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M Scheinin

Publications and source records attributed to M Scheinin.

At least 109 records · Page 6Linked to original sources
PubMed1993

Cloning and expression of a fish alpha 2-adrenoceptor.

1. Pigment granule aggregation in specialized cells (melanophores) from the skin of teleost fishes has been shown to be mediated by receptors with an alpha 2-adrenoceptor pharmacology. We now report the cloning of the alpha 2-F, a fish skin alpha 2-receptor from the cuckoo wrasse (Labrus ossifagus). 2. Degenerate oligonucleotides corresponding to conserved regions of the human alpha 2-adrenoceptor subtypes were used in a polymerase chain reaction (PCR) with cDNA prepared from mRNA isolated subtypes were used in a polymerase chain reaction (PCR) with cDNA prepared from mRNA isolated from the skin of the cuckoo wrasse. An 876 base pair (bp) product was obtained that was homologous with that of the human alpha 2-adrenoceptor and was used to screen a genomic library from the cuckoo wrasse. 3. A clone (pTB17BS) consisting of approximately 5 kb of genomic DNA was obtained which contained the nucleotide sequence of the initial PCR product. In addition, it contained an open reading frame that encoded a protein of 432 amino acids and approximately 2 kb of 5'untranslated sequence. The deduced amino acid sequence of this protein showed 47-57% identity with the human alpha 2-adrenoceptors and thus appeared to encode a fish alpha 2-adrenoceptor. 4. In the 5'-untranslated region of the gene, nucleotide sequences were present suggesting that transcription of the alpha 2-F might be regulated by cyclic AMP, calcium and/or steroids. 5. The alpha 2-F was expressed in COS-7 cells and radioligand binding studies were performed with [3H]-rauwolscine. The binding was of high affinity and it was saturable with a KD of 0.8 +/- 0.1 nM and a Bmax of 5.7 +/- 1.0 pmol mg-1 of protein.6. Competition curves for the displacement of specific [3H]-rauwolscine binding showed the following order of potency: for agonists, medetomidine > clonidine >p-aminoclonidine> B-HT 920> (- )-noradrenaline;for antagonists, rauwolscine > atipamezole > yohimbine > phentolamine > prazosin.7. These results show that alpha2-F has characteristics of both the human alpha2-CIO and alpha2-C4 and that it might represent an ancestral alpha2-adrenoceptor subtype.

Amino Acid Sequence↗
PubMed1993

Reduced turnover of dopamine and 5-hydroxytryptamine in discrete dopaminergic, noradrenergic and serotonergic rat brain areas after acutely administered medetomidine, a selective alpha 2-adrenoceptor agonist.

Monoamine metabolism and turnover were investigated in discrete dopaminergic, noradrenergic and serotonergic brain areas in the rat after acute administration of the selective alpha 2-adrenoceptor agonist, medetomidine. Medetomidine (3, 30 and 100 micrograms/kg subcutaneously) was given 90 min. before decapitation and discrete brain nuclei were punched from frozen brain slices for the analysis of concentrations of noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). In a separate experiment, the accumulation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) was measured after inhibition of L-aromatic amino acid decarboxylase by NSD 1015: medetomidine (3, 10 and 100 micrograms/kg subcutaneously) was given 60 min. before NSD 1015 (100 mg/kg intraperitoneally), and the rates of DOPA and 5-HTP accumulation were determined over 30 min. Finally, the antagonistic effect of idazoxan (1 mg/kg subcutaneously), a selective alpha 2-adrenoceptor blocking agent, on the medetomidine-induced changes in monoamine metabolism was investigated. Medetomidine markedly decreased the metabolism and turnover of DA in the nucleus caudatus, but not in the nucleus accumbens or substantia nigra. In all dopaminergic areas, the turnover of 5-HT was markedly inhibited by medetomidine. These effects were significantly counteracted by idazoxan pretreatment demonstrating the alpha 2-receptor mediated action of medetomidine. The turnover of 5-HT was also reduced by medetomidine in the nucleus raphe dorsalis, the A1-C1 area, locus coeruleus, nucleus tractus solitarius and the A5 area. The accumulation of DOPA was markedly inhibited in the A1-C1 area, nucleus tractus solitarius and nucleus raphe dorsalis, but not in locus coeruleus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1993

Monoamine metabolite and catecholamine measurements in cerebrospinal fluid in determining the quality of the pre-operative night's sleep.

