Effects of furosemide on renal haemodynamics and proximal tubular sodium reabsorption in conscious rats.

1. The effects of furosemide given as constant i.v. infusion (7.5 mg kg-1 h-1) or bolus injections (0.5, 7.5 and 120 mg kg-1) on renal haemodynamics and proximal tubular Na reabsorption were studied in conscious water diuretic rats. The clearance of Li (CLi) was used as marker for Na delivery from the proximal tubules, and clearance of [14C]-tetraethylammonium (CTEA) and [3H]-inulin (CIn) as markers for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively. 2. Furosemide caused a transient increase of RPF and GFR followed by a secondary decrease below baseline levels; the latter could in part be counteracted by volume replacement. The filtration fraction (FF = GFR/RPF) was not significantly changed by furosemide. Fractional proximal Na excretion (CLi/CIn) was significantly increased by all doses of furosemide independent of changes in RPF, GFR and FF. 3. The peak diuretic/natriuretic effect of furosemide was markedly potentiated by volume replacement, probably due to prevention of antinatriuretic mechanisms triggered by volume depletion. 4. It is concluded that following i.v. furosemide administration there is a biphasic change in renal haemodynamics in conscious, restrained rats, and that the inhibition of proximal Na reabsorption, as manifested by changes in fractional Li excretion, is not likely to be due to changes in total renal haemodynamics.     

Furosemide inhibits the centrally-mediated pressor response to clonidine in conscious, normotensive rats.

1. The effect of furosemide on the pressor response induced by intracerebroventricular (i.c.v.) injection of clonidine was investigated in freely moving, normotensive rats with chronically implanted arterial catheters. 2. When injected i.c.v., clonidine at doses of 5 and 10 micrograms produced a dose-dependent pressor response and a decrease in heart rate. No depressor response was induced by clonidine. 3. Systemic (i.v.) pretreatment with furosemide (2-10 mg kg-1) increased urine volume and dose-dependently inhibited the pressor response to i.c.v. clonidine (10 micrograms), and a long-lasting depressor response to clonidine was observed. However, furosemide treatment did not alter the bradycardia produced in response to clonidine. 4. The systemic treatment with furosemide (10 mg kg-1, i.v.) had no effect on the pressor response to i.v. noradrenaline. 5. These results suggest that reduction of body fluid volume inhibits the centrally-mediated pressor response to clonidine and leads to the hypotensive effect. We also suggest that combined treatment with a diuretic increases the hypotensive efficacy of clonidine.     

Diuretic action of the novel loop diuretic torasemide in the presence of angiotensin II or endothelin-1 in anaesthetized dogs.

The effects of torasemide (0.1 and 1 mg kg-1, i.v.) and furosemide (3 mg kg-1) on renal haemodynamics and excretory responses in the presence of angiotensin II and endothelin-1 was examined in anaesthetized dogs. Angiotensin II or endothelin-1 was continuously infused into the renal artery throughout the experiment and a bolus of torasemide or furosemide was injected into the bracheal vein. Continuous intrarenal arterial (i.r.a.) infusion of angiotensin II, at a dose of 5 ng kg-1 min-1, increased renal vascular resistance (RVR) and decreased renal blood flow (RBF) and glomerular filtration rate (GFR), but had no effect on systemic mean arterial pressure (MAP). Urinary excretion of sodium (UNaV) and urine flow (UF) were significantly decreased during angiotensin II infusion. Intravenous injections of torasemide in the presence of angiotensin II caused a dose-dependent increase in UF, UNaV and urinary excretion of potassium (UKV), while a decrease in RVR was accompanied by an increase in RBF. UKV was greater in the furosemide group than in the torasemide group, despite both groups having the same degree of aquaresis and natriuresis. Continuous i.r.a. infusion of endothelin-1, 1.5 ng kg-1 min-1, produced effects similar to those of angiotensin II on renal haemodynamics; however, the onset of action was extremely slow compared with the effects produced by angiotensin II. Endothelin-1 caused a significant decrease in UF, UNaV and UKV only at a later period, despite a relatively early depression of renal haemodynamics. Torasemide and furosemide also produced a sufficient diuretic action in this model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Input rate as a major determinant of furosemide pharmacodynamics: influence of fluid replacement and hypoalbuminemia.

