Effect of lignocaine on arginine-vasopressin plasma levels: baseline or induced by frusemide.

1. To assess whether or not lignocaine influences baseline and frusemide-induced (5 mg kg-1) plasma concentrations of arginine-vasopressin (AVP), 2 groups of rabbits received an infusion of lignocaine (130 micrograms min-1 kg-1) for 6 h. Lignocaine-induced changes in AVP plasma concentrations were substantiated by measurement of diuresis and natriuresis and hepatic plasma flow, by means of an infusion of indocyanine green (ICG) (249 micrograms min-1 kg-1). 2. Baseline plasma AVP levels were 4.9 +/- 0.9 pg ml-1 (+/- s.e.), and following lignocaine, these values were reduced to 0.7 +/- 0.1 pg ml-1 (P less than 0.01). Frusemide increased AVP levels to 134.1 +/- 73.6 pg ml-1 (P less than 0.05) and lignocaine totally prevented this increase, e.g. mean AVP levels of 2.7 pg ml-1. 3. Lignocaine enhanced baseline diuresis secondary to an increase in free water clearance; none of the experimental conditions affected the diuresis and natriuresis induced by frusemide. 4. Frusemide reduced the hepatic plasma flow and this decrease was not reversed by the infusion of lignocaine. 5. It is concluded that in healthy rabbits lignocaine reduces baseline secretion of AVP and its antidiuretic effect; in addition, lignocaine prevents the rise in AVP induced by frusemide.     

The effect of medetomidine, an alpha 2-adrenoceptor agonist, on plasma atrial natriuretic peptide levels, haemodynamics and renal excretory function in spontaneously hypertensive and Wistar-Kyoto rats.

1. The effects of the selective alpha 2-adrenoceptor agonist, medetomidine, were assessed on plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP), haemodynamics and on urine water and solute excretion in conscious, chronically cannulated, 7 month-old spontaneously hypertensive (SHR) and age-matched Wistar-Kyoto (WKY) rats, in order to examine the role of alpha 2-adrenoceptors in the control of ANP secretion. 2. A 60 min i.v. infusion of medetomidine (0.2 or 0.6 microgram kg-1 min-1) decreased heart rate dose-dependently in both strains. Medetomidine infusion (0.6 microgram kg-1 min-1) resulted in an increase in mean arterial pressure in WKY, whereas both doses decreased blood pressure in SHR. There was a slight increase in the right atrial pressure in both strains (WKY: +1.18 +/- 0.26 mmHg; SHR: +1.64 +/- 0.64 mmHg, NS) in response to infusion of 0.6 microgram kg-1 min-1 of medetomidine. 3. No differences were found in resting plasma IR-ANP levels between WKY (114 +/- 8 pg ml-1, n = 19) and SHR (117 +/- 10 pg ml-1, n = 21). Infusion of equibradycardic doses of medetomidine increased dose-dependently plasma IR-ANP levels in WKY, but did not affect the plasma IR-ANP concentration in SHR rats. 4. Despite the different effect of medetomidine on ANP release in WKY and SHR rats, i.v. administration of medetomidine affected renal excretory functions similarly in both strains; urine flow and sodium excretion increased and urine osmolality decreased significantly, while there was no consistent change in urinary potassium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Failure of drugs that selectively inhibit thromboxane synthesis to modify endotoxin shock in conscious rats.

The effects of two thromboxane synthetase inhibitors ( dazoxiben and UK 38485) were investigated on the cardiovascular and metabolic effects of Escherichia coli endotoxin infusion in the conscious, unrestrained rat. Infusion of E. coli endotoxin (41.7 ng kg-1 min-1) for 4 h produced a fall in mean arterial pressure, an increase in heart rate, a transient hyperglycaemia (at 1 h) followed by hypoglycaemia (evident at 6 h), an elevation in plasma lactate and a profound thrombocytopenia. The above changes were accompanied by a marked elevation in plasma thromboxane B2 concentrations (e.g. endotoxin-treated 935 +/- 150 pg ml-1 at 1 h compared with pre-endotoxin values of 125 +/- 30 pg ml-1). The administration of either dazoxiben (30 mg kg-1 i.v., given 30 min before starting the endotoxin infusion) or UK 38485 (15 mg kg-1 given 30 min before, and again 4 h after, starting the endotoxin infusion) prevented the rise in plasma thromboxane B2 concentrations. Neither dazoxiben nor UK 38485 prevented the metabolic, cardiovascular or thrombocytopenic effects of endotoxin and did not modify mortality. These results suggest that, although large amounts of thromboxane are generated in response to endotoxin, they do not play an important role in the major pathophysiological consequences of acute endotoxaemia.     

