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M Scheinin

Publications and source records attributed to M Scheinin.

At least 55 records · Page 3Linked to original sources
PubMed1999

Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene.

The role of the alpha2C-adrenoceptor subtype in mediating the beneficial effect of alpha2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 microg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha2C-adrenoceptor subtype.

Adrenergic alpha-Agonists↗
PubMed1999

QT dispersion after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) causes a stress response with increased concentrations of plasma catecholamines and serious cardiac arrhythmias. Increased QT dispersion has been shown to predispose to cardiac arrhythmias. In SAH patients, QT dispersion has not been studied previously. QT dispersion was analyzed in 26 patients with SAH and in 16 patients (control group) scheduled for ligation of a nonruptured cerebral aneurysm. In 15 patients with SAH, the plasma concentrations of catecholamines were analyzed, and an 18-hour continuous electrocardiogram (ECG) recording was obtained. In the other 11 patients, electrocardiography was repeated daily for up to 9 days for analysis of QT dispersion. The median (25th and 75th percentiles) QT dispersion in all SAH patients was 78 milliseconds (50 and 109 milliseconds, respectively), and in control patients, it was 25 milliseconds (15 and 33 milliseconds, respectively) (P < .001). There was a positive correlation with QT dispersion and the plasma concentration of DHPG, a metabolite of norepinephrine (P < .05). All patients had episodes of cardiac arrhythmia during the 18-hour recording period. In conclusion, increased QT dispersion is a common finding after SAH and may be a result of high plasma concentrations of catecholamines in these patients.

Adrenergic Agonists↗
PubMed1999

Identification of a three-amino acid deletion in the alpha2B-adrenergic receptor that is associated with reduced basal metabolic rate in obese subjects.

The alpha2-adrenergic receptors mediate part of the actions of the catecholamines noradrenaline and adrenaline on the regulation of energy balance. As part of an ongoing study on the genetics of obesity, the entire coding sequence of the alpha2B-adrenoceptor gene was screened in 58 obese, nondiabetic Finns by PCR-single stranded conformational analysis (PCR-SSCA). A polymorphism that leads to a deletion of 3 glutamic acids from a glutamic acid repeat element (Glu x 12, amino acids 297-309) present in the third intracellular loop of the receptor protein was identified. This repeat element has previously been shown to be important for agonist-dependent receptor desensitization. Of 166 genotyped subjects, 47 (28%) had 2 normal (long) alleles (Glu12/Glu12), 90 (54%) were heterozygous (Glu12/Glu9), and 29 (17%) were homozygous for the short (Glu9/Glu9) form. The basal metabolic rate, determined by indirect calorimetry and adjusted for fat-free body mass, fat mass, sex, and age, was 94 Cal/day (5.6%) lower (95% confidence interval for difference, 32, 156) in subjects homozygous for the short allele than in subjects with two long alleles (F = 4.84; P = 0.009, by ANOVA). Thus, a genetic polymorphism of the alpha2B-adrenoceptor subtype can partly explain the variation in basal metabolic rate in an obese population and may therefore contribute to the pathogenesis of obesity.

Adult↗
PubMed1999

Pharmacokinetics and safety of deramciclane during multiple oral dosing.