To investigate how the response to a bolus and an infusion of furosemide is modulated by the rate of fluid replacement and by hypoalbuminemia, rabbits received 5 mg/kg of furosemide as a bolus or infused over 60 min, whereas diuresis was replaced with 13, 121, or 238 ml/h NaCl 0.9%/glucose 5% (50:50). Natriuretic and diuretic efficiencies were greater with the infusion than with the bolus of furosemide. Fluid replacement increased natriuretic and diuretic efficiency of furosemide bolus but only diuretic efficiency of furosemide infusion. Furosemide net fluid depletion reached a plateau when fluid replacement increased beyond 121 ml/h. Repeated plasmapheresis decreased plasma albumin by 30% (P <.05) and increased furosemide unbound fraction (P <.05). Compared with control rabbits, hypoalbuminemia decreased the natriuresis of the bolus (22.7 +/- 1.5-16.6 +/- 1.3 mmol, P <.05) but not that elicited by furosemide infusion (26.2 +/- 1.8 mmol). Given as a bolus, furosemide natriuretic and diuretic response as a function of its urinary rate of excretion exhibited an hyperbolic relationship, and after its infusion a clockwise hysteresis, denoting tolerance. Plasma renin activity was increased by the bolus and the infusion of furosemide, even in the presence of 121 ml/h of fluid replacement. It is concluded that: 1) the increase in natriuretic/diuretic efficiency of the bolus induced by fluid replacement is greater than when furosemide is infused, 2) furosemide net effect does not increase proportionally to fluid replacement, and 3) the infusion of furosemide prevents the hypoalbuminemia-induced decrease in response of furosemide given as a bolus.     

The neuroprotective action of dizocilpine (MK-801) in the rat middle cerebral artery occlusion model of focal ischaemia.

1. An acute model of focal ischaemia, which involves permanent occlusion of the middle cerebral artery of the rat with 4 h survival, was used to find the minimum effective plasma concentration of dizocilpine (MK-801) and to determine its dose-effect relationship. 2. MK-801 was administered at the time of occlusion and was given as an i.v. bolus followed by an infusion for 4 h to maintain a steady state plasma concentration of the drug throughout the study. MK-801 was given at 3 dose levels; 0.04 mg kg-1 i.v. bolus + 0.6 micrograms kg-1 min-1 infusion; 0.12 mg kg-1 i.v. bolus + 1.8 micrograms kg-1 min-1 infusion; 0.4 mg kg-1 i.v. bolus + 6 micrograms kg-1 min-1 infusion, which gave mean plasma levels over the 4 h of 8.0 ng ml-1, 18.9 ng ml-1 and 113.2 ng ml-1 respectively. 3. MK-801 at 8.0 ng ml-1 gave 10% reduction in the volume of ischaemic brain damage in the cerebral cortex which just reached significance. The middle dose of MK-801 (18.9 ng ml-1) gave a highly significant reduction in the volume of ischaemic brain damage in the cerebral cortex and hemisphere, volumes of ischaemic tissue being reduced by 60% and 50% compared to saline-treated animals, respectively. The highest plasma concentration of MK-801 (113.2 ng ml-1) resulted in a 35% reduction in the volume of hemispheric damage and a 40% reduction in the volume of cortical damage, which were significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional and cardiac haemodynamic effects of NG-nitro-L-arginine methyl ester in conscious, Long Evans rats.