Pharmacokinetics of chloroquine in Thais: plasma and red-cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria.

1. Chloroquine diphosphate (15 mg base kg-1) was given by constant rate intravenous infusion to two groups of Thai subjects. Eleven were patients with malaria (10 with Plasmodium vivax and one case with Plasmodium malariae) and 10 were healthy normal volunteers. 2. Plasma and packed red-cell concentrations of chloroquine, electrocardiographic intervals, arterial blood pressure and pulse were measured at frequent intervals. 3. Peak plasma concentrations at the end of the infusion ranged from 979 to 2,900 ng ml-1 in the malaria patients. In the group of healthy subjects the range was 550-2,200 ng ml-1. Values for terminal elimination rate constant, (lambda z) plasma clearance (CL), initial volume of distribution (V1) and volume of distribution at steady state (Vss) were calculated. For the healthy subjects, mean estimates of these parameters were lambda z = 0.062 +/- 0.030 day-1, CL = 597 +/- 238 ml min-1, V1 = 0.66 +/- 0.71 l kg-1 and Vss = 132 +/- 50 l.kg-1 For the group of malaria patients, the corresponding values were lambda z = 0.055 +/- 0.032 day-1, CL = 535 +/- 246 ml min-1, V1 = 0.74 +/- 0.75 l kg-1 and Vss = 136 +/- 64 l kg-1 There was no statistically significant difference in the estimates for any parameter between groups (P less than or equal to 0.05). 4. Chloroquine concentrations in packed red blood cells consistently exceeded those in plasma and showed no consistent change with time throughout the period of study in either group. The median value for the red cell to plasma ratio was between 3 and 4 in each group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Histamine and Nt-methylhistamine in the circulation during intravenous infusion of histamine in normal volunteers

Plasma levels of histamine and Nt-methylhistamine were measured simultaneously by high performance liquid chromatography during the intravenous infusion of histamine acid phosphate in six normal volunteers. Progressive, dose-related increases in plasma histamine were noted, reaching a maximum value of 3.1 +/- 0.14 ng ml-1 corresponding to a maximum infusion rate of 180 ng kg-1 min-1 (means +/- SEM). Increases in plasma histamine were accompanied by a significant dose-related fall in mean diastolic blood pressure (baseline 74.0 +/- 4.4 mm Hg falling to 60.0 +/- 3.3 mm Hg at maximum infusion rate, p less than 0.001) and an increase in pulse rate (baseline 76.3 +/- 2.8 beats min-1 rising to 89.24 beats min-1 at maximum infusion rate, p less than 0.05). All subjects exhibited facial flushing, the threshold plasma histamine level for this effect being 1.3 +/- 0.15 ng ml-1 corresponding to an infusion rate of 60 ng kg-1 min-1. Elevation of plasma Nt-methylhistamine was seen in only one subject, who exhibited a level of 0.5 ng ml-1 at the highest infusion rate. These results suggest that measurements of plasma Nt-methylhistamine are unlikely to provide a useful index of histamine release into the circulation.     

Pharmacological manipulation of cyclo-oxygenase-2 in the inflamed hydronephrotic kidney.