UNLABELLED: Deramciclane is a new putative non-benzodiazepine-type anxiolytic compound. It is a selective serotonin 5-HT(2A) and 5-HT(2C) receptor antagonist and has also inverse agonist properties. The aim of this study was to reveal the pharmacokinetics and tolerability of deramciclane during repeated oral dosing in healthy male volunteers. SUBJECTS, MATERIAL AND METHODS: A randomized double-blind, placebo-controlled design was used. The study had three consecutive groups that received first a single oral dose of 10, 30 and 60 mg of deramciclane followed by twice a day administration for seven days. The total number of subjects was 28. The pharmacokinetic parameters were calculated for a single dose and after repeated administration. Tolerability was assessed by monitoring safety laboratory variables, electrocardiogram, heart rate, blood pressure and adverse events. RESULTS: The steady-state was reached during the seven-day administration. The pharmacokinetics of deramciclane was dose-proportional at steady-state at each dose level. Deramciclane accumulated about three-fold during repeated administration. The relative bioavailability of deramciclane increased about 1.4-fold compared to that of a single dose at each dose level. The mean elimination half-life of deramciclane for 10, 30 and 60 mg doses prolonged from 24.3, 20.9 and 22.9 h after a single dose to 30.5, 25.6 and 28.7 h at steady-state, respectively. Only few adverse events were reported, all mild and transient in nature. The most frequently reported adverse drug reactions were tiredness and headache. There were no deramciclane-induced changes in the clinical chemistry or hematology variables, blood pressure, heart rate or in electrocardiogram. CONCLUSIONS: In conclusion, the pharmacokinetics of deramciclane is linear over the dose range of 10 - 60 mg at steady-state. The slight non-linearity within the dose levels during repeated administration of seven days was regarded as clinically irrelevant. Deramciclane was safe and well tolerated up to doses of 60 mg b.i.d. for seven days.

Administration, Oral↗
PubMed1998

Modulation of agonist binding to recombinant human alpha2-adrenoceptors by sodium ions.

Agonist binding to alpha2-adrenoceptors is modulated by a number of factors such as Mg2+ and Na+ ions and by experimental manipulations which interfere with receptor-G-protein-coupling such as pertussis toxin pre-treatment or the presence of guanine nucleotides. Agonist binding assays may therefore offer an opportunity to make inferences, albeit indirect, about receptor states or conformations and about the molecular nature of the processes involved in receptor activation. We have investigated possible differences in the effects of Na+ ions on the binding of agonists to the three human alpha2-adrenoceptor subtypes, alpha2A, alpha2B and alpha2C, recombinantly expressed in S115 mouse mammary tumour cells. NaCl (40 mM) influenced the apparent affinity of a panel of alpha2-adrenoceptor ligands in a complex compound- and subtype-dependent manner. Sodium ions affected both high- and low-affinity conformations of the receptors, as defined by co-incubation with 10 microM 5'-guanylylimidodiphosphate (Gpp(NH)p). The effects of NaCl and Gpp(NH)p on agonist binding were additive indicating different modes of action for the two allosteric modulators. Thus, quite marked differences between closely related receptor subtypes were noted in the molecular details of agonist-receptor interactions and in the integration of allosteric modulation by Na+ ions. Possible explanations for the experimental findings are discussed within the theoretical framework of multi-state models, and a proposal is presented for a potential physiological role of the modulatory effect of Na+ ions, where intracellular Na+ concentrations would direct the activating influence of receptors to different G-proteins.

Adrenergic alpha-Agonists↗
PubMed1998

Subtype-specific stimulation of [35S]GTPgammaS binding by recombinant alpha2-adrenoceptors.

We measured agonist-stimulated binding of the stable GTP-analog guanosine-5'-O-(3-[35S]thiotriphosphate) ([35S]GTPgammaS) as a functional assay to monitor G-protein activation by recombinant human alpha2-adrenoceptor subtypes alpha2A, alpha2B and alpha2C. (-)-Noradrenaline was a full agonist in all receptors. Dexmedetomidine, UK14,304, clonidine and oxymetazoline showed subtype-selectivity in efficacy. Dexmedetomidine was a full agonist at alpha2B and a partial agonist at alpha2A; UK14,304 was a full agonist at alpha2A and a partial agonist at alpha2B. Clonidine and oxymetazoline were weak partial agonists at the alpha2B-subtype, but appeared inactive at alpha2A and alpha2C. The [35S]GTPgammaS binding assay provides functional information on pertussis toxin-sensitive G-protein activation, complementing radioligand binding assays and conventional second messenger assays.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1998

Adrenergic alpha2C-receptors modulate the acoustic startle reflex, prepulse inhibition, and aggression in mice.