1. Regional haemodynamic responses to i.v. bolus doses (0.1-10.0 mg kg-1) of NG-nitro-L-arginine methyl ester (L-NAME) were measured in conscious, Long Evans rats (n = 8) chronically instrumented with renal, mesenteric and hindquarters pulsed Doppler flow probes and intravascular catheters. 2. L-NAME caused dose-dependent pressor effects associated with renal, mesenteric and hindquarters vasoconstrictions. The mesenteric vascular bed showed earlier onset with more rapid, and greater, maximum vasoconstrictions than the renal or hindquarters vascular beds; however, the hindquarters vasoconstriction was more persistent. D-NAME was without significant effects (n = 2). 3. Primed infusion of L-arginine (100 mg kg-1 bolus followed by 100 mg kg-1 h-1 infusion), starting 10 min after an i.v. bolus injection of L-NAME (10 mg kg-1), caused significant reversal of the pressor responses, and renal and mesenteric vasoconstrictions, but not of the hindquarters vasoconstriction. Primed infusions of L-arginine (100 mg kg-1, 100 mg kg-1 h-1) starting 5 min after L-NAME (1 mg kg-1) additionally caused some reversal of the hindquarters vasoconstriction, but this effect was transient. 4. Primed infusion of L-arginine (100 mg kg-1, 100 mg kg-1 h-1) starting 30 min before i.v. bolus injection of L-NAME (10 mg kg-1) caused significant attenuation of the pressor effects and the renal and mesenteric vasoconstrictions but not of the hindquarters vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thrombolytic effect of a plasminogen-plasminogen activator chimera in a photochemically induced thrombosis (PIT) model.

The thrombolytic effects of the plasminogen/plasminogen activator chimera (SUN9216), comprising the fibrin-binding kringle 1 domain of plasminogen and two kringle and the serine protease domain of the wild-type tissue plasminogen activator (t-PA) including a modification of the mannose glycosylation on the kringle 1 of t-PA (PK1 delta FE1X), was compared with tht of t-PA by use of a photochemically induced thrombus (PIT) in the rat femoral artery. When SUN9216 was administered either as an i.v. infusion (1.0 mg kg-1) or as a single bolus i.v. injection (1.0 mg kg-1), all parameters were markedly improved compared to t-PA administered as an i.v. infusion (3.0 mg kg-1). A higher concentration of plasminogen activator (PA) activity in plasma was observed after administration of SUN9216 which persisted for longer than that after t-PA. It is concluded that the thrombolytic effect of SUN9216 is markedly greater than that of t-PA.     

Effect of route of administration on the relative efficacy and potency of 2-aminoethyl-4-(1,1-dimethylethyl)-6-iodophenol HCl (MK447) and furosemide

2-Aminoethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (MK447) is a chemically novel diuretic that has oral efficacy and potency greater than furosemide (FUR). In this study, the relative efficacy and potency of MK447 and FUR were assessed following oral, i.v. bolus and i.v. infusion administration in rats and dogs. MK447 was more potent than furosemide but the two were equally efficacious when administered orally to rats and dogs. The relative potency remained unchanged when administered as an i.v. bolus to rats (1 mg/kg). However, when infused continuously there was no difference in potency or efficacy between the two compounds. These observations lead to the conclusion that pharmacokinetic differences between the two compounds play a major role in determining their relative oral potency. Comparative studies of the effects of compounds given by different routes of administration are useful in providing insight into the role of pharmacokinetics in overall response to different compounds.     

The relationship of the pharmacokinetics of chloroquine to dose in the rabbit

Four albino rabbits were treated with 4 different doses of chloroquine phosphate (30-50 mg kg-1) given intragastrically and 10 others were given the hydrochloride (2.5-12.5 mg kg-1 i.v.). The i.v. doses were given as bolus into the median ear vein over 5-8 min. Samples (3-5 mL) of whole blood were subsequently collected at intervals for up to 6 weeks and analysed by HPLC. From the results, log concentration-time curves were drawn and the i.v. data fitted by computer to 3-compartment (8 rabbits) or 2-compartment curves (2 rabbits). The area under the curve (AUC) and half-lives were calculated for the different doses. A plot of AUC versus dose yielded a straight line but the half-lives showed wide inter-individual variation from the same doses.     