Temazepam 20 mg (n = 18), midazolam 15 mg (n = 14), placebo (n = 15) or no medication (n = 20) were given orally as pre-operative hypnotic in healthy patients operated on under spinal analgesia. The quality of the pre-operative night's sleep assessed subjectively was significantly better in patients receiving temazepam (P = < 0.05) and midazolam (P = < 0.05) compared with those receiving no drug. The concentrations of cortisol and monoamine neurotransmitters or their metabolites in cerebrospinal fluid were of no value in monitoring the quality of the pre-operative night's sleep.

Adult↗
PubMed1993

Hormonal responses to physical exercise in patients with polycystic ovarian syndrome.

OBJECTIVE: To examine the effects of obesity and polycystic ovarian syndrome (PCOS) on the endocrine responses to physical exercise. SETTING: Outpatient clinic of reproductive endocrinology at the University Central Hospital of Turku and the Department of Pharmacology, University of Turku, Turku, Finland. PATIENTS: Nine oligomenorrheic women with PCOS (body mass index [BMI] 19.5 to 46.0 kg/m2) and eight control women with regular menstrual cycles (BMI 20.0 to 53.5 kg/m2). INTERVENTIONS: A bicycle ergometer test was performed at 8 A.M. RESULTS: The only hormone response that was different between PCOS patients and controls was the exercise-induced increase in circulating GH levels. This response was significantly greater in controls than in PCOS patients. There was also a negative correlation between the GH response and BMI. The increases in the concentrations of adrenaline, noradrenaline, 3,4-dihydroxyphenylglycol, glucose, and insulin:C-peptide ratios during the bicycle ergometer test were correlated negatively to BMI. CONCLUSION: Obesity is an important determinant of the hormonal responses to physical exercise. This applies also to women with PCOS. Taking obesity into account in the analysis of exercise-induced hormone responses, only little, if any, of the variation in the hormonal responses measured by us could be attributed to PCOS per se. The only hormone response that was different between PCOS patients and controls was the GH response.

Adult↗
PubMed1992

Characterization of [3H]atipamezole as a radioligand for alpha 2-adrenoceptors.

Atipamezole (MPV-1248, 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole), a potent alpha 2-adrenoceptor antagonist, was tritiated to high specific activity. We then compared [3H]atipamezole and [3H]rauwolscine as radioligands for alpha 2-adrenoceptors in rat cerebral cortex, neonatal rat lung, and human platelets. (-)-Noradrenaline and phentolamine were used to define specific alpha 2-adrenergic binding. Unlabelled atipamezole was used in a similar manner to define saturable, high-affinity non-adrenergic binding. [3H]Atipamezole binding to human platelets (Kd 1.3 nM) and rat brain membranes (Kd 0.5 nM) equilibrated rapidly and was displaced in the expected manner by alpha 2-adrenergic ligands. In contrast, [3H]atipamezole binding in neonatal rat lung membranes was only effectively inhibited by unlabelled atipamezole, and by high concentrations of idazoxan. The total density of binding sites for [3H]atipamezole was clearly in excess of the density of alpha 2-adrenoceptors in this tissue, as defined by [3H]rauwolscine binding. We conclude that [3H]atipamezole binds with high affinity to alpha 2-adrenoceptors in human platelets and rat cerebral cortex, and that the compound can be used to investigate alpha 2-adrenoceptor properties and drug actions in these tissues. In neonatal rat lung, [3H]atipamezole identified an additional population of binding sites, distinct from both classical alpha 2-adrenoceptors and idazoxan-defined imidazoline receptors. The pharmacological identity of these binding sites remains to be elucidated. This non-adrenergic component in the binding characteristics of [3H]atipamezole complicates its use as a general alpha 2-adrenoceptor radioligand.

