Pharmacology &amp Toxicology (Pharmacol Toxicol )

Publisher: Nordisk selskab för farmakologi


Pharmacology & Toxicology is an independent journal, publishing original scientific research in all fields of experimental pharmacology and toxicology, including biochemical, cellular and molecular pharmacology and toxicology. Manuscripts on clinical pharmacology and its aspects, pharmacodynamics and pharmacokinetics, are also accepted.

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    Pharmacology & toxicology, Pharmacology and toxicology
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: The present study investigated the effects of mepivacaine on the response of rat aorta to vasoconstrictors in normal and aortic-banded animals. Cardiac hypertrophy was induced in Wistar rats by aortic banding, while sham-operated animals served as controls. Isolated aortic rings with or without endothelium were contracted with potassium chloride and phenylephrine in the presence of mepivacaine (10(-3) M). Maximal tension was measured at the highest concentration of potassium chloride and phenylephrine. Maximal response to potassium chloride was reduced in the presence of mepivacaine both in normal and aortic-banded rings. As regards the vascular reactivity to phenylephrine, aortic rings with intact endothelium from aortic-banded rats have shown increased response as compared to normal. After mepivacaine administration this difference between normal and aortic-banded rats was abolished. In conclusion, in a model of cardiac hypertrophy such as that of aortic-banding, increased response to alpha1-adrenergic stimulation is observed, which is blunted by mepivacaine administration.
    Pharmacology &amp Toxicology 01/2004; 93(6):269-74.
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    ABSTRACT: To clarify the antioxidative role of uric acid, its ability to scavenge carbon-centered and peroxyl radicals and its inhibitory effect on lipid peroxidation induced by various model systems were examined. Uric acid efficiently scavenged carbon-centered and peroxyl radicals derived from the hydrophilic free radical generator 2,2'-azobis-(2-amidinopropane)-dihydrochloride (AAPH). All damage to biological molecules, including protein, DNA and lipids induced by AAPH, was strongly prevented by uric acid. In contrast, alpha-tocopherol had little effect on damage to biological molecules. Lipid peroxidation by the lipophilic free radical generator 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN) was little inhibited by uric acid, but not by alpha-tocopherol. Copper-induced lipid peroxidation was inhibited by uric acid and alpha-tocopherol. NADPH- and ADP-Fe(3+)-dependent microsomal lipid peroxidation was efficiently inhibited by alpha-tocopherol, but not by uric acid. Uric acid seems to scavenge free radicals in hydrophilic conditions to inhibit lipid peroxidation on the lipid-aqueous boundary, and the antioxidation is only little in lipophilic conditions.
    Pharmacology &amp Toxicology 01/2004; 93(6):284-9.
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    ABSTRACT: The aim of this study was to investigate the effects of ginsenoside Rh(2) (G-Rh(2)) on differentiation of SMMC-7721 hepatocarcinoma cell line in culture. We studied G-Rh(2)-induced differentiation of SMMC-7721 cells through cell proliferation, cell morphology, ultrastructure, cell cycle, cell function and metabolism. The proliferation of treated cells was inhibited, the morphology and ultrastructure seemed normal, the secretory amount and expression of alpha-foetoprotein, and the specific activity of gamma-glutamyl transpeptidase, and heat-resistant alkaline phosphatase were all significantly decreased, the secretory amount of albumin and alkaline phosphatase activity were remarkably increased, and the cell was arrested at the G(1)/G(0) phase. Furthermore, G-Rh(2) induced elevated expression of the cyclin-dependent kinase inhibitor p21(WAF1) and p16(INK4a), and declined expressions of cyclin D1 and cyclin E. In addition, G-Rh(2) almost completely inhibited telomerase activity, as measured by polymerase chain reaction-based telomeric repeat amplification protocol coupled with enzyme-linked immune sorbent assay, and human telomerase reverse transcriptase mRNA. Based on these data, it is suggested that G-Rh(2) could induce cell differentiation tending to normal and effectively reduce telomerase activity with affecting transcription levels of human telomerase reverse transcriptase, paralleling the induction of cell differentiation.