The pharmacological modulation of thrombin-induced cerebral thromboembolism in the rabbit.

1. Intracarotid (i.c.) administration of thrombin induced a marked accumulation of 111indium-labelled platelets and 125I-labelled fibrinogen within the cranial vasculature of anaesthetized rabbits. 2. Thrombin (100 iu kg-1, i.c.) - induced platelet accumulation was completely abolished by pretreatment with desulphatohirudin (CGP 39393; 1 mg kg-1 i.c., 1 min prior to thrombin). Administration of CGP 39393 1 or 20 min after thrombin produced a significant reduction in platelet accumulation. 3. Intravenous (i.v.) administration of the platelet activating factor (PAF) receptor antagonist BN 52021 (10 mg kg-1) 5 min prior to thrombin (100 iu kg-1, i.c.) had no effect on platelet accumulation. 4. An inhibitor of NO biosynthesis, L-NG-nitro arginine methyl ester (L-NAME; 100 mg kg-1, i.c.), had no significant effect on the cranial platelet accumulation response to thrombin (10 iu kg-1, i.c.) when administered 5 min prior to thrombin. 5. Defibrotide (32 or 64 mg kg-1 bolus i.c. followed by 32 or 64 mg kg-1 h-1, i.c., infusion for 45 min) treatment begun 20 min after thrombin (100 iu kg-1, i.c.) did not significantly modify the cranial platelet accumulation response. 6. Cranial platelet accumulation induced by thrombin (100 iu kg-1, i.c.) was significantly reversed by the fibrinolytic drugs urokinase (20 iu kg-1, i.c., infusion for 45 min), anisoylated plasminogen streptokinase activator complex (APSAC) (200 micrograms kg-1, i.v. bolus) or recombinant tissue plasminogen activator (rt-PA; 100 micrograms kg-1, i.c. bolus followed by 20 micrograms kg-1 min-1, i.c., infusion for 45 min) administered 20 min after thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of prostanoid TP- and DP-receptors in the bronchoconstrictor effect of inhaled PGD2 in anaesthetized guinea-pigs: effect of the DP-antagonist BW A868C.

1. In anaesthetized, pump-ventilated guinea-pigs, bolus intravenous injection of prostaglandin D2 (PGD2 5-160 micrograms kg-1) caused a dose-dependent rise in both heart rate and systemic mean arterial blood pressure with only a small monophasic rise in pulmonary inflation pressure (PIP). 2. In contrast, inhaled PGD2 (0.1-1 mg ml-1, 30s) provoked a substantial concentration-dependent biphasic rise in PIP. The bronchoconstrictor action of inhaled PGD2 was accompanied by minimal cardiovascular effects. 3. The 3-benzyl substituted hydantoin BW A868C (0.1-1 mg kg-1 i.v.) a novel prostanoid DP-receptor antagonist, had no significant effect on the cardiovascular or bronchoconstrictor effects of intravenously administered or inhaled PGD2. 4. However, BW A868C (0.1-1 mg kg-1 i.v.) did inhibit the hypotensive actions of the DP-receptor agonist, BW 245C (1-3 micrograms kg-1 i.v.). 5. The prostanoid TP-receptor antagonist BM 13.177 (2.5 mg kg-1 i.v.) strongly inhibited the bronchoconstrictor effect of inhaled PGD2, abolishing the first phase of this response and reducing the peak increase in PIP provoked by PGD2 (0.1 or 1 mg ml-1 for 30 s), by 67 +/- 16% and 44 +/- 5% respectively. 6. A combination of BW A868C (0.1 or 1 mg kg-1 i.v.) with BM 13.177 (2.5 mg kg-1 i.v.) produced no greater inhibition of the bronchoconstrictor effect of inhaled PGD2 than that seen with BM 13.177 (2.5 mg kg-1 i.v.) alone. 7. Neither bilateral vagotomy, nor selective inhibition of arachidonate cyclo-oxygenase with indomethacin or 5-lipoxygenase with the novel acetohydroxamic acid BW A4C, significantly reduced the bronchoconstrictor effect of inhaled PGD2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of calcium channel blockers on postprandial gastrointestinal motility in the dog.