Adrenergic alpha-Antagonists↗
PubMed1992

Stable expression of recombinant human alpha 2-adrenoceptor subtypes in two mammalian cell lines: characterization with [3H]rauwolscine binding, inhibition of adenylate cyclase and RNase protection assay.

Cloning of the genes encoding distinct subtypes of human alpha 2-adrenergic receptors (alpha 2-AR) allows the separate recombinant expression of each individual subtype in heterologous systems. We report here the transfection, selection and preliminary pharmacological characterization of two mammalian cell lines, adherent Shionogi S115 mouse mammary tumour cells and human B-lymphoblastoid IBW4 cells growing in suspension, expressing the human alpha 2-AR subtypes alpha 2-C4 and alpha 2-C10 at densities of approx. 2 x 10(5) receptors/cell. Transfection of the subtype genes was verified using a specific RNase protection assay. Pharmacological characterization was carried out with [3H]rauwolscine binding, which was inhibited by oxymetazoline and prazosin in a subtype-selective manner. The sensitivity of (-)-noradrenaline binding to the GTP-analogue 5'-guanylylimidodiphosphate suggested that the receptors are coupled to G-proteins. This was verified in S115 cells by efficient inhibition of forskolin-stimulated cAMP production by the alpha 2-AR agonists, (-)-noradrenaline and clonidine. These cell lines thus appear to be suitable for pharmacological studies on receptor function and ligand binding.

Adenylyl Cyclase Inhibitors↗
PubMed1992

Alpha 2-adrenoceptor density in forebrain areas of Zucker rats: no effect of genetic obesity or antiglucocorticoid treatment.

The density of alpha 2-adrenoceptors was determined in different forebrain regions of lean and obese Zucker rats by para-[125I]iodoclonidine ([125I]PIC) receptor autoradiography. No significant differences were observed between the Zucker phenotypes in the density of alpha 2-adrenoceptors in any brain areas examined. Four days treatment with the antiglucocorticoid mifepristone (RU 38486) did not affect [125I]PIC-binding. It is concluded that the hyperphagia and abnormal corticosterone secretion of genetically obese Zucker rats do not appear to be associated with changes in alpha 2-adrenoceptor density in brain.

Animals↗
PubMed1992

Tryptophan and biogenic amine metabolites in post-mortem human cisternal fluid: effects of post-mortem interval and agonal time.

Cisternal fluid (CF) tryptophan (TRP), 5-hydroxyindole-3-acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were measured from 40 adult cadavers. They were divided into 4 groups (n = 10 in each group), with samples taken 2, 4, 10 and 24 h after death. The CF concentrations of TRP and all determined biogenic amine metabolites were distinctly higher than in lumbar CSF during life, and concentrations of 5-HIAA were also higher in post-mortem samples than in cisternal or ventricular CSF in living humans. The means of the samples of 5-HIAA, DOPAC, HVA and MHPG were not statistically significantly different over time, but some trends were evident. TRP concentrations in CF increased linearly with time (from 4.6 to 23.6 mumol/l, P less than 0.001). CF DOPAC and HVA concentrations were dependent on agonal time and dopamine infusions. Our results imply that both ante-mortem and post-mortem conditions may influence monoamine metabolite and TRP concentrations in CF. These conditions should be accounted for in studies using post-mortem samples to study differences between patient groups in CNS neurochemistry.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Differential expression of two alpha 2-adrenergic receptor subtype mRNAs in human tissues.