Studies on animal models of stress, anxiety, aggression, and sensorimotor gating have linked specific monoamine neurotransmitter abnormalities to the cognitive and behavioral disturbances associated with many affective neuropsychiatric disorders. Although alpha2-adrenoceptors (alpha2-ARs) have been suggested to have a modulatory role in these disorders, the specific roles of each alpha2-AR subtype (alpha2A, alpha2B, and alpha2C) are largely unknown. The restricted availability of relevant animal models and the lack of subtype-selective alpha2-AR drugs have precluded detailed studies in this area. Therefore, transgenic mice were used to study the possible role of the alpha2C-AR subtype in two well established behavioral paradigms: prepulse inhibition (PPI) of the startle reflex and isolation-induced aggression. The alpha2C-AR-altered mice appear grossly normal, but subtle changes have been observed in their brain dopamine (DA) and serotonin (5-HT) metabolism. In this study, the mice with targeted inactivation of the gene encoding alpha2C-ARs (alpha2C-KO) had enhanced startle responses, diminished PPI, and shortened attack latency in the isolation-aggression test, whereas tissue-specific overexpression of alpha2C-ARs (alpha2C-OE) was associated with opposite effects. Correlation analyses suggested that both the magnitude of the startle response and its relative PPI (PPI%) were modulated by the mutations. In addition, the differences in PPI, observed between drug-naive alpha2C-OE mice and their wild-type controls, were abolished by treatment with a subtype nonselective alpha2-agonist and antagonist. Thus, drugs acting via alpha2C-ARs might have therapeutic value in disorders associated with enhanced startle responses and sensorimotor gating deficits, such as schizophrenia, attention deficit disorder, post-traumatic stress disorder, and drug withdrawal.

Adrenergic Uptake Inhibitors↗
PubMed1998

D-amphetamine and L-5-hydroxytryptophan-induced behaviours in mice with genetically-altered expression of the alpha2C-adrenergic receptor subtype.

Three human and mouse genes encoding alpha2-adrenoceptor subtypes (alpha2A, alpha2B, and alpha2C) have been cloned. The alpha2C-adrenoceptor is the most abundant alpha2-adrenoceptor subtype in the striatum and modulates metabolism of both dopamine and serotonin. To investigate the possible involvement of the alpha2C-adrenoceptor subtype in behaviours regulated by dopamine and serotonin, two strains of genetically-engineered mice were examined. One had a targeted inactivation of the alpha2C-adrenoceptor gene, and the other had tissue-specific over-expression of alpha2C-adrenoceptors. The locomotor activity of the mice was evaluated after stimulation with D-amphetamine, and the behavioural serotonin syndrome and head twitches were investigated after L-5-hydroxytryptophan treatment. In addition, the effects of D-amphetamine and L-5-hydroxytryptophan were studied after pretreatment with dexmedetomidine, a subtype-nonselective alpha2-adrenoceptor agonist. The lack of alpha2C-adrenoceptor expression increased and the over-expression of alpha2C-adrenoceptors decreased the response to D-amphetamine stimulation. The effect of alpha2C-adrenoceptor gene inactivation was more prominent in D-amphetamine-treated males than in females. Dexmedetomidine inhibited D-amphetamine-induced hyperlocomotion and the L-5-hydroxytryptophan-induced serotonin syndrome, but the inhibition was attenuated in mice lacking alpha2C-adrenoceptors. However, the head twitches induced by L-5-hydroxytryptophan were effectively inhibited by dexmedetomidine in all studied mice, which suggests that alpha2A-adrenoceptors mediate the inhibition of the head twitch response. The results lend further support to the proposed existence of functionally distinct alpha2-adrenoceptor subtypes that can serve as new and specific therapeutic targets in various neuropsychiatric diseases.