We have compared the ability of nifedipine and lacidipine, a new 1,4-dihydropyridine, to interfere with postprandial gastrointestinal motility. Five conscious dogs, fitted with 8 bipolar electrodes along the gastrointestinal tract, were studied. Gastrointestinal spike activity was evaluated by means of a computer system. Lacidipine (8 micrograms kg-1) was administered as an i.v. bolus immediately followed by a 10 micrograms kg-1 h-1 i.v. infusion for 3 h, starting 30 min before a standard meal. This dose of lacidipine decreased systolic blood pressure by approximately 20%. Nifedipine was used at equihypotensive doses (30 micrograms kg-1 i.v. bolus followed by 300 micrograms kg-1 h-1 i.v. infusion). Lacidipine had no effect on either gastric or intestinal postprandial spike activity. Nifedipine significantly delayed the appearance of the fed pattern and reduced the number of spikes in the small bowel, while it had no effect on gastric spike activity. We conclude that equihypotensive doses of lacidipine and nifedipine differ in their effects on the gastrointestinal tract, lacidipine having a better cardiovascular selectivity profile than nifedipine, and that the sensitivity to nifedipine varies in different parts of the gut.     

Pharmacokinetics of morphine and its surrogates. XI: Effect of simultaneously administered naltrexone and morphine on the pharmacokinetics and pharmacodynamics of each in the dog

There were no dramatic modifications of the pharmacokinetics in the dog of i.v. bolus doses of 0.5, 2.7 and 5 mg kg-1 morphine by coadministering i.v. 5 mg kg-1 naltrexone as bolus injections over 15-20s and 12.3 mg kg-1 by continuous infusion. Morphine's terminal half-life, clearances, apparent volumes of distribution (except for that of the central compartment), percentages of drug and conjugated metabolite excreted in urine and bile did not differ significantly by paired t-test (probability (p) greater than 0.05 for rejection of the null hypothesis of no difference) when naltrexone was coadministered. There were no statistically significant (by t-test) modifications of the plasma pharmacokinetics in the dog of i.v. bolus doses of 5 mg kg-1 naltrexone with and without morphine coadministration except for the coefficient of the second (or terminal) exponential of the sum that fitted the plasma concentration-time data of naltrexone. Although morphine coadministration did not significantly affect the terminal half-life of naltrexone, its clearances or apparent volumes of distribution by t-test of the differences between averages (with each dog equally weighted), drug coadministration did significantly (by t-test) affect the fraction of naltrexone dose secreted into bile as conjugate (fB), the fraction of the dose excreted as conjugate in urine, and the fraction excreted elsewhere (f'B). Although naltrexone reversed the central action of morphine in affecting monitored pupil diameters, it did not antagonize the peripheral effects of morphine in perturbing renal and biliary flow rates. This led to a larger fraction of the naltrexone dose being metabolized to conjugate on morphine coadministration. Since less naltrexone conjugate was renally and biliary excreted initially, due to morphine inhibition of the initial renal and biliary processes, naltrexone conjugate plasma concentrations were higher when morphine was coadministered.     

