. This phenomenon was observed in R1.1 parent mouse thymoma cell line and recently in CHO cells expressing kappa-opioid receptor. This study demonstrates that unlike some neuronal preparations, chronic opioid treatment of the thymoma cell lines resulted in receptor down-regulation without desensitization.     

Stereospecificity of the effects of ozolinone on renal hemodynamics and on segmental tubular sodium reabsorption in conscious rats

The study was performed to elucidate the effects of the two stereoisomers of ozolinone (d,l) on renal hemodynamics and proximal tubular Na reabsorption. Clearance experiments were performed in conscious water-loaded female Wistar rats. The clearances of [3H]inulin, [14C]tetraethylammonium and lithium were used as estimates for glomerular filtration rate, renal plasma flow and delivery of fluid from the proximal tubules, respectively. When the baseline parameters had stabilized, d- or l-ozolinone was injected i.v. in doses of 4, 20 and 100 mg/kg. 1-Ozolinone caused a transient and dose-dependent diuretic-natriuretic response with no evidence of a ceiling. At peak natriuresis, 2.5-5 min after 100 mg/kg of 1-ozolinone, the fractional Na excretion was increased from 0.5 to 25%; this was associated with an increased fractional excretion of lithium from 27 to 60%, and small transient decreases of renal hemodynamic parameters. d-Ozolinone had no significant effects except for a small natriuresis after 100 mg/kg. It is concluded that in water-loaded conscious rats 1-ozolinone is a powerful diuretic which, in contrast to d-ozolinone, increases the delivery of fluid from the proximal tubule as judged from changes in lithium clearance.     

Kappa opioid-induced diuresis in female vs. male rats

Kappa opioid agonists may produce dissimilar discriminative and analgesic effects in female vs. male subjects. The present study was conducted to determine whether a prototypic physiological effect of kappa agonists--diuresis--also differs between the sexes. When data were not corrected for individual differences in body weight, the kappa agonists U69,593 (0.03-3.0 mg/kg), U50,488 (0.3-10 mg/kg), (-)-bremazocine (0.001-0.1 mg/kg) and (-)-pentazocine (1-10 mg/kg), as well as a nonopioid diuretic, furosemide (1-10 mg/kg) produced significantly greater diuresis in normally hydrated, age-matched males than females; however, there was no sex difference in the diuretic effect of butorphanol (0.3-3.0 mg/kg), or in the antidiuretic effect of the mu agonist morphine (1.0-5.6 mg/kg, in water-loaded rats). In contrast, when data were corrected for individual difference in body weight, U69,593, U50,488, (-)-bremazocine, (-)-pentazocine, and furosemide produced nearly equivalent diuresis/kg in females and males, whereas butorphanol produced slightly greater diuresis/kg, and morphine produced significantly less antidiuresis/kg, in females than males. U69,593-induced diuresis was highly similar in males and females of similar body weight (i.e., different ages). U69,593 effects were dose-dependently antagonized by the kappa antagonist nor-binaltorphimine in both sexes, indicating a common, kappa receptor-mediated mechanism of action. (-)-Bremazocine was slightly more potent in suppressing vasopressin in 24-h water-deprived males than females. These results suggest that the greater diuretic effects of kappa receptor-selective opioid agonists in male rats are primarily due to males' larger body size (greater body water) relative to age-matched females, but may also be attributed to slightly greater vasopressin suppression in males.     

Effect of kappa-opioid receptor agonists on morphine analgesia in morphine-naive and morphine-tolerant rats

The effect of i.p. administration of kappa-opioid receptor agonists, bremazocine, tifluadom and U-50,488H on morphine (8 mg/kg i.p.)-induced analgesia in morphine-naive and morphine tolerant male Sprague-Dawley rats was determined using the tail-flick test. The tolerance to morphine in the rats was induced by s.c., implantation of six morphine pellets during a 7-day period. Implantation of morphine pellets resulted in the development of tolerance as evidenced by the decrease in the analgesic response to morphine when compared to placebo pellets implanted rats. Bremazocine (0.3, 1.0 and 3.0 mg/kg) and U-50,488H (16 mg/kg) antagonized morphine-induced analgesia in morphine-naive rats while tifluadom (8 and 16 mg/kg) potentiated the effect. In morphine-tolerant rats, bremazocine (3 mg/kg) and U-50,488H (16 mg/kg) potentiated morphine-induced analgesia. Tifluadom at any of the doses had no effect on morphine-induced analgesia in morphine-tolerant rats. These results provide evidence that different kappa-opioid agonists modify morphine-induced analgesia differentially in morphine-naive and morphine-tolerant rats.     

Renal effects of torasemide in the rat. Clearance and micropuncture studies

The effects of torasemide on renal glomerular and tubular functions were studied in rats using clearance and micropuncture techniques. A dose-response relationship of torasemide in the range of 0.2-20 mg/kg b.w. on the increase of urine volume, urinary sodium and potassium excretion was established. The effect of a dose of 0.2 mg/kg b.w. torasemide was completely abolished by preinjection of 10 mg/kg probenecid, whereas the effects of higher doses remained unchanged. Torasemide had no significant effect on glomerular filtration rate. Proximal fractional reabsorption was not influenced. A remarkable depression of fluid and electrolyte reabsorption, however, occurred in the loop of Henle after torasemide under free flow conditions, as well as in functionally isolated microperfused loops of Henle. No further inhibition of fluid and electrolyte reabsorption between the early distal convoluted tubules and the final urine could be detected. In contrast, a compensatory increase of reabsorption was observed in this part of the nephron. The activity of the tubuloglomerular feedback system was completely and reversibly blocked by torasemide. Torasemide did not differ from other typical loop diuretics with respect to the different renal actions studied here.