1. Bradykinin (BK, 1 microgram) caused a small (2 fold at 6 h) increase in prostaglandin E2 (PGE2) in the normal rabbit kidney, perfused ex vivo. This was exaggerated (6 fold at 6 h) in the hydronephrotic kidney (HNK). The exaggerated release of PGE2 was attenuated by cycloheximide, an inhibitor of protein synthesis or by dexamethasone, a steroid known to inhibit the induction of cyclo-oxygenase (COX-2). BK (1 microgram) when injected at 6 h of perfusion increased the release of PGE2 from 90 +/- 33 pg ml-1 min-1 to 3069 +/- 946 pg ml-1 min-1. This was reduced to 200 +/- 30 pg ml-1 min-1 in kidneys infused with cycloheximide (1 microM) and to 250 +/- 40 pg ml-1 min-1 in kidneys infused with dexamethasone (n = 8). 2. When tested on human and murine recombinant COX-1 and COX-2 enzymes, DuP-697 was at least 50 fold more selective for COX-2 than for COX-1. 3. DuP-697 reduced the exaggerated release of PGE2 elicited by BK in the HNK (e.g., at 6 h of perfusion BK-evoked PGE2 release decreased from 3069 +/- 946 pg ml-1 min-1 to 187 +/- 22 pg ml-1 min-1 after perfusion with 1 microM DUP-697, n = 8). 4. Cycloheximide, dexamethasone or DuP-697 at doses used to inhibit completely the exaggerated release of PGE2 in the hydronephrotic kidney, failed to inhibit the release of PGE2 elicited by the injection of BK (1 microgram) in the normal contralateral kidney. 5. Indomethacin (1 microM), a non-selective COX-1 and COX-2 inhibitor, completely inhibited PGE2 release in the normal contralateral as well as in the hydronephrotic kidney. 6. We suggest that renal prostaglandin production in the normal kidney is driven by the activity of constitutive COX-1 while at sites of inflammation, such as the hydronephrotic kidney, there is induction of COX-2 that can be blocked selectively by anti-inflammatory glucocorticoids or selective COX-2 inhibitors.     

Lack of effect of TNF antibodies on the cardiovascular sequelae of lipopolysaccharide infusion in conscious rats.

1. The aims of the present study were to determine the profile of tumour necrosis factor (TNF) release, and the effect of monoclonal antibodies to TNF, on the changes in regional haemodynamics and the responses to vasodilator and vasoconstrictor challenges, during a continuous 24 h low dose infusion of lipopolysaccharide (LPS) in conscious rats. 2. Male Long Evans rats were chronically instrumented for measurement of regional haemodynamics (renal, superior mesenteric and hindquarters) and were challenged with 3 min infusions of acetylcholine (22 nmol min-1), methoxamine (120 nmol min-1), salbutamol (0.83 nmol min-1) and bradykinin (14.4 nmol min-1). The rats were given either saline, or the TNF antibodies, TN3g1 or TN3g2a, 1 h before the start of a continuous infusion of LPS (150 micrograms kg-1 h-1) and were subsequently re-tested with the vasodilator and vasoconstrictor challenges 2, 6 and 24 h after the start of the LPS infusion. 3. Prior to infusion of LPS, TNF was not detectable in the plasma. During continuous infusion of LPS there was a transient elevation in plasma TNF levels, reaching a maximum (approximately 2300 pg ml-1) after approximately 1 h, and returning to undetectable levels after approximately 3 h of LPS infusion. 4. In the saline pretreated group, after 1-2 h of LPS infusion, there was a small hypotension and a marked renal vasodilation; 6 h after the start of LPS infusion there was a minor elevation in MAP above control levels, renal vasodilatation was maintained and a hindquarters vasoconstriction occurred; after 24 h of LPS infusion, there was a hypotension and renal and hindquarters vasodilatation. There were significant reductions in the tachycardic and renal vasodilator responses and an enhanced depressor response to acetylcholine after 24 h of LPS infusion. LPS infusion also caused a generalized hyporesponsiveness to the cardiovascular effects of methoxamine and salbutamol. The major changes in response to bradykinin were reduced tachycardic and enhanced depressor responses throughout the LPS infusion, a biphasic decrease and increase in renal conductance and enhanced hindquarters vasodilatation at 24 h. 5. Pretreatment with either TN3g1 or TN3g2a antibodies had no major effects on the changes in resting haemodynamics, or on the changes in response to methoxamine, salbutamol or bradykinin challenges during LPS infusion. However, the tachycardic responses to acetylcholine were generally preserved, and its hypotensive effect after 24 h of LPS infusion was not enhanced after TN3g1 or TN3g2a pretreatment. Thus, despite substantial, but transient, elevation of plasma TNF levels during continuous LPS infusion, it appears that the majority of cardiovascular changes were dependent on factors other than plasma TNF.     