    Pharmacology &amp Toxicology 01/2004; 93(6):275-83.
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    ABSTRACT: Amyloid beta peptide in the senile plaques of patients with Alzheimer's disease is considered to be responsible for the pathology of Alzheimer's disease. We have previously reported that 6-ethyl-N,N'-bis(3-hydroxyphenyl)[1,3,5]triazine-2,4-diamine, RS-0466, is capable of significantly inhibiting amyloid beta-induced cytotoxicity in HeLa cells. To determine various profiles of RS-0466, we investigated whether RS-0466 would enhance the neuroprotective effect of brain-derived neurotrophic factor on amyloid beta(1-42)-induced cytotoxicity in rat cortical neurones. Consistent with previous observations, brain-derived neurotrophic factor ameliorated amyloid beta(1-42)-induced cytotoxicity. Furthermore, co-application of RS-0466 enhanced the neuroprotective effect of brain-derived neurotrophic factor. RS-0466 also reversed amyloid beta(1-42)-induced decrease of brain-derived neurotrophic factor-triggered phosphorylated Akt. These results raise the possibility that RS-0466 or one of its derivatives has potential to enhance the neuroprotective effect of brain-derived neurotrophic factor, and could serve as a therapeutic agent for patients with Alzheimer's disease.
    Pharmacology &amp Toxicology 01/2004; 93(6):264-8.
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    ABSTRACT: Mercury exerts a variety of toxic effects in the body. Lipid peroxidation, DNA damage and depletion of reduced glutathione by Hg(II) suggest an oxidative stress-like mechanism for Hg(II) toxicity. Melatonin, the main secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. N-Acetylcysteine, a precursor of reduced glutathione and an antioxidant, is used in the therapy of acute heavy metal poisoning. In this study the protective effects of melatonin in comparison to that of N-acetylcysteine against Hg-induced oxidative damage in the kidney, liver, lung and brain tissues were investigated. Wistar albino rats of either sex (200-250 g) were divided into six groups, each consisting of 8 animals. Rats were intraperitoneally injected with 1) 0.9% NaCl, control (C) group; 2) a single dose of 5 mg/kg mercuric chloride (HgCl2), Hg group; 3) melatonin in a dose of 10 mg/kg, 1 hr after HgCl2 injection, Hg-melatonin group; 4) melatonin in a dose of 10 mg/kg one day before and 1 hr after HgCl2 injection, melatonin-Hg-melatonin group; 5) N-acetylcysteine in a dose of 150 mg/kg, 1 hr after HgCl2 injection, Hg-N-acetylcysteine group, and 6) N-acetylcysteine in a dose of 150 mg/kg one day before and 1 hr after HgCl2 injection, N-acetylcysteine-Hg-N-acetylcysteine group. Animals were killed by decapitation 24 hr after the injection of HgCl2. Tissue samples were taken for determination of malondialdehyde, an end-product of lipid peroxidation; glutathione (GSH), a key antioxidant, and myeloperoxidase activity, an index of neutrophil infiltration. The results revealed that HgCl2 induced oxidative tissue damage, as evidenced by increases in malondialdehyde levels. Myeloperoxidase activity was also increased, and GSH levels were decreased in the liver, kidney and the lungs. All of these effects were reversed by melatonin or N-acetylcysteine treatment. Since melatonin or N-acetylcysteine administration reversed these responses, it seems likely that melatonin or N-acetylcysteine can protect all these tissues against HgCl2-induced oxidative damage.
    Pharmacology &amp Toxicology 01/2004; 93(6):290-6.