Genetic subtypes of alpha 2-adrenergic receptors (AR) may mediate distinct physiological functions, and undergo differential cell type-specific regulation. Thus, these distinct receptor subtypes are possible targets for the development of subtype-selective drugs. We have analyzed the tissue distribution of two human alpha 2-adrenoceptor subtype gene mRNAs, alpha 2-C4 and alpha 2-C10, in normal human fetal and adult tissues. Both receptor subtype mRNAs were abundantly expressed in fetal brain and choroid plexus. In non-neural fetal tissues, alpha 2-C10 mRNA was detected in spleen, kidney, adrenal gland, and skin, while alpha 2-C4 transcripts were observed only in kidney and skin. Most regions of the adult brain also expressed both subtypes, but with marked quantitative differences. For example, cerebral cortex contained predominantly alpha 2-C10 mRNA, whereas the caudate nucleus expressed mostly alpha 2-C4 mRNA. In adult peripheral tissues, alpha 2-C10 mRNA expression was most abundant in spleen and renal cortex, and expression of alpha 2-C4 mRNA was strongest in renal cortex and medulla. These different expression patterns provide evidence for the differential regulation of the two alpha 2-adrenergic receptor genes and warrant further investigation with techniques capable of improved anatomical resolution. Regional differences in receptor subtype expression may be valuable for the development of new, subtype-selective pharmacological agents with more targeted actions compared to currently used alpha 2-adrenoceptor agonists and antagonists.

Animals↗
PubMed1992

Effects of short-term thermal stress on plasma catecholamine concentrations and plasma renin activity in pregnant and nonpregnant women.

OBJECTIVE: The purpose of this study was to find out whether the effects of thermal stress on plasma catecholamines and plasma renin activity are altered by pregnancy. STUDY DESIGN: Nonpregnant (n = 15) and pregnant (13 to 14 weeks, n = 23; 36 to 37 weeks, n = 23) healthy women were examined. Samples were taken before the exposure, in the heat chamber (70 degrees C), and during the recovery. The BMDP statistical software was used. RESULTS: The concentration of epinephrine in plasma increased significantly only in the nonpregnant group. The epinephrine concentrations in the pregnancy groups increased most in the subjects who felt discomfort during or after the exposure. Plasma norepinephrine concentrations increased without significant differences between the groups. Plasma renin activity increased in each group, but the increases were significantly lower in the pregnancy groups as compared with the nonpregnant group. CONCLUSIONS: Pregnancy does not alter the thermally induced increase in norepinephrine release. The adrenaline response is mostly dependent on the mental discomfort. The plasma renin activity response to thermal stress is blunted during pregnancy.

Adult↗
PubMed1992

Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine.

The pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine--a novel alpha 2-adrenergic receptor agonist under development for preanesthetic use--were studied in healthy male volunteers. Single intramuscular doses of dexmedetomidine (0.5, 1.0, and 1.5 microgram/kg) and placebo were administered to six subjects in a single-blind, multiple crossover study. Dexmedetomidine induced dose-related impairment of vigilance assessed both objectively and subjectively. The drug also caused moderate decreases in blood pressure and heart rate. Plasma norepinephrine was dose-dependently (maximum 89%) decreased. The intramuscular doses resulted in linearly dose-related plasma concentrations of dexmedetomidine. Pharmacokinetic calculations revealed a time to maximum concentration from 1.6 to 1.7 hours, an elimination half-life of 1.6 to 2.4 hours, an apparent total plasma clearance of 0.7 to 0.9 L/hr/kg, and apparent volume of distribution of 2.1 to 2.6 L/kg. The sedative effect of dexmedetomidine dissipated during the 6-hour observation time, but all other effects were still evident 6 hours after administration of the higher doses, paralleling the plasma concentration curves. The relationship of plasma concentrations of dexmedetomidine to pharmacodynamic variables was consistent with a linear pharmacodynamic model. The pharmacodynamic-pharmacokinetic profile of intramuscular dexmedetomidine may be suited to the proposed preanesthetic clinical use of this alpha 2-agonist.