PHARMACOLOGICAL PROFILE OF ORALLY ADMINISTERED YM087, A VASOPRESSIN ANTAGONIST, IN CONSCIOUS RATS

1. YM087 is a newly synthesized non-peptide arginine vasopressin (AVP) antagonist that shows high affinity for both V1A and V2 receptors. In the present study, the V1A and V2 receptor antagonist effects of orally administered YM087 were assessed in conscious rats. 2. In conscious rats, orally administered YM087 (0.1, 0.3 and 1.0 mg/kg) did not affect basal blood pressure, but YM087 dose-dependently inhibited 30 mU/kg, i.v., AVP-induced pressor responses. This inhibition lasted for over 8 h following the oral administration of the highest dose of YM087 (1 mg/kg). 3. In rats deprived of water and food for 16-18 h, oral administration of YM087 (0.1, 0.3, 1 and 3 mg/kg) dose-dependently increased urine volume and reduced urine osmolality, with associated increases in urinary sodium and potassium excretion. However, these increases in electrolyte excretion were lower than those seen at comparable diuretic doses of furosemide (3, 10, 30 and 100 mg/kg, p.o.). 4. Oral administration of YM087 (0.3, 1 and 3 mg/kg) produced a dose-dependent increase in urine volume in rats allowed free access to water, with the diuretic effect peaking 2-4 h post-dosing at all dose levels. The diuretic effect of YM087 was sustained 8-10 h after a dose of 3 mg/kg; this is in contrast with the transient diuresis seen after furosemide (100 mg/kg, p.o.) dosing. 5. The present results demonstrate that YM087 is an orally active AVP antagonist with potent and long-lasting effects. YM087 suppressed V1A receptor-mediated pressor responses to AVP with minimal effects on basal haemodynamics and exerted a diuretic effect without increased electrolyte excretion by inhibiting V2 receptor-mediated water reabsorption.     

On the selectivity of intravenous mu- and kappa-opioids between nociceptive and non-nociceptive reflexes in the spinalized rat.

1. In electrophysiological experiments in spinalized, alpha-chloralose anaesthetized rats, opioids and anaesthetics were tested intravenously (i.v.) on the responses of individual motoneurones to alternating noxious (heat or pinch) and non-noxious (tap or vibration) stimuli. 2. On cells that were sensitive to low doses of mu-opioids, both fentanyl (0.5-4 micrograms kg-1 i.v.) and morphine (0.5 mg kg-1 i.v.) selectivity reduced reflexes to noxious stimuli to a greater degree than the higher doses required to reduce nociceptive reflexes (fentanyl 8 micrograms kg-1 i.v.; morphine 1-8 mg kg-1 i.v.) depressed non-nociceptive reflexes to a similar degree. 3. A similar spectrum of selectivity was seen with U-50,488 (0.5-16 mg kg-1 i.v.) although statistically significant selective depression of reflexes was only evident at the lowest dose tested (0.5 mg kg-1 i.v.). All effects of U-50,488 were readily reversed by low doses of the opioid antagonist, naloxone (10-100 micrograms kg-1 i.v.). 4. The dissociative anaesthetic/PCP ligand ketamine (0.5-4 mg kg-1 i.v.) was similar in having selective actions at low doses on sensitive cells but non-selective actions when higher doses were required. In contrast, the general anaesthetics methohexitone (4 mg kg-1 i.v.) and alphadolone/alphaxalone (1 mg kg-1 i.v.) were consistently non-selective between reflexes to noxious and non-noxious stimuli. alpha-Chloralose (20-40 mg kg-1 i.v.) had very little effect on reflexes to any of the synaptic inputs tested.     

Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxic shock in the anaesthetized rat.