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    ABSTRACT: Dietary antioxidants protect laboratory animals against induction of tumours by a variety of chemical carcinogens. Among possible mechanism, protection against chemical carcinogenesis could be mediated via antioxidant-dependent induction of detoxifying enzymes, including quinone reductase and glutathione S-transferase (GSH transferase). Probucol is used cholesterol-lowering drug used in the clinic, with pronounced antioxidant effect that protect against chemical carcinogenesis and toxicity. In the present study we therefore examined the ability of probucol to induce activities of quinone reductase in the cytosolic fractions of various tissues of mice. Quinone reductase activity was increased significantly in 6 of 8 tissues examined from probucol-fed mice. The greatest proportionate increase, to 1.8 times control levels, was observed in liver. Probucol also increased quinone reductase activities of forestomach, heart, kidney, lungs and spleen. Quinone reductase is a major enzyme of xenobiotic metabolism that carries out obligatory two-electron reductions and thereby protects cells against toxicity of quinones. It is induced in many tissues coordinately with other enzymes that protect against electrophilic toxicity. The protective effects of probucol appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the non-oxidative metabolism of a wide variety of xenobiotics. The induction of such enzyme, quinone reductase by probucol suggests the potential value of this compound as a protective agent against chemical carcinogenesis and other forms of electrophilic toxicity. The significance of these results can be implicated in relation to cancer chemopreventive effects of probucol in various target organs.
    Pharmacology &amp Toxicology 01/2004; 93(6):259-63.
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    ABSTRACT: Seven-transmembrane G-protein-coupled receptors play a central role in physiology by facilitating cell communication through recognition of a wide range of ligands. Even more important, they represent important drug targets. Unfortunately, for many of these receptors the endogenous ligands, and hence their functions, remain to be identified. These receptors are referred to as "orphan" receptors. A pre-requisite for the identification of ligands activating orphan receptors is powerful assay systems. Until now, reporter gene assays have not been in common use in this process. Here, we summarize our development of improved reporter gene assays. We optimized reporter gene assays in respect of (i) the promoter region of the construct, (ii) the reporter enzyme used, (iii) and the assay procedure. Furthermore, an unique fluorescence-based clone selection step was introduced, allowing rapid selection of the most sensitive reporter cell clones when establishing stable reporter cell lines. Mathematical formulae are provided to enable a simple and reliable comparison between different cell lines, when tested with a compound of interest. The resulting reporter cell lines responded in a very sensitive way to the stimulation of various test receptors. The reporter system was termed HighTRACE (high-throughput reporter assay with clone election). Its high assay quality makes it suitable as a primary screening tool. Ligands for two recently unknown 7TM receptors were identified using the HighTRACE system i.e., two cell surface free fatty acid receptors, GPR40 (FFA1R) and GPR43 (FFA2R). The identification was accomplished using a reverse pharmacology approach.
    Pharmacology &amp Toxicology 01/2004; 93(6):249-58.
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    ABSTRACT: Acute effects on the behaviour of the organophosphate insecticide dichlorvos and its standard antidotes possessing behavioural activity, atropine and diazepam, were studied separately and in combinations in male Wistar rats. In the spontaneous locomotor activity test, dichlorvos and diazepam decreased, whereas atropine increased performance. The effect of dichlorvos was obtained at a dose (5 mg/kg) that induced overt intoxication, and could not be reversed during first half hour-period after administration of any combination of drugs. In the other two tests, active avoidance learning and rotarod performance, the effective dose of dichlorvos (2 mg/kg) was devoid of somatic signs of intoxication. In these more sensitive tests, the effective atropine dose (40 mg/kg) completely reversed dichlorvos-induced incapacitation. In the rotarod test, diazepam (0.5 mg/kg) contributed to the incapacitating effect of dichlorvos, and impeded desirable influence of atropine as well. In the active avoidance test, diazepam (2.5 mg/kg) contributed to failure to escape; it did not influence the dichlorvos-induced decrease of avoidance performance, nor did it impair the completely reversing effects of atropine. The results point to the possible summation of acute incapacitating effects of organophosphates and diazepam on motor performance, which seems to be, at least partly, antagonized by sufficiently high doses of atropine. However, taking into account the long-term neuroprotective role of the anticonvulsant diazepam, and hence its delayed beneficial influences on behaviour, the immediate testing of atropine/diazepam treatment of organophosphate intoxication in active avoidance paradigm could possess beside sensitivity the predictive value as well.
    Pharmacology &amp Toxicology 12/2003; 93(5):211-8.