Adrenergic alpha-Agonists↗
PubMed1992

Dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and reduces the need for thiopentone and peroperative fentanyl.

The effects of the new, highly selective alpha 2-adrenergic agonist, dexmedetomidine, were studied in a randomized, placebo-controlled, double-blind trial in 24 ASA I patients. Dexmedetomidine 0.6 micrograms kg-1 or saline was given i.v. 10 min before induction of anaesthesia. The required dose of thiopentone was significantly (P less than 0.001) smaller in the dexmedetomidine group (mean 4.4 (sd 0.9) mg kg-1) than in the control group (6.9 (1.6) mg kg-1), and the drug attenuated the cardiovascular responses to laryngoscopy and tracheal intubation. The concentration of noradrenaline in mixed venous plasma was smaller in the dexmedetomidine group during all phases of induction (P less than 0.01). During surgery, fentanyl was required in a dose of 0.5 (0.6) mg kg-1 and 2.8 (2.6) mg kg-1 in the dexmedetomidine and control groups, respectively (P less than 0.001). During 2 h postoperative follow-up, oxycodone 0.06 (0.06) mg kg-1 and 0.16 (0.1) mg kg-1 (P less than 0.05) was given to the two groups respectively.

Adrenergic alpha-Agonists↗
PubMed1992

Dexmedetomidine reduces intraocular pressure, intubation responses and anaesthetic requirements in patients undergoing ophthalmic surgery.

We studied the effects of a single i.v. dose of dexmedetomidine, a highly selective and specific alpha 2 adrenoceptor agonist, on intraocular pressure (IOP), haemodynamic and sympathoadrenal responses to laryngoscopy and tracheal intubation, and on anaesthetic requirements in ophthalmic surgery. Thirty ASA I-II patients undergoing cataract surgery were allocated randomly to receive either dexmedetomidine 0.6 microgram kg-1 or saline placebo i.v. 10 min before induction of anaesthesia in a double-blind design. After dexmedetomidine there was a 34% (95% confidence interval (CI) 27-43%) reduction in IOP (P less than 0.001) and 62% (CI 57-68%) decrease in plasma noradrenaline concentrations (P less than 0.001). After intubation, maximum heart rate was 18% (CI 3-33%, P = 0.036) and the maximum IOP 27% (CI 11-43%, P = 0.005) less in the dexmedetomidine group compared with the patients treated with placebo. Within 10 min after intubation, maximum systolic and diastolic arterial pressures were also significantly (P = 0.013 and P = 0.020) smaller in the dexmedetomidine group. The induction dose of thiopentone was smaller (23% (CI 20-26%) P = 0.012), and the use of isoflurane or fentanyl supplements during anaesthesia was less frequent in the dexmedetomidine group. The patients premedicated with dexmedetomidine recovered faster from anaesthesia (P = 0.042). These results suggest that dexmedetomidine may be a useful anaesthetic adjunct in ophthalmic surgery.

Adolescent↗
PubMed1992

Diazepam and atropine as premedicants: no discrimination by monoamine metabolite and catecholamine measurements in cerebrospinal fluid and plasma.

The relationships between self-reported assessments of the quality of the preoperative night's sleep, preoperative anxiety, and several biochemical and physiological indicators of stress reaction were investigated in pregnant women at term receiving no premedication (n = 15), a placebo tablet (n = 15), diazepam 5 mg p.o. (n = 15), or atropine 0.01 mg/kg i.m. (n = 15), in connection with spinal analgesia for elective caesarean section. In the patients receiving no premedication, the subjective estimate of the quality of the preoperative night's sleep was negatively associated with concentrations of noradrenaline (NA) and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF, and with plasma adrenaline. The anxiolytic effect of diazepam was reflected as significantly lower plasma levels of another metabolite of NA, 3,4-dihydroxyphenylglycol (DHPG). Placebo and diazepam, and to a lesser extent atropine, confounded the statistical relationships between the clinical and biochemical responses found in the patients with no premedication. On the whole, the biochemical monoamine measurements were of little use in determining the clinical effects of different kinds of premedicants.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Sympatho-adrenal activity and the clinical sedative effect of detomidine in horses.