Mechanisms of sympathetic enhancement and inhibition of parasympathetically induced salivary secretion in anaesthetized dogs.

1. The effects of superimposed and continuous sympathetic nerve stimulation on submandibular parasympathetic salivation were investigated in anaesthetized dogs. 2. Superimposed sympathetic nerve stimulation (1-2 min) initially enhanced and later inhibited salivary secretion induced by parasympathetic nerve stimulation (2-8 Hz) in glands with uncontrolled blood supply or constant-flow vascular perfusion. Propranolol (0.05 mg kg-1, i.a.) did not affect the diphasic sympathetic action whereas phentolamine (0.1 mg kg-1, i.a.) abolished it. Prazosin (0.025 mg kg-1, i.a.) greatly lessened the initial enhancement while yohimbine (0.025 mg kg-1, i.a.) alleviated the late inhibition. 3. Salivary secretion, induced by parasympathetic nerve stimulation (4 Hz) or acetylcholine infusion (10 micrograms kg-1 min-1, i.a.), was abolished by atropine (0.05 mg kg-1, i.a.), increased by phenylephrine infusion (0.25 microgram kg-1 min-1, i.a.) and depressed by clonidine infusion (0.75 microgram kg-1 min-1, i.a.). Hexamethionium (12.5 mg kg-1, i.a.) abolished the nerve-induced secretion but had no effect on the acetylcholine-induced secretion. 4. Continuous background sympathetic nerve stimulation decreased parasympathetic nerve-induced salivary secretion in glands with uncontrolled blood supply or constant-flow vascular perfusion. 5. These results show that parasympathetic salivation can be modified by the sympathetic system at the postsynaptic level; enhancement is via alpha 1-adrenoceptors whereas inhibition is via alpha 2-adrenoceptors.     

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)     

Inhibition of elevated arginine vasopressin secretion in response to osmotic stimulation and acute haemorrhage by U-62066E, a kappa-opioid receptor agonist.

1. The effect of kappa (kappa) opioid receptor activation on the increase in arginine vasopressin (AVP) secretion evoked by two acute and quite different stimuli (i.e., haemorrhage and osmotic stimulus due to hypertonic saline infusion) were evaluated in conscious Long-Evans rats, by use of U-62066E, a highly selective kappa-opioid receptor agonist, and MR2266, an opioid receptor antagonist with some selectivity for kappa-receptors. 2. An acute haemorrhage, which reduced the mean blood pressure by approximately 50%, resulted in a large increase in the plasma AVP (pAVP) levels of control rats. However, the administration of U-62066E (0.2 mg kg-1 or 2.0 mg kg-1) reduced the increase due to haemorrhage in a dose-dependent manner. In contrast, concomitant administration of 2.0 mg kg-1 of MR2266 with U-62066E significantly attenuated the inhibition of pAVP levels produced by U-62066E 2.0 mg kg-1. 3. Hypertonic saline infusion (5% hypertonic saline solution at a rate of 0.24 ml kg-1 min-1 for 10 min) caused the elevation of plasma osmolality (pOsm) from 294.0 +/- 1.6 mosmol kg-1 to 304.4 +/- 1.9 mosmol kg-1, simultaneously resulting in a significant increase in pAVP levels from 2.34 +/- 0.28 pg ml-1 to 4.54 +/- 0.51 pg ml-1. However, the administration of U-62066E (0.05 mg kg-1 or 0.2 mg kg-1) reduced the osmotically induced increase in pAVP in a dose-dependent manner although pOsm showed the same degree of increase as in controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal effects of a synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) in anesthetized dogs

The effects of a synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) on renal hemodynamics and urine formation were investigated in anesthetized dogs. Intrarenal arterial infusion of the peptide (1.0 microgram/min) increased renal blood flow, glomerular filtration rate and urine flow with no change in systemic blood pressure. A lower dose of alpha-hANP (0.2 micrograms/min) produced a significant diuresis and natriuresis, while renal hemodynamics remained unchanged. The urinary excretion of Na, Cl and Ca was increased in proportion to the urine flow. We propose that alpha-hANP inhibits tubular reabsorption of electrolytes, and in higher dose produces renal vasodilation.     

Effect of dehydration and hyperosmolal hydration on lignocaine and metabolites disposition in conscious rabbits.