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    ABSTRACT: Stereoselectivity has been known to play a role in drug action for 100 years or more. Nevertheless, chiral drugs have been developed and used as racemates, neglecting the fact that they comprise mixtures of two or more compounds which may have quite different pharmacological properties. A very limited access to pure enantiomers in the past has been responsible for this unsatisfactory state of affairs. During the last 20 years, significant achievements have made it possible to perform stereoselective synthesis and analysis. Today, novel chiral drugs are as a rule developed as single enantiomers. Yet, studies of old racaemic drugs are still designed, performed and published without mention of the fact that two or more compounds are involved. In recent years, a number of old racaemic drugs have been re-evaluated and re-introduced into the clinical area as the pure, active enantiomer (the eutomer). While in principle correct, the clinical benefit of this shift from a well established racaemate to a pure enantiomer often seems to be limited and sometimes exaggerated. Racaemic drugs with a deleterious enantiomer that does not contribute to the therapeutic effect (the distomer), may have been sorted out in the safety evaluation process. However, in the future any pharmacological study of racaemic drugs must include the pure enantiomers. This will generate new, valuable information on stereoselectivity in drug action and interaction.
    Pharmacology &amp Toxicology 12/2003; 93(5):203-10.
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    ABSTRACT: Fentanyl is a potent synthetic opioid that is increasingly being used in transdermal drug delivery systems. The target organ concentration of a drug administered dermally will depend on the rate of dermal absorption and the systemic elimination. We have studied the intra- and interindividual variation in dermal penetration of fentanyl in an in vitro model (static diffusion cells) with human skin, and compared the absorption of fentanyl from an aqueous solution with absorption from a commercial patch. The intraindividual variation in dermal penetration of fentanyl in aqueous solution was limited (18%) and no differences in penetration characteristics were observed between breast and abdominal skin. The interindividual variation in dermal penetration of fentanyl was extensive, with maximal fluxes ranging from 21-105 ng/cm2/hr following application of an infinite dose of fentanyl to the donor chamber. Use of transdermal drug delivery systems (patches) reduced the inter-individual variation. The permeability coefficients after application of fentanyl in aqueous solution and through patches were identical (0.0011 cm/hr). One person had a higher than average penetration rate following patch application, which may indicate that the human skin and not the patch barrier was the rate-determining factor for the other individuals included in this study.
    Pharmacology &amp Toxicology 12/2003; 93(5):244-8.
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    ABSTRACT: Microdialysis was used to sample extracellular unbound concentrations of alovudine in order to study the influence of well-known transport inhibitors (probenecid and quinidine) on the transport of alovudine between the blood and the brain extracellular fluid or whole brain tissue. The AUC (area under the time versus concentration curve) ratio brain extracellular fluid/serum was 0.17+/-0.036 after a subcutaneous injection of alovudine 25 mg/kg in rats treated with probenecid 25 mg/kg subcutaneous (n=5), which was not significantly different from the control group (AUC ratio 0.24+/-0.039). Perfusion through the microdialysis probe with probenecid 100 microM (n=4) also had no effect on the brain extracellular fluid/serum AUC ratio after alovudine 25 mg/kg subcutaneous. The AUC ratio brain extracellular fluid/serum was 0.085+/-0.009 after subcutaneous injection of alovudine 25 mg/kg in rats treated with quinidine 25 mg/kg intraperitoneally (n=8), which was significantly lower than the control group. However, the whole brain tissue concentration was not significantly different between control rats (n=5) and rats treated with quinidine (n=4) 1 hr after subcutaneous injection of alovudine 25 mg/kg (brain to serum ratios being 0.11+/-0.006 and 0.10+/-0.005 respectively). Finally, the microdialysis recovery of alovudine increased with increasing concentrations (10, 50, 250, 1250 microM) of alovudine in the perfusion fluid. The recovery of alovudine was increased in quinidine-treated rats but not in those given probenecid. Thus, probenecid does not significantly influence the concentration gradient of alovudine over the blood-brain barrier in the rat after systemic or after local administration, while quinidine lowered brain extracellular fluid concentration of alovudine, but not total brain tissue concentration. The mechanism behind this phenomenon is not yet known.
    Pharmacology &amp Toxicology 12/2003; 93(5):226-32.