5-Hydroxytryptophan↗
PubMed1998

Comparison of the effects of moclobemide and selegiline on tyramine-evoked mydriasis in man.

AIMS: To examine the feasibility of using the human iris in vivo for the assessment of the interaction between tyramine and monoamine oxidase (MAO) inhibitors. To examine the relative roles of the two forms of MAO in terminating the response to sympathomimetic amines in the iris, by comparing the effects of single oral doses of moclobemide, a selective MAO-A inhibitor, and selegiline, a selective MAO-B inhibitor, on mydriatic responses to tyramine. METHODS: Twelve healthy male volunteers participated in three monthly sessions, each associated with ingestion of one capsule (moclobemide 450 mg, selegiline 10 mg, or placebo), according to a double-blind, balanced, cross-over design. Tyramine hydrochloride eye-drops (75 mM, 2 x 10 microl) were instilled three times in the left conjuctival sac at 40 min intervals. Pupil diameter was monitored with a binocular infrared television pupillometer before and for 4.5 h after ingestion of the capsule. The pupillary response to tyramine was expressed as the area under the pupil diameter x time curve (arbitrary units). A blood sample was taken before and 2 h after ingestion of the capsule, for the assay of platelet MAO-B activity, and plasma 3,4-dihydroxyphenylglycol (DHPG) concentration, an index of MAO-A activity. Platelet MAO activity was assayed radiochemically, using [14C]-phenylethylamine as substrate, and plasma DHPG by high performance liquid chromatography (h.p.l.c.). The results were analysed using analysis of variance with repeated measures, followed by Bonferroni's corrected t-test, using a significance criterion of P < 0.05. RESULTS: Both moclobemide and selegiline, compared with placebo, caused significant miosis in the right (untreated) eye. The changes in pupil diameter (mm +/- s.e. mean) from the pretreatment measurement were: placebo -0.09 +/- 0.07, moclobemide -0.52 +/- 0.09, selegiline -0.26 +/- 0.1. The mydriatic response to tyramine was potentiated by moclobemide, compared with the response recorded in the presence of placebo. The responses to tyramine (arbitrary units +/- s.e. mean) were: placebo 77.08 +/- 11.65, moclobemide 140.25 +/- 18.9, selegiline 72.75 +/- 12.35. Both moclobemide and selegiline significantly reduced platelet MAO activity, compared with placebo. The changes in platelet MAO activity (nmol h(-1) mg(-1) protein +/- s.e. mean) from the pretreatment level were: placebo 0.5 +/- 0.62, moclobemide -6.7 +/- 0.66, selegiline -17.7 +/- 0.87. Moclobemide significantly reduced plasma DHPG concentration, compared with placebo. The changes in plasma DHPG concentration (nmol l(-1) +/- s.e. mean) from the pretreatment level were: placebo -0.01 +/- 0.24, moclobemide -4.98 +/- 0.32, selegiline -0.51 +/- 0.26. CONCLUSIONS: The potentiation of tyramine-evoked mydriasis by moclobemide is likely to reflect the inhibition of MAO-A activity in the iris, consistent with the activity of this enzyme in sympathetic nerve terminals. The lack of effect of selegiline on tyramine-evoked mydriasis argues against a role of MAO-B in terminating the effects of sympathomimetic amines in the iris. The effects of the two drugs on platelet MAO activity and plasma DHPG concentration are in agreement with previous reports and consistent with the relative selectivity of moclobemide for MAO-A and of selegiline for MAO-B. The miosis caused by the two MAO inhibitors is likely to be due to a central sympatholytic action of the drugs.

Adult↗
PubMed1998

A comparison of gasless mechanical and conventional carbon dioxide pneumoperitoneum methods for laparoscopic cholecystectomy.