1. The present study aimed to investigate the effect of dehydration and hyperosmolal hydration on the disposition of lignocaine and two of its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). 2. Lignocaine was infused to three groups of conscious rabbits: controls, rabbits previously deprived of water for 48 h and rabbits receiving an infusion of 2.5% NaCl. 3. In dehydrated and hyperosmolal-hydrated rabbits, plasma osmolality was 321 +/- 1 and 313 +/- 1 mOsm kg-1, respectively (P < 0.01 compared to controls, 285 +/- 1 mOsm kg-1). In dehydrated animals, baseline values of plasma arginine vasopressin (AVP) concentrations and plasma renin activity (PRA) were higher than in controls, i.e. 12.4 +/- 1.4 pg ml-1 and 15.4 +/- 1.7 ng AI ml-1 h-1 vs. 3.4 +/- 0.2 pg ml-1 (P < 0.01), and 5.1 +/- 0.6 ng AI ml-1 h-1 (P < 0.01), respectively; atrial natriuretic peptide (ANP) decreased from 55 +/- 11 to 32 +/- 4 pg ml-1 (P < 0.05). Compared to controls, hyperosmolal hydration only increased AVP to 15.5 +/- 0.7 pg ml-1 (P < 0.01). 4. Under both experimental conditions, lignocaine plasma concentrations were almost double (P < 0.01) those in controls, due to a lower systemic clearance, e.g. 54 +/- 3 and 59 +/- 1 vs. 96 +/- 5 ml min-1 kg-1, respectively. Plasma levels of MEGX increased (P < 0.01) only in dehydrated animals, although GX plasma concentrations were augmented (P < 0.01) about three fold in both groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Concentration-dependent clearance of procainamide in normal subjects

Four normal volunteers each received two intravenous doses of PA. The mean low dose was 3.30 mg kg-1 (infused over 20 minutes) while the mean high dose was 12.5 mg kg-1 (infused over 60 minutes). Blood samples were collected for 12 hours and urine was collected for 48 hours after each dose. PA concentrations were determined by both HPLC and fluorescent immunoassay methods. The reported concentrations and pharmacokinetic parameters are from the HPLC data unless otherwise indicated. The mean peak serum PA concentrations resulting from the low and high doses were 3.18 and 9.07 micrograms ml-1, respectively. Total PA clearance averaged 763 ml min-1 and 577 ml min-1 while renal clearance averaged 360 ml min-1 and 318 ml min-1 after the low and high doses, respectively. Concentration-dependent decreases in nonrenal PA clearance ranged from 31 to 43 percent (p less than 0.05) in the four subjects. Total clearance decreases ranged from 4.7 to 36 per cent (p less than 0.05). Differences between doses in renal clearance, elimination rate constant, and volume of distribution were not statistically significant. This study demonstrates that the nonrenal and total clearances of PA are concentration-dependent in normal subjects at therapeutic plasma PA concentrations and suggests that the total clearance changes are of sufficient magnitude to be clinically important.     

Capsaicin-induced bronchoconstriction in the guinea-pig: contribution of vagal cholinergic reflexes, local axon reflexes and their modulation by BW443C81.

1 The objective of the study was to investigate the central vagal and local axon reflex components of bronchoconstrictor responses evoked by inhalation of capsaicin aerosol in anaesthetized guinea-pigs. This was accomplished by comparing the effects of bilateral vagotomy, atropine and the peripherally-acting polar enkephalin analogue, BW443C81, on bronchoconstrictor responses evoked by capsaicin. The effects of codeine were also determined. 2 Aerosols of capsaicin were generated from a 0.9 microgram ml-1 solution. Inhalation of capsaicin aerosol in 5, 10 and 15 breaths evoked dose-related bronchoconstrictor responses. The responses were immediate in onset and of extended duration. 3 Capsaicin-induced bronchoconstrictor responses were significantly inhibited following bilateral vagotomy or atropine (0.3 mg kg-1, i.v.) pretreatment by 46% +/- 14% (P less than 0.05) and 59% +/- 13% (P less than 0.01), respectively. 4 Administration of BW443C81 by intravenous infusion (3, 30 and 100 micrograms kg-1 min-1) caused a significant inhibition of capsaicin-induced bronchoconstrictor responses which achieved a greater maximum than either bilateral vagotomy or atropine. Codeine (100 micrograms kg-1 min-1, i.v.) did not significantly inhibit the bronchoconstrictor responses. 5 Inhibition of capsaicin-induced bronchoconstrictor responses by BW443C81 (30 micrograms kg-1 min-1, i.v.) was significantly (P less than 0.05) reduced by the peripherally-acting opioid antagonist N-methyl nalorphine (100 micrograms kg-1 min-1, i.v.). 6 These results show that capsaicin-induced bronchoconstrictor responses are mediated by at least two mechanisms, a vagal and/or cholinergic reflex pathway and a non-cholinergic pathway.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential cardiovascular and neuroendocrine effects of epinine and dopamine in conscious pigs before and after adrenoceptor blockade.