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    ABSTRACT: Activation of cholinergic receptors in the spinal cord increases the intraspinal release of acetylcholine (ACh) and produces potent analgesia. The mechanisms that regulate the release of spinal ACh are not fully known. In the present study, we investigated the role of nicotinic ACh receptors in the regulation of intraspinal ACh release. Using an in vivo intraspinal microdialysis technique, nicotine was administered alone and in combination with the nicotinic antagonists mecamylamine (50 microM), dihydro-beta-erythroidine (DbetaE) (500 microM) and methyllycaconitine (MLA) (40 nM). Administration of nicotine (1 microM-1 mM) produced a dose dependent increase of intraspinal ACh release, while 10 mM nicotine resulted in dramatic increase in ACh release followed by a decrease to baseline. Administration of mecamylamine or DbetaE also induced an increased ACh release while MLA caused a decreased release. Mecamylamine and DbetaE, but not MLA pretreatment attenuated the stimulatory effect of 100 microM nicotine on intraspinal ACh release. It is suggested that spinal ACh release is regulated by different nicotinic ACh receptors. These receptors may tonically regulate spinal ACh release either directly or indirectly via inhibitory interneurones. Some of these receptors may be desensitised by high nicotine concentrations leading to a reduction of ACh release.
    Pharmacology &amp Toxicology 11/2003; 93(4):169-73.
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    ABSTRACT: Aspirin (acetylsalicylate) is an inexpensive drug that is used extensively to reduce cardiovascular disease risk. Emerging evidence suggests that aspirin reduces the risk of other chronic diseases such as certain forms of cancer. Salicylate may contribute to the disease reduction effects. It is present naturally in fruits and vegetables and individuals with a low intake of these foods may be 'salicylate deficient'. This deleterious state may constitute a significant public health threat. Interventions to prevent deficiency, such as low-dose aspirin programmes, could have substantial beneficial health impacts around the world.
    Pharmacology &amp Toxicology 11/2003; 93(4):153-5.
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    ABSTRACT: 2,6-Dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) induces persistent olfactory mucosal metaplasia and a strong glial fibrillary acidic protein increase in the olfactory bulb of mice. Furthermore, 2,6-diClPh-MeSO2 gives rise to a long-lasting hyperactivity along with an impaired radial arm maze performance. To study cause-effect relationships, olfactory mucosal histopathology, glial fibrillary acidic protein induction and neurobehavioural deficits were re-examined in mice and rats of both sexes given a single intraperitoneal dose of 2,6-diClPh-MeSO2 (16 and 65 mg/kg). There was a clear difference in the character of the olfactory mucosal lesions in the two species. In mice, an extensive metaplasia characterised by severe fibrosis, cartilage and bone formation accompanied with large polyps filling the nasal lumen was confirmed. In rats, a dose-dependent weak metaplasia with patchy loss of olfactory epithelium was observed three weeks after dosing, preferentially at the dorsal meatus, nasal septum, and the tips of the middle ethmoturbinates. Large areas of intact olfactory epithelium remained in all animals, particularly in the low dose rats. In both species, 2,6-diClPh-MeSO2 gave rise to significantly increased motor-activities, impaired performance in the radial arm maze, and glial fibrillary acidic protein-induction. Only rats showed hyperactivity at the low dose. Performance in the Morris water maze was unaffected in rats of both sexes indicating that a general impairment in spatial learning could not be supported. We propose that the observed hyperactivity and radial arm maze acquisition deficits originated from a direct effect of 2,6-diClPh-MeSO2 in the brain rather than being a consequence of the olfactory mucosal lesion.
    Pharmacology &amp Toxicology 11/2003; 93(4):156-68.