1. This study investigates the effects of the non-selective ETA/ETB receptor antagonist, SB 209670, on systemic haemodynamics, renal function, liver function, acid-base balance and survival in a rat model of endotoxic shock. 2. Injection of E. coli lipopolysaccharide (LPS, 10 mg kg-1, i.v.) resulted in increases in the serum levels of tumour necrosis factor-alpha (TNF-alpha, maximum 60 min after LPS), endothelin-1, (ET-1; maximum 120 min after LPS), and interferon-gamma (IFN-gamma, maximum 180 min after LPS). 3. Injection of LPS also resulted in a fall in blood pressure from 113 +/- 3 mmHg (time = 0) to 84 +/- 4 mmHg at 360 min (n = 15) as well as a hyporeactivity to the vasoconstrictor responses elicited by noradrenaline (NA, 1 microgram kg-1, i.v.). Pretreatment of rats with a continuous infusion of SB 209670 (3 mg kg-1, i.v. bolus + 100 micrograms kg-1, i.v. infusion commencing 15 min prior to LPS) significantly augmented the hypotension as well as the vascular hyporeactivity to NA caused by endotoxaemia. 4. Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus given 15 min prior to LPS) or infusion of SB 209670 (bolus dose and infusion as above) resulted in a reduction in 6 h-survival from 71% (control) to 30% and 13%, respectively. 5. Endotoxaemia for 4 h resulted in rises in the serum levels of urea and creatinine (indicators of renal failure), but not in the serum levels of bilirubin, GPT and GOT (indicators of liver dysfunction and/or hepatocellular injury). Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus 15 min prior to LPS) significantly augmented the serum levels of creatinine, bilirubin, GPT and GOT caused by endotoxin. In addition, endotoxaemia caused, within 15 min, an acute metabolic acidosis (falls in pH, HCO3- and base excess) which was compensated by hyperventilation (fall in PaCO2). Pretreatment of LPS-rats with SB 209670 (3 mg kg-1, i.v. bolus) significantly augmented the metabolic acidosis caused by LPS. 6. Thus, the non-selective ETA/ETB receptor antagonist, SB 209670, augments the degree of (i) hypotension, (ii) vascular hyporeactivity to noradrenaline, (iii) renal dysfunction and (iv) metabolic acidosis caused by endotoxin in the anaesthetized rat. In contrast to rats treated with LPS alone, LPS-rats treated with SB 209670 exhibited liver dysfunction and hepatocellular injury. We propose that the release of endogenous ET-1 serves to maintain blood pressure and subsequently organ perfusion in septic shock.     

Pharmacodynamics and pharmacokinetics of the basic triamterene analogue dimethylaminohydroxypropoxytriamterene

The diuretic, natriuretic and potassium retaining effects of dimethylaminohydroxypropoxytriamterene (RPH 2823), a basic triamterene derivative, were studied in male Wistar rats. Compared to triamterene (TA) RPH 2823 has a pronounced effect on urine volume and on the excretion of sodium; in addition it possesses a higher antikaliuretic potency than TA. In combination with furosemide, 2.5 mumol/kg RPH 2823 can avoid the kaliuresis of 25 mumol/kg furosemide. The pharmacokinetics of RPH 2823 after i.v. application of 1 mg/kg and 5 mg/kg were studied in female rats. The substance is not metabolized. RPH 2823 has a terminal elimination half-life of 3 h. About 47% of the given dose are excreted unchanged with urine. Furthermore, the volume of distribution VD beta and the total body clearance were calculated.     

Factors affecting the regional haemodynamic responses to glyceryl trinitrate and molsidomine in conscious rats.

1. A series of experiments was performed in conscious, unrestrained, male, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics. 2. Infusion of glyceryl trinitrate (GTN, 0.1 mg kg-1 min-1, i.v.) for 10 min elicited tachycardia, but no sustained change in mean arterial blood pressure. Renal haemodynamics were unaffected, but there were reductions in hindquarters flow and vascular conductance together with substantial increases in flow and conductance in the mesenteric vascular bed. 3. In the presence of captopril (2 mg kg-1 bolus, and 1 mg kg-1 h-1 infusion, i.v.) GTN elicited significant hypotension and increases in renal blood flow and vascular conductance, indicating that activation of the renin-angiotension system opposed the dilator effects of GTN in this vascular bed. However, the mesenteric and hindquarters haemodynamic effects of GTN were not affected by captopril. In contrast, in the presence of enalaprilat (2 mg kg-1 bolus, and 1 mg kg-1 h-1 infusion, i.v.) there was significant enhancement of the mesenteric, as well as renal, haemodynamic effects of GTN. Hence, these results provide no evidence for the sulphydryl groups in captopril exerting a specific effect to enhance the haemodynamic actions of GTN in our experimental protocols. 4. Administration of molsidomine alone (1 mg kg-1, i.v. bolus) elicited tachycardia and hypotension; there were no changes in mesenteric or hindquarters haemodynamics, but renal flow and vascular conductance fell. Thus, the hypotensive effect of molsidomine was probably due to a reduction in cardiac output, consequent upon venodilatation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological properties of the novel highly potent diuretic 7-chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt.