1. The effects of epinine or dopamine (both 1-10 micrograms kg-1 min-1) on systemic haemodynamics and plasma concentrations of catecholamines and prolactin were studied in conscious pigs before and after combined non-selective alpha- and beta-adrenoceptor blockade. 2. The plasma concentrations of the two compounds did not differ from each other over the entire dose-range. 3. Epinine increased aortic blood flow (AoBF, 24 +/- 6%), which was due to an increase in heart rate (HR) for doses less than 10 micrograms kg-1 min-1. At 10 micrograms kg-1 min-1, HR decreased slightly (10 +/- 3%, as compared to the value obtained at 5 micrograms kg-1 min-1) and stroke volume increased up to 15% (P < 0.05). Mean arterial pressure (MAP, 99 +/- 3 mmHg at baseline) decreased dose-dependently (14 +/- 2%, P < 0.05) up to the infusion rate of 5 micrograms kg-1 min-1, but increased by 4.0 +/- 1.8 mmHg during infusion of 10 micrograms kg-1 min-1. Systemic vascular resistance (SVR) decreased up to 23 +/- 3% for doses less than 10 micrograms kg-1 min-1, but did not change further during infusion of the highest dose. LVdP/dtmax increased during the two highest infusion rates up to 22 +/- 6% (P < 0.05). After the infusion was stopped there was an abrupt increase in HR (18 +/- 4%, P < 0.05) and a further decrease in SVR before all parameters returned to baseline. 4.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nifedipine kinetics in the rat and relationship between its serum concentrations and uterine and cardiovascular effects.

1. The kinetics of nifedipine and the relationship between its serum concentration and uterine and cardiovascular effects were investigated in 3 groups of animals. These were ovariectomized (ovx) anaesthetized non-pregnant rats following bolus i.v. injection (400 micrograms kg-1) and during 300 min infusion (10 micrograms kg-1 min-1) and ovx, progesterone-treated late pregnant rats during infusion. Also, the kinetics were determined in ovary-intact late pregnant rats following bolus i.v. injection (400 micrograms kg-1). 2. Measurement of serum nifedipine concentrations after bolus i.v. injection in ovx non-pregnant rats showed a biexponential decay with time from which the following parameters were calculated: V beta = 300 +/- 30 ml kg-1; rate constants k12 = 0.51 +/- 0.18 min-1; k21 = 0.07 +/- 0.02 min-1; ke1 = 0.10 +/- 0.05 min-1; elimination clearance = 2.4 +/- 0.2 (ml min-1) kg-1; t1/2 alpha = 2.5 +/- 1.0 min; t1/2 beta = 102 +/- 15 min. In intact pregnant rats, a biexponential decay of serum nifedipine concentrations with time was also observed after bolus i.v. administration with similar parameters to non-pregnant animals. These kinetic parameters, used to calculate serum nifedipine concentrations obtained during infusion, predicted values similar to experimental values for 180 min, but thereafter slightly underestimated experimental values. 3. Immediate reductions in uterine contractions, mean blood pressure and heart rate were observed following bolus i.v. injection of nifedipine to ovx non-pregnant rats, with returns towards control values as serum nifedipine concentrations declined. IC15 values (15% change from baseline), calculated from log10 serum concentration-response curves, of 0.3 +/- 0.05 micrograms ml-1 for inhibition of uterine contractions, 0.8 +/- 0.3 micrograms ml-1 for depression of blood pressure and 3.8 +/- 1.0 micrograms ml-1 for reduction in heart rate were obtained. 4. In ovx non-pregnant rats, nifedipine infusion produced a maximum reduction in integral of uterine contractions of 70% by 120 min and a maximum reduction of 15% in heart rate. Mean blood pressure was not significantly different from vehicle-treated rats. IC15 values were 0.7 +/- 0.1 micrograms ml-1 and 2.8 +/- 0.6 micrograms ml-1 for inhibition of uterine contractions and heart rate respectively. 5. In ovx, progesterone-treated late pregnant rats, nifedipine infusion produced similar serum concentrations to those of non-pregnant rats but completely abolished uterine contractions by 70 min. Maximum reductions of 30% in heart rate and blood pressure were observed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Attenuation of adrenomedullin-induced renal vasodilatation by NG-nitro L-arginine but not glibenclamide.

