Riluzole antagonizes the anxiogenic properties of the β-carboline FG 7142 in rats

The possible anxiolytic activity of riluzole, a drug which interferes with glutamic acid neurotransmission, was studied in rats using operant conflict procedures. In both anxiolytic and anxiogenic procedures, riluzole alone did not possess any anticonflict or proconflict effect at doses of 2 and 4 mg/kg PO. Riluzole over the same dose-range was able to antagonize the well known proconflict effect of the -carboline derivative FG 7142, an inverse agonist at the GABA-benzodiazepine-chloride ionophore receptor complex. This effect could be related to the possible interaction of riluzole with glutamic acid neurotransmission, since it has been demonstrated previously that -carbolines such as DMCM and -CCM were able to deplete the levels of aspartic and glutamic acids in rodent cortex, perhaps by enhancing release of amino acid neurotransmitters. If one subscribes to the hypothesis that the anxiety induced by -carboline derivatives is related to depression, riluzole might be of value in the treatment of anxiety related to depression.     

The effect of midazolam and β-carboline carboxylic acid ethyl ester on behaviour,steroid hormones and central monoamine metabolites in social groups of talapoin monkeys

Established social groups of talapoin monkeys show rank-related differences in aggressive, social and sexual behaviours and visual monitoring, as well as in endocrine and monoamine profiles. Here we describe the effects on these variables of an anxiogenic drug, -carboline carboxylic acid ethyl ester (-CCE), and an anxiolytic drug (midazolam) given to either dominant or subordinate male talapoins. In dominant animals -CCE increased aggression and visual monitoring but reduced sexual behaviour. Treatment of subordinate animals with -CCE served only to increase visual monitoring. Conversely, treatment with a non-sedative acute dose of midazolam in dominants reduced aggressive behaviour and increased sexual behaviour, whereas in subordinates no behavioural changes were noted. Significant effects on endocrine and neurochemical variables were not seen with the acute drug treatments employed. Nevertheless, the results show that drugs which modulate anxiety produce status-dependent behavioural effects.     

Influence of sildenafil on copulatory behaviour in sluggish or normal ejaculator male rats: a central dopamine mediated effect?

The present study investigates the effects induced by sildenafil (1 mg/kg, p.o.) and the dopamine agonist, SND 919 (0.1 mg/kg, i.p.) on copulatory behaviour of male rats, categorized, on the basis of seven consecutive mating pre-tests, as sluggish and normal ejaculators (SE and NE, respectively). The data obtained show that sildenafil modifies both sexual arousal and ejaculatory mechanisms of copulation. It appears that, although it induced a facilitatory effect on ejaculation of all rats, similarly to SND 919, the lowering of ejaculatory threshold was achieved by means of a reduction of mount frequency and intromission frequency in SE and NE groups, respectively. Differently from SND 919, sildenafil increased sexual arousal, diminishing post ejaculatory interval in SE animals and inter-intromission interval in both SE and NE rats. As the dopamine antagonist, (-)eticlopride (0.02 mg/kg, s.c.), significantly inhibited sildenafil-induced enhancement of sexual arousal in SE rats, it is suggested that the drug acts both peripherally and centrally.     

Alcohol and “bursts” of aggressive behavior: ethological analysis of individual differences in rats

A quantitative ethological analysis of rodent aggression was performed in order to characterize the aggression-heightening effects of alcohol in certain individuals. In dyadic confrontations, a resident rat pursues, threatens and attacks an intruder, who reacts with defensive, flight and submissive behaviors. The behavioral data from five series of experiments conducted from 1984 through 1989 were subjected to a lag sequential analysis that identified highly predictable sequences of aggressive behavior, and to interval analysis that delineated a burst pattern of aggressive behavior. These analyses revealed a distinct behavioral sequence of pursuit sideways threat attack bite aggressive posture that occurs in bursts with an inter-event interval of less than 6.6 s. In the total population, alcohol heightened attack behavior at low acute doses (0.1, 0.3, 1.0 g/kg) in 47% of the animals (n=44), suppressed reliably attack behavior in another 25% (0.1–3.0 g/kg;n=23) and had unreliable effects in the remaining 28% (n=24). The peak enhancement of aggressive behavior was seen over more than a log cycle of alcohol doses (0.1, 0.3 or 1.0 g/kg) in different individuals. In an additional group of rats (n=20), individuals were identified according to whether or not acute low alcohol doses enhanced or suppressed the frequency of attack bites. In the subgroup of five rats who doubled their attack frequency upon acute alcohol challenge, this aggression-heightening effect was confirmed on repeated occasions. The aggression-heightening effects of alcohol were seen during the high-rate interactions in the initial phase of the confrontation and particularly during the lower level of fighting later on. Regardless of alcohol dose and subgroup, the highly predictable sequence of pursuit sideways threat attack bite aggressive posture remained intact as long as the individual was able to fight. The present analysis identifies those individuals in whom low alcohol doses increase the frequency of attack behavior, the number of aggressive elements in bursts and particularly the time in burst. Alcohol produces these changes without altering the latency to initiate aggressive behavior, the rate of aggressive behavior within a burst or the number of bursts in an encounter. Alcohol may lengthen aggressive bursts by preventing termination of longer aggressive sequences rather than by altering the initiation of this behavior.We dedicate this paper to our friend Dr. Milos Krsiak, Professor of Pharmacology, Charles University, Prague, Czechoslovakia     

