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Biomedical subjects

M Scheinin

Publications and source records attributed to M Scheinin.

At least 19 recordsLinked to original sources
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

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↗
PubMed1992

Intramuscularly administered dexmedetomidine attenuates hemodynamic and stress hormone responses to gynecologic laparoscopy.

The hemodynamic and endocrine effects of three different doses of dexmedetomidine (0.6, 1.2, and 2.4 micrograms/kg), oxycodone (0.13 mg/kg), and saline solution, injected intramuscularly 45-60 min before induction of general anesthesia, were compared in a double-blind, randomized study involving 100 women undergoing gynecologic diagnostic laparoscopy. Anesthesia was induced with thiopental (4.5 mg/kg) and maintained with 0.3% end-tidal isoflurane and 70% nitrous oxide in oxygen. Arterial blood pressure and heart rate increased after endotracheal intubation and during laparoscopy in all groups