Thirty-nine horses were given detomidine 10 micrograms/kg bodyweight (bwt) intravenously (iv) and six horses were given a corresponding volume of saline solution before minor procedures. Venous blood samples were collected for catecholamine and cortisol determination immediately before the detomidine or saline injection and 20 mins after it. The behaviour of the horse at the time of detomidine injection and the extent of sedation were evaluated. Plasma adrenaline, noradrenaline and the catecholamine metabolites, 3,4-dihydroxyphenylglycol (DHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC), and cortisol concentrations decreased significantly after administration of detomidine, but they remained unchanged in the control group. A high plasma adrenaline concentration before detomidine injection, indicative of a high level of stress, seemed to correspond with a reduced sedative effect of detomidine. The extent of sedation also was related to the concentrations of adrenaline, noradrenaline and DHPG in plasma after the detomidine injection. The reductions in the plasma catecholamine concentrations may have been caused, in part, by decreased secretion of catecholamines due to the sedative effects of detomidine; but detomidine also influences the plasma catecholamine concentrations by reducing directly sympatho-adrenal activity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Mode of delivery, plasma catecholamines and Doppler-derived cardiac output in healthy term newborn infants.

Umbilical cord arterial and venous concentrations of epinephrine, norepinephrine and the catecholamine metabolites 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylacetic acid were determined in 41 healthy newborn infants delivered vaginally, vaginally with epidural analgesia, by cesarean section under general anesthesia or by cesarean section under epidural anesthesia. Doppler-derived cardiac output and arterial blood pressure were repeatedly measured during the first 48 h of life. There were fairly small differences in umbilical arterial and venous plasma concentrations of epinephrine and norepinephrine between the groups, with the highest levels of norepinephrine in infants delivered vaginally without analgesia (about 10 times as high as in the cesarean, general anesthetized group). No significant differences were found in the metabolite concentrations. Doppler-derived cardiac output and heart rate decreased in all groups during the study period and, in spite of increased catecholamine levels in the vaginally delivered infants, the differences between the groups were marginal. Healthy term infants with no signs of asphyxia were well prepared for a normal hemodynamic adaptation irrespective of mode of delivery or mode of obstetric anesthesia/analgesia.

Analgesia, Epidural↗
PubMed1992

Sympathoadrenal activity in preterm infants during the first five days of life.

We measured plasma concentrations of epinephrine (E), norepinephrine (NE), 3,4-dihydroxyphenylacetic acid (DOPAC), and 3,4-dihydroxyphenylglycol (DHPG) as well as urinary concentrations of metanephrine (M), normetanephrine (NM) and 3-methoxy-4-hydroxymandelic acid (MOMA) on day 2 and day 5 in preterm infants; gestational age less than 30 weeks (G less than 30; n = 16) and gestational age 30-34 weeks (G 30-34; n = 19). Concentrations of E (0.00-2.28 nmol/l) and NE (0.6-9.1 nmol/l) in plasma were much lower than those previously reported during preterm and term delivery. The E:NE ratio decreased from 1:10 on day 2 to 1:30 on day 5, and the M:NM ratio decreased from 1:4 on day 2 to 1:8 on day 5, indicating relatively higher catecholamine secretion from the adrenals than from the sympathetic nerve terminals in preterm infants during postnatal adaptation. Plasma concentrations of DOPAC and DHPG were significantly higher in G less than 30 than in G 30-34 (DOPAC, p = 0.0494; DHPG, p = 0.0092), probably relating to a low urinary excretion rate of catecholamine metabolites in infants in G less than 30. Plasma and urinary concentrations of catecholamines and their metabolites varied considerably, and no significant correlations to postnatal events could be demonstrated.

3,4-Dihydroxyphenylacetic Acid↗