Enhancing effect of heroin on social recognition learning in male Sprague–Dawley rats: modulation by heroin pre-exposure

Rationale  There is evidence that pre-exposure to drugs of abuse can induce sensitization to several of their effects. Objective  Four experiments were conducted to investigate the effect of heroin pre-exposure on modulation of memory consolidation as indexed by heroin's action on rate of learning. Materials and methods  Male Sprague–Dawley rats were tested on a social recognition learning task which assesses changes in investigation during repeated exposure to the same rat (habituation training: four sessions) and during exposure to a novel rat (dishabituation test). In the first experiment, rats received 0, 0.3, or 1 mg/kg heroin s.c. immediately following each training session, or 1 mg/kg heroin 2 h post-training. In experiments 2 and 3, rats received 1 mg/kg heroin post-training after a 7-day drug-free period from heroin pre-exposure achieved through conditioned place preference (1 mg/kg s.c., 1 injection/day × 4 days) or intravenous self-administration (0.05 mg/kg/infusion i.v., 3 h/day × 9 days) training. In experiment 4, rats received 0, 0.03, 0.3, or 3 mg/kg heroin post-training after a 7-day drug-free period from a regimen of heroin administration (i.e., 1 mg/kg heroin/day s.c. × 7 days) that induced locomotor sensitization. Results  Post-training administration of heroin enhanced social recognition learning in a dose- and time-dependent manner. Importantly, no regimen of heroin pre-exposure significantly altered this effect of heroin. Conclusions  These results do not support the hypothesis that heroin pre-exposure leads to sensitization to its effect on memory consolidation of non-drug-related learning. However, this requires further testing using alternative heroin pre-exposure regimens, a wider range of post-training heroin doses, as well as other types of learning tasks.     

The effects of repeated social defeat on long-term depressive-like behavior and short-term histone modifications in the hippocampus in male Sprague–Dawley rats

Rationale  

Social stress has been linked to several neuropsychiatric diseases, including depression, which is a debilitating disease that has genetic, environmental, and epigenetic underpinnings.     

The effect of isoprenaline on plasma concentrations of immunoreactive β-endorphin and β-lipotropin in the conscious rat

Summary The effect of the -adrenoceptor agonist isoprenaline on the plasma concentrations of -endorphin (-E) and -lipotropin (-LPH) was investigated in conscious rats. Isoprenaline (i.m.) elevated plasma -endorphin-like immunoreactivity (-EI) as measured by radioimmunoassay of unextracted plasma, with peak values 24 min after drug administration. This effect was dose-dependent. The lowest effective dose of isoprenaline was 15 g kg^–1; 240 g kg^–1 exerted a maximum effect, raising plasma -EI about ten-fold above control values. Plasma vasopressin concentrations also increased in response to isoprenaline following a timecourse identical to that of plasma -EI. (±)-Propranolol (1 mg kg^–1) but not phentolamine (10 mg kg^–1) rendered isoprenaline (240 g kg^–1) injections almost ineffective. Because of the cross-reactivity of -LPH in the radioimmunoassay used, plasma was extracted by means of a cation exchange resin and subjected to gel chromatography on a Sephadex G-50 column, avoiding artefactual degradation of the peptides. In isoprenaline-treated rats about 50% of the -EI behaved similar to human -LPH, whereas 45% co-migrated with human -E; immunoreactivity corresponding to -LPH or -E comprised about 70% or 30%, respectively, in the plasma extract of vehicle-treated rats. Dexamethasone pretreatment reduced the isoprenaline-induced increase in plasma -EI by 87%, but left the simultaneous elevation of plasma vasopressin concentrations unchanged.These data demonstrate that isoprenaline stimulates -LPH and -E release in vivo. The possibility of an interrelationship between vasopressin and -E release is discussed.     