UNLABELLED: Carbon dioxide (CO2) insufflation with increased intraabdominal pressure (IAP) has adverse hemodynamic, pulmonary, and renal effects. To avoid these problems, an abdominal wall lift method with a retractor was used to provide the surgical view without CO2 insufflation. Twenty-six patients undergoing elective laparoscopic cholecystectomy were randomly allocated to either the gasless, retractor group, or conventional CO2 pneumoperitoneum group (CPP). Hemodynamic data, ventilatory variables, urine output, urine oxygen tension, and blood samples for determining stress hormones were collected throughout the perioperative period. Patients in the retractor group had lower mean arterial pressure, heart rate, and central venous pressure (P < 0.001). They also had higher pulmonary dynamic compliance and needed a lower minute volume of ventilation to achieve normocarbia (P < 0.001). Urine output and oxygen tension in urine were higher (P < 0.05) with the retractor method than with CPP. Increase in plasma renin activity (P < 0.05) and decrease in core temperature (P < 0.001) were smaller with the gasless method than with CPP. The gasless method for laparoscopic cholecystectomy might be beneficial, especially in patients with compromised cardiorespiratory or renal function. IMPLICATIONS: Totally gasless laparoscopic cholecystectomy was compared with conventional pressure pneumoperitoneum with CO2 insufflation. The gasless method resulted in more stable hemodynamics and pulmonary function, as well as higher urine, output than conventional pressure pneumoperitoneum. No changes in renal oxygenation was seen with the gasless method, compared with conventional pressure pneumoperitoneum.

Adult↗
PubMed1998

Effects of esmolol on haemodynamic response to CO2 pneumoperitoneum for laparoscopic surgery.

BACKGROUND: Carbon dioxide (CO2) pneumoperitoneum for laparoscopic surgery increases arterial pressures, systemic vascular resistance and heart rate and decreases urine output. METHODS: In this double-blind randomized study esmolol, an ultrashort-acting beta1-adrenoceptor antagonist was compared with physiological saline (control) in 28 patients undergoing laparoscopic surgery in standardized 1 MAC isoflurane anaesthesia. Alfentanil infusion was used to prevent the increase of mean arterial pressure more than 25% from baseline. RESULTS: Esmolol effectively prevented the pressor response to induction and maintenance of CO2 pneumoperitoneum. Significantly (P<0.001) less alfentanil was needed in the esmolol group than in the control group. Urine output was higher (P<0.05) and plasma renin activity (P<0.01) and urine N-acetyl-beta-D-glucosaminidase levels lower in the esmolol group when compared with the control group. CONCLUSIONS: Esmolol blunts the pressor response to induction and maintenance of pneumoperitoneum and may protect against renal ischaemia during pneumoperitoneum.

Acetylglucosaminidase↗
PubMed1998

Chloroethylclonidine binds irreversibly to exposed cysteines in the fifth membrane-spanning domain of the human alpha2A-adrenergic receptor.

The alpha2-adrenergic receptors (alpha2-ARs) mediate signals to intracellular second messengers via guanine nucleotide binding proteins. Three human genes encoding alpha2-AR subtypes (alpha2A, alpha2B, alpha2C) have been cloned. Several chemical compounds display subtype differences in their binding and/or functional activity. Site-directed mutagenesis and molecular modeling are new tools with which to investigate the subtype selectivity of ligands. In this study, we introduce a new approach to mapping of the binding site crevice of the human alpha2A-AR. Based on a three-dimensional receptor model, we systematically mutated residues 197-201 and 204 in the fifth transmembrane domain of the human alpha2A-AR to cysteine. Chloroethylclonidine, an alkylating derivative of the alpha2-adrenergic agonist clonidine, binds irreversibly to alpha2A-ARs by forming a covalent bond with the sulfhydryl side chain of a cysteine residue exposed in the binding cavity, leading to inactivation of the receptor. Irreversible binding of chloroethylclonidine was used as a criterion for identifying introduced cysteine residues as being exposed in the binding cavity. The results supported a receptor model in which the fifth transmembrane domain is alpha-helical, with residues Val197, Ser200, Cys201, and Ser204 exposed in the binding pocket. Residues Ile198, Ser199, Ile202, and Gly203 face the lipid bilayer of the plasma membrane. This approach emerges as a powerful tool for structural characterization of the alpha2-ARs.