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    ABSTRACT: The effect of added food mixture (as if food was present in the stomach of an intoxicated patient) or 4 different types of ice cream (added as a flavouring and lubricating agent) on the adsorption of paracetamol (acetaminophen) to 2 formulations of activated charcoal was determined in vitro and compared with results from previous investigations showing a maximum adsorption capacity to the two activated charcoal-water slurries at about 0.62-0.72 g paracetamol/g activated charcoal. Activated charcoal (Carbomix or Norit Ready-To-Use), simulated gastric (pH 1.2) or intestinal (pH 7.2) fluid, and paracetamol were mixed with either food mixture or ice cream followed by one hr incubation. The maximum adsorption capacity of paracetamol to activated charcoal was calculated using Langmuirs adsorption isotherm. Paracetamol concentration was analyzed using high pressure liquid chromatography. In the presence of food, the paracetamol adsorption capacity of the 2 activated charcoals was reduced by max. 19% (P<0.05) for Carbomix(R) and by max. 11% (P<0.05) for Norit Ready-to-use compared to control without food (Hoegberg et al. 2002). Depending on which type of ice cream was mixed with the charcoal, the reductions compared to control (Hoegberg et al. 2002) varied between 11% and 26%. Even though a reduction in drug adsorption to activated charcoal was observed when food mixture or ice cream was added, the remaining adsorption capacity of both types of activated charcoal theoretically was still able to provide an effective gastrointestinal decontamination.
    Pharmacology &amp Toxicology 11/2003; 93(5):233-7.
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    ABSTRACT: The antioestrogens, tamoxifen and its more recent homologue toremifene, are used in the therapy of breast cancer. Tamoxifen has been reported to cause retinal changes as side effects. Both compounds inhibited glutamate uptake in retinal pigment epithelial cells, and the present study was conducted to clarify the mechanism of this inhibition. Retinal pigment epithelial cells are part of the blood-retina barrier, and their glutamate transporters are essential for retinal glutamate homeostasis. Glutamate uptake was investigated in human retinal pigment epithelial cell line D407 and in cultured pig retinal pigment epithelial cells using L-[3H]glutamate as a tracer. The cells were exposed to 7.5 microM tamoxifen and toremifene. beta-Hydroxyaspartate, a transportable inhibitor of glutamate transport, was used as a reference compound. In kinetic analyses, beta-hydroxyaspartate increased the Km constant for glutamate transport. Tamoxifen and toremifene exhibited the same effect, which indicates that inhibition evoked by them is also competitive in nature. Both drugs were more effective in the human retinal pigment epithelial cell line than in the pig retinal pigment epithelial cells. The results show for the first time that the antioestrogens tamoxifen and toremifene could possibly hamper glutamate transport by replacing glutamate as the substrate.
    Pharmacology &amp Toxicology 11/2003; 93(4):174-9.
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    ABSTRACT: We have previously observed that in the rat vas deferens nitric oxide synthase pathway potentiated phenylephrine-induced contractility raising the possibility of a facilitatory role on neurotransmission by nitric oxide. To confirm this hypothesis we studied the effect of phenylephrine on the concentration response curves obtained in preparations from reserpine-treated rats in the absence and presence of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). The endogenous noradrenaline released by normal preparations (without reserpine) was measured in the perfusion fluid of preparations stimulated with phenylephrine, in the absence and presence of L-NMMA, L-NMMA + the nitric oxide donor 3-morpholinosydnonimine hydrochloride (SIN-1), the alpha1-adrenoceptor antagonist prazosin and the blocker of noradrenaline carrier desipramine. The phenylephrine-induced noradrenaline release in a calcium-free medium was also measured. L-NMMA decreased the Emax of phenylephrine concentration response curves obtained in preparations from normal (reserpine-untreated) but not from reserpine-treated rats. In the perfusion fluid of preparations incubated with phenylephrine, a concentration-dependent increase of noradrenaline was observed which was reversed by L-NMMA and restored when SIN-1 was added together with the nitric oxide synthase inhibitor. The concentration-dependent phenylephrine-induced noradrenaline increase was not modified by desipramine but was abolished by 10 microM prazosin. In calcium-free medium, phenylephrine failed to increase the noradrenaline concentration. These results suggest that in the rat vas deferens, nitric oxide pathway potentiates the phenylephrine-induced contractility through a mechanism which involves calcium-dependent release of endogenous noradrenaline and seems to depend, at least partially on the activation of alpha1-adrenoceptors.
    Pharmacology &amp Toxicology 11/2003; 93(4):191-6.

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