The effect of Polygonum multifiorum on the memory of AD rats and the APP cleaveing enzyme in their hippocampus

Objective. To approach the therapy mechanism of Polygonum multiflorum on AD. Methods. 30 AD rats were randomly divided into Polygonum multiflorum group （PMG） and physiological saline group （PSG） with 15 rats for each group. 15 young rats were selected as yong group （YG） .All rats were tested with maze, and were breeded at the experimental animal centre of Central South University. Lavaged with Polygonum multiflorum or physilological saline one time every day for total 4 weeks, The YG and PSG were lavaged with 1.5ml physiological saline injection every time,     

The effect of luteolin-7-O-β-d-glucuronopyranoside on gastritis and esophagitis in rats

This study evaluated the inhibitory action of luteolin-7-O-beta-D-glucuronopyranoside, luteolin which was isolated from Salix gilgiana leaves, and omeprazole on reflux esophagitis and gastritis in rats. Reflux esophagitis and gastritis were induced surgically and by the administration of indomethacin, respectively. The intraduodenal administration of luteolin-7-O-beta-D-glucuronopyranoside decreased the ulcer index, injury area, gastric volume and acid output, and increased the gastric pH compared with luteolin. Luteolin-7-O-beta-D-glucuronopyranoside significantly decreased the size of the gastric lesions that had been induced by exposing the gastric mucosa to indomethacin. The malondialdehyde content, which is the end product of lipid peroxidation, was increased significantly after inducing of reflux esophagitis. The malondialdehyde content was decreased by Luteolin-7-O-beta-D-glucuronopyranoside but not luteolin or omeprazole. Luteolin-7-O-beta-D-glucuronopyranoside has a more potent antioxidative effect than luteolin. Luteolin-7-O-beta-D-glucuronopyranoside is a promising drug for the treatment of reflux esophagitis and gastritis.     

Light effect on the stability of β-lapachone in solution: pathways and kinetics of degradation

Objectives The purpose of this work was to study the chemical stability of the new antitumoral β‐lapachone (βLAP) to determine the degradation pathway/s of the molecule and the degradation kinetics in addition to identifying several degradation products. Method Samples of βLAP in solution were stored under conditions of darkness and illumination at 40°C at which the pseudo‐first order rate constants for the βLAP degradation were determined. Furthermore, drug degraded solutions were concentrated and purified using Sephadex LH‐20 and preparative thin‐layer chromatography and degradation products were identified by nuclear magnetic resonance spectroscopy. Key findings The results revealed that βLAP shows two different degradation routes: hydrolysis in the dark and photolysis under the light. The βLAP exposure to light accelerated the drug degradation about 140 fold, compared with the samples stored in the absence of light. The hydrolysis produced hydroxylapachol as the main degradation product. The photolysis yielded phthalic acid, 6‐hydroxy‐3methylene‐3H‐isobenzofuran‐1‐one and a benzomacrolactone together with a complex mixture of other phthalate‐derivatives such as 2‐(2‐carboxy‐acetyl)‐benzoic acid. Conclusions This study provides useful information for the development of βLAP dosage forms, their storage, manipulation and quality control.     

The effect of β-adrenoceptor blocking agents on evolving myocardial necrosis in coronary ligated rats with and without reperfusion

Summary The left coronary artery of rats was ligated either permanently, or for a period of 40 or 60 min, with subsequent reperfusion. In experiments with permanent occlusion, the hearts were removed and investigated 5 h after the coronary ligation, or immediately after death in animals which died earlier. The hearts from the reperfusion experiments were investigated 60 min after reopening the occluded artery.The extent of the ischaemic and necrotic areas of the hearts was determined. A quantitative photometric method was developed, for this purpose, using negative staining with Evans blue for the ischaemic area, and negative staining with triphenyltetrazolium chloride for the necrotic area.In experiments in which ligation was permanent, the percentage of the ischaemic area which underwent necrosis increased with the time after coronary occlusion. In reperfusion experiments, myocardial necrosis was detected earlier than in experiments with permanent coronary ligation.The -adrenoceptor blocking agents pindolol, propranolol, and metoprolol significantly decreased the percentage of necrosis in experiments with permanent ligation of the coronary artery. The most selective of the -adrenoceptor blockers, i.e. metoprolol was tested in the reperfusion experiments. In these experiments, the amount of necrosis was also significantly decreased.An abstract was given at the Joint Meeting of the French and German Pharmacological and Toxicological Societies in Freiburg, 19–22 September 1983; W. Bernauer, Naunyn-Schmiedeberg's Arch Pharmacol, Supplement to Vol 324, R 9 (1983)     