1. The present study was conducted in order to elucidate the in vivo contribution of nitric oxide (NO) and the glibenclamide-sensitive potassium channel in the renal action of adrenomedullin in anaesthetized dogs. 2. Intrarenal arterial infusion of adrenomedullin (20 ng kg-1 min-1) elicited a pronounced increase in renal blood flow with no changes in systemic blood pressure. The renal vasodilator action of adrenomedullin was markedly attenuated by pretreatment with NG-nitro L-arginine (L-NOARG), but this was reversed by continuous infusion of L-arginine. 3. Pretreatment with glibenclamide almost completely blocked the renal vasodilatation induced by lemakalim, but had no effect on the renal vasodilator and diuretic action of adrenomedullin. 4. Intrarenal arterial infusion of adrenomedullin induced diuresis and natriuresis. Diuretic and natriuretic action of adrenomedullin was also attenuated by L-NOARG. L-Arginine partly reversed the effect of L-NOARG and adrenomedullin-induced diuresis and natriuresis. 5. These data indicate that the in vivo renal vasodilator action of adrenomedullin is mediated by the release of NO. The glibenclamide-sensitive potassium channel is not involved in the renal action of adrenomedullin, at least, not in anaesthetized dogs. Since the inhibition of L-NOARG of adrenomedullin-induced diuresis occurred concomitantly with the attenuation of the renal vasodilator action of adrenomedullin, direct involvement of NO in adrenomedullin-induced diuresis remains to be established.     

Peripheral sympatho-inhibitory cardiovascular effects of opioid peptides in anaesthetized rabbits.

1. Opioid agonists influence isolated cardiovascular tissues from rabbits, as well as the cardiovascular system of pithed rabbits, through presynaptic receptors on postganglionic sympathetic nerve fibres. The present experiments were carried out in order to study effects which result from activation of these receptors in anaesthetized rabbits. 2. In pithed rabbits with electrically stimulated sympathetic outflow, infusion of [D-Ala2-D-Leu5]-enkephalin (DADLE) 10 micrograms kg-1 min-1 and dynorphin-(1-13) (dynorphin) 1 microgram kg-1 min-1 decreased the plasma noradrenaline concentration, mean arterial pressure (MAP) and heart rate. The effects of dynorphin and, less completely, those of DADLE were antagonized by the peripherally selective opioid antagonists N-methyl naloxone bromide (NMN) 1.3 mg kg-1 and N-methyl levallorphan methanesulphonate (NML) 1-3 mg kg-1. 3. In pentobarbitone-anaesthetized rabbits, DADLE 3-30 micrograms kg-1 min-1 and dynorphin 0.3-3 micrograms kg-1 min-1 decreased the plasma noradrenaline concentration and MAP. The highest dose of dynorphin also decreased heart rate, whereas DADLE 10 micrograms kg-1 min-1 caused slight cardioacceleration. The effects of DADLE but not those of dynorphin decreased upon repeated administration. 4. The effects of dynorphin 10 micrograms kg-1 min-1 were abolished or greatly attenuated by NMN 1.3 mg kg-1 and NML 3 mg kg-1. In contrast, the antagonists reduced only slightly the blood pressure-lowering effect of DADLE 10 micrograms kg-1 min-1 and did not reduce significantly the effects of DADLE on the plasma noradrenaline level and heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.