Adrenergic alpha-Antagonists↗
PubMed1998

Alpha2C-adrenoceptor-overexpressing mice are impaired in executing nonspatial and spatial escape strategies.

Drugs acting via alpha2-adrenoceptors modulate cognitive functions mediated via frontostriatothalamic feedback loops. The alpha2C-adrenoceptor subtype is expressed in the basal ganglia, hippocampus, and neocortex, areas that are involved in memory and other cognitive functions. alpha2C-Overexpressing (OE) mice were impaired in spatial or nonspatial water maze (WM) tests, and alpha2 antagonist treatment fully reversed the WM escape defect in OE mice. However, alpha2C-overexpression did not influence open field and passive avoidance behaviors or cortical EEG arousal or the actions of alpha2 agonist or antagonist drugs on these functions. Our results suggest that alpha2C-adrenoceptors can modulate navigation to a hidden or visible escape platform, whereas many other actions of alpha2-adrenergic agents, such as sedation, are not mediated via alpha2C-adrenoceptors. Therefore, alpha2-agonists lacking alpha2C-AR affinity or alpha2C-AR subtype-selective alpha2 antagonists could modulate functioning of frontostriatothalamic feedback loops more effectively than the current subtype-nonselective drugs.

Adrenergic alpha-Agonists↗
PubMed1998

Antenatal dexamethasone treatment decreases plasma catecholamine levels in preterm infants.

Antenatal corticosteroid therapy (ACT) has many beneficial effects on preterm infants. The cellular mechanisms of action of ACT include beta-adrenergic receptor-mediated cAMP generation. This study investigated the effects of ACT on sympathoadrenal mechanisms during immediate postnatal adaptation of preterm infants. Plasma epinephrine, norepinephrine, 3,4-dihydroxyphenylglycol, and cAMP were measured within 12 h after birth in 103 preterm infants (gestational age 24-36 wk), who were divided into two groups (non-ACT and ACT group) according to whether the mother had received dexamethasone treatment. Infants in the ACT group had significantly lower concentrations of plasma catecholamines than infants in the non-ACT group; plasma epinephrine was 38% lower, and plasma norepinephrine was 20-40% lower in the ACT group, depending on gestational age (r = -0.37 in the non-ACT group and r = -0.28 in the ACT group, p < 0.05). Plasma cAMP concentrations were similar in the two groups. Antihypertensive treatment of the mother was associated with low plasma cAMP (p < 0.001), whereas tocolytic treatment was associated with high plasma cAMP (p = 0.001) of the infant. The results indicate that ACT attenuates the birth-related increase in plasma catecholamines. Still, plasma cAMP levels remain high, which suggests enhanced beta-adrenoceptor signaling after ACT.

Antihypertensive Agents↗
PubMed1997

Assessment of alpha2-adrenoceptor antagonist potency with GTPase assay.

Membranes from Chinese hamster ovary (CHO) cells expressing high densities of alpha2A-, alpha2B- or alpha2C-adrenoceptor subtypes were used to monitor potencies of alpha2-adrenoceptor antagonists with a GTPase assay. Receptor-activated high-affinity GTPase activity was determined by measuring the rate of release of 32P from [gamma-32P]GTP. Concentration-response curves to the full agonist (-)-noradrenaline were obtained in the presence of different antagonist concentrations and pA2 values were calculated by Schild analysis. Three antagonists (rauwolscine, prazosin and chlorpromazine) showed subtype-selectivity, which agrees with earlier radioligand binding results. We suggest that the GTPase assay described here is useful for characterization of the functional potency and subtype-selectivity of alpha2-adrenoceptor antagonists.

Adrenergic alpha-2 Receptor Antagonists↗