Influence of prenatal undernutrition on the effects of clozapine and aripiprazole in the adult male rats: relevance to a neurodevelopmental origin of schizophrenia?

Epidemiological and experimental data indicate that maternal undernutrition may sensitize the offspring to the apparition of chronic diseases such as metabolic syndrome and schizophrenia, suggesting that these pathologies may have a developmental origin. To test this hypothesis, we have compared the effects of a 4 weeks treatment of clozapine (30 mg/kg once daily, p.o.) or aripiprazole (10 mg/kg once daily, p.o.) on metabolic and hormonal parameters in 4-month-old male animals from control or 70% prenatally food-restricted mothers (FR30 model). Both neuroleptics did not markedly modify body weight gain and food intake in both controls and FR30 rats. Clozapine decreased insulin secretion in both groups but significantly diminished leptin, corticosterone and glucose plasma levels only in FR30 animals. Aripiprazole decreased corticosterone plasma levels only in FR30 animals. Using quantitative RT-PCR array containing 84 obesity-related genes, we identified several genes involved in energy metabolism regulation whose expression was modified by clozapine or aripiprazole in adult male rat hypothalami. In addition, we demonstrated that expression of some of these genes was differentially affected by each neuroleptic in the hypothalamus of both FR30 and control animals. Although no marked metabolic alterations were observed in both control and FR30 animals after clozapine or aripiprazole treatment, our data indicate that offspring from undernourished mothers exhibit a modified sensitivity to atypical neuroleptics. Our results do not rule out a putative developmental origin of schizophrenia and may help to understand the way by which atypical neuroleptics, such as clozapine, sensitize schizophrenic patients to the development of metabolic disorders.     

Mechanism of the inhibitory effect of endogenous histamine on epilepsy in rats

Clinical data demonstrated that long-term epilepsy, especially among children, or ingesting anticonvulsant drugs over time are likely to result in cognitive deficits (e. g. memory or attention problems as well as other CNS side effects such as psychomotor speed abnormalities, somnolence, asthenia, and dizziness. New drug therapy has been expected. The histaminergic neuron system seems to be involved in various physiological and behavioral functions including sleep - wake cycles, stress behavior, neuroendocrine, learning and memory through histamine HI, H2 and H3 receptors. The role of brain histamine in regulating seizure susceptibility has been studied, and a possible anticonvulsant action of endogenous histamine has been postulated     

Tolerance development to a disruptive effect of β-phenylethylamine (PEA) on a learned behavior in rats

Several doses (8–64 mg/kg) of -phenylethylamine (PEA), a naturally-occurring sympathomimetic amine structurally related to amphetamine and with similar effects on animal behavior, were administered (IP, daily for ten days) to Fisher 344 rats that were trained to perform a shuttlebox conditioned avoidance response (CAR) at a high, stable rate. PEA 8 mg/kg did not influence avoidance responding after single or multiple injections. Acute administration of PEA 16 mg/kg produced dose-dependent disruptions of the CAR. With repeated administration, complete tolerance to CAR disruption was acquired by the third injection of PEA 16 mg/kg or by the fifth injection of PEA 32 mg/kg and maintained with both doses through ten injections; the use of appropriate controls indicated that tolerance was pharmacological and not behavioral. Over the course of ten injections, tolerance did not develop to shuttlebox disruption caused by 64 mg/kg, and this dose of PEA did not elicit tolerance to stereotyped behavior after 21 injections. These data were interpreted as showing differential tolerance to low vs. high dose effects of PEA: Lower doses produce tolerance to disruption of the CAR, but the highest dose did not because of the presence of incompatible response tendencies (e.g., stereotypy) interfering with the CAR. Our data showing development of tolerance to lower doses of PEA is the first demonstration in the literature that tolerance can develop to a behavioral effect of this compound.     