7-Chloro-2,3-dihydro-1-(2-methylbenzoyl)-4(1H)-quinolinone 4-oxime-O-sulfonic acid potassium salt (M17055, CAS 114417-20-8) showed potent diuretic and saluretic effects dose-dependently, in rats (p.o.), mice (p.o.) and dogs (i.v.), at doses of 0.1-100 mg/kg, 0.3-100 mg/kg and 0.01-30 mg/kg, respectively. The efficacy of M17055 for diuresis, natriuresis and chloruresis was much higher than that of hydrochlorothiazide and almost the same as that of furosemide. These results indicate that this compound may be classified as a "high ceiling diuretic". The potencies of M17055 for natriuresis in rats (p.o.), mice (p.o.) and dogs (i.v.) calculated with ED50 values were 38, 34 and 24 times, respectively, more potent than those of furosemide. Urinary excretions of sodium, chloride and potassium increased in parallel with urinary volume with the administration of M17055 or furosemide, whereas an apparent dissociation with urinary calcium and sodium excretion was observed with M17055 alone. In rats, the increase of urinary calcium excretion with M17055 was significantly lower than that with furosemide under comparable conditions of natriuresis. Moreover, in mice, M17055 decreased urinary calcium excretion at doses with low effectiveness. In clearance studies using anesthetized dogs, M17055 suppressed negative free water clearance (CH2O) under saline loaded conditions, and it decreased positive CH2O under water diuretic conditions. These changes in the effects on CH2O induced by M17055 resemble those of loop diuretics. However, M17055 could not shift negative CH2O to positive, while furosemide was able to do so. Moreover, positive CH2O decreased to nearly zero with M17055, while urine remained dilute with furosemide even at 30 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interactions between the vascular peptide endothelin-1 and sensory neuropeptides in gastric mucosal injury.

1. The interactions between endogenous and exogenous sensory neuropeptides on gastric mucosal injury induced by endothelin-1 (ET-1) have been investigated in the anaesthetized rat. 2. Close intra-arterial infusion of ET-1 (4-20 pmol kg-1 min-1) dose-dependently induced vasocongestion and haemorrhagic necrosis in the gastric mucosa. 3. Capsaicin-pretreatment, two weeks earlier to deplete sensory neuropeptides from primary afferent neurones, augmented the mucosal damage induced by ET-1, as assessed by both macroscopic and histological examination. 4. The damage induced by threshold doses of ET-1 alone or in capsaicin-pretreated rats was further enhanced by administration of indomethacin (5 mg kg-1, i.v.), indicating a modulatory influence of endogenous prostanoids. 5. Morphine administration (3 mg kg-1, i.v.), which can prevent neuropeptide release, augmented the damage induced by threshold doses of ET-1, this effect being reversed by naloxone (1 mg kg-1, i.v.). 6. Concurrent local intra-arterial infusion of rat alpha-calcitonin gene-related peptide (10-50 pmol kg-1 min-1) dose-dependently reduced the mucosal injury induced by ET-1. 7. These findings suggest interactions between ET-1 and sensory neuropeptides, which may reflect an important influence of these peptide mediators in the regulation of mucosal integrity.