The subchronic oral toxicity of the β-isomer of hexachlorocyclohexane in rats

The 13-week oral toxicity of β-HCH, a nonpesticidal isomer of hexachlorocyclohexane, was investigated in rats with doses of 0, 2, 10, 50, or 250 mg/kg feed. Parameters studied comprised clinical signs, growth and food intake, biochemistry, hematology, organ weights, and histopathology. In all dose groups liver effects comprising increase of organ weight, centrilobular hepatocytic hypertrophy, and proliferation of smooth endoplasmic reticulum or increased activity of microsomal enzymes, were observed. In the 50 mg/kg group the weights of thymus and testes were affected. In the highest dose group, progressive clinical signs leading to the unscheduled sacrifice of approximately 50% of the rats were observed. Moreover, in the males of this group atrophy of the testes, characterized by a reduced size of the seminiferous tubules and a decreased number of interstitial cells was observed in association with spermatogenic arrest. The females in this group showed atrophy of the ovaries with impaired oogenesis and focal hyperplasia and metaplastic changes of the endometrial epithelium. These effects are discussed with respect to a possible estrogenic action of β-HCH.     

Food–drug interactions: effect of capsaicin on the pharmacokinetics of galantamine in rats

1. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide, CAP) is a naturally occurring alkaloid extracted from the fruit of Capsicum plant family. It represents an important ingredient in spicy foods consumed throughout the world. However, little is known about the metabolic interactions between CAP and clinically used drugs.

2. This study attempted to investigate the effect of CAP on the pharmacokinetics of galantamine, a competitive and reversible cholinesterase inhibitor. CAP, dexamethasone or sodium salt of carboxymethyl cellulose (CMC-Na) was given to rats for seven consecutive days and on the seventh day galantamine (10 mg/kg) was administered orally. Dexamethasone was used as a CYP inducer and CMC-Na was used as a vehicle.

3. The results showed that the pretreatment of rats with CAP resulted in a decrease in the AUC_0–∞ of galantamine of about 49.70% (p < 0.01) compared with the control group. After oral administration of galantamine (10 mg/kg), the apparent oral clearance of galantamine was raised by 2.05-fold by pretreatment with CAP (p < 0.05). These results demonstrate that the chronic ingestion of high doses of CAP will decrease the bioavailability of galantamine to a significant extent in rats.

     

Metabolism and disposition of a β3-adrenergic receptor agonist LY368842 in male Fisher 344 rats

The metabolism and disposition of LY368842, a β₃-adrenergic receptor agonist, were characterized in F344 rats following oral or intravenous administration of [¹⁴C]LY368842. These studies were conducted as part of the investigation of the mechanism of dark liver pigmentation in LY368842-treated F344 rats. The maximum plasma concentration of LY368842 was reached at 3?h after an oral dose, with an elimination half-life of 4?h. The oral bioavailability of LY368842 was determined as 8%. A tissue distribution study by quantitative whole-body autoradiography indicated high concentrations of radiocarbon in gastrointestinal contents and moderate concentrations in liver. The radiocarbon was rapidly eliminated in rats, with approximately 3% of the dose recovered in urine and 90% in faeces over 168?h. In bile duct-cannulated rats, about 42% of the dose was recovered in bile and 41% remained in the faeces. Metabolites of LY368842 were identified in rat urine, faeces, bile and plasma samples. Oxidative metabolism of LY368842 led to the formation of a hydroxy metabolite, an indole-2,3-dione metabolite and oxidative cleavage products such as amine and diol metabolites. Several glucuronide conjugates were also identified in rat bile. These data suggest that LY368842 is not completely absorbed but is widely distributed, extensively metabolized and rapidly eliminated in rats after oral administration.     

The effects of glyburide and insulin on the decreased β-adrenergic responsiveness of the gastrointestinal tract in rats with non-insulin-dependent diabetes

• 1.1. Decreased β-adrenergic responses have been reported in gastro-intestinal tract of rats with diabetes mellitus. Effects of glyburide and insulin on the decreased β-adrenergic responsiveness of the gastro-intestinal tract due to non-insulin-dependent diabetes were investigated using duodenum, jejunum and ileum from rats which were injected with alloxan in their neonatal periods.
• 2.2. Insulin treatment of non-insulin-dependent diabetic rats for 10 days corrected the decreased β-adrenergic responses of the isolated duodenum, jejunum and ileum confirming the previous results obtained from insulin-dependent diabetic rats.
• 3.3. Glyburide treatment alone for 3 weeks also reversed the changes in the gastro-intestinal β-adrenergic responses of non-insulin-dependent diabetic rats. Combination of glyburide with insulin, however, did not cause an additive or supra-additive interaction in terms of β-adrenergic sensitivities of the diabetic tissues.
• 4.4. The results obtained in the present study strongly suggested that non-insulin-dependent diabetes may cause a decrease in the number of gastro-intestinal β-adrenoceptors, while glyburide and insulin treatments correct the changes related to β-adrenoceptors. The effect of insulin on the β-adrenergic sensitivity of diabetic rat duodenum, jejunum and ileum may occur via a direct mechanism, whereas glyburide seems to be effective on the β-adrenergic responses through the increases in the insulin secretion and/or in the number of gastro-intestinal insulin receptors.

     

The mechanism underlying the synergetic hypocholesterolemic effect of sesamin and α-tocopherol in rats fed a high-cholesterol diet

Sesamin is a major lignan in sesame seed. We confirmed that ingestion of sesamin and α-tocopherol synergistically reduced the concentration of blood cholesterol in rats given a high-cholesterol diet. To elucidate the molecular mechanism behind this effect, we analyzed the gene-expression profiles in rat liver after co-ingestion of sesamin and α-tocopherol. Six-week-old male Sprague-Dawley rats were fed a 1% cholesterol diet (HC) or HC containing 0.2% sesamin, 1% α-tocopherol or sesamin + α-tocopherol for 10 days. Blood samples were collected on days 1, 3, 7, and 10 and livers were excised on day 10. The gene expressions of ATP-binding cassette, sub-family G (WHITE), members 5 (ABCG5) and 8 (ABCG8) were significantly increased, while the gene expression of apolipoprotein (Apo) A4 was significantly decreased. ABCG5 and ABCG8 form a functional heterodimer that acts as a cholesterol efflux transporter, which contributes to the excretion of cholesterol from the liver. ApoA4 controls the secretion of ApoB, which is a component of low-density-lipoprotein cholesterol. These studies indicate that the cholesterol-lowering mechanism underlying the effects of co-ingestion of sesamin and α-tocopherol might be attributable to increased biliary excretion of cholesterol and reduced ApoB secretion into the bloodstream.     

Portal hypertension and liver cirrhosis in rats: effect of the β3-adrenoceptor agonist SR58611A

BACKGROUND AND PURPOSE

β₃-Adrenoceptors participate in the regulation of vascular tone in physiological and pathological conditions. We aimed to assess the effect of pharmacological modulation of β₃-adrenoceptors on portal pressure (PP) and systemic haemodynamics and their expression in the liver and mesenteric vessels of cirrhotic rats.

EXPERIMENTAL APPROACH

PP, central venous pressure (CVP) and systemic haemodynamics were invasively assessed in control and CCl₄-treated cirrhotic rats before and during infusion of the selective β₃-adrenoceptor agonist, SR58611A. Tissue samples were also collected from liver, heart, portal vein and mesenteric artery for immunohistochemistry and molecular biology analysis. The effect of SR58611A on isolated portal vein was assessed.

KEY RESULTS

At baseline, cirrhotic rats showed portal hypertension, reduced CVP and hyperdynamic circulation. SR58611A induced a significant, dose-dependent decrease in PP in cirrhotic rats, but not in controls. Although both groups manifested a dose-dependent reduction in mean arterial pressure, this effect was associated with decreased cardiac index (CI) and unchanged indicized peripheral vascular resistance (PVRI) in cirrhotic rats and increased CI and decreased PVRI in control animals. Pretreatment with the selective β₃-adrenoceptor antagonist SR59230 prevented all SR58611A-induced changes in cirrhotic rats. SR58611A concentration-dependently relaxed portal vein in cirrhotic rats to a significantly greater extent than in healthy rats; pretreatment with SR59230A completely prevented SR58611A-induced cirrhotic portal vein relaxation. Finally, β₃-adrenoceptors were identified in the liver, heart and portal vein of cirrhotic and control animals; their expression was increased in cirrhotic rats.

CONCLUSIONS AND IMPLICATIONS

β₃-Adrenoceptors are altered in portal hypertension of experimental cirrhosis and may represent a novel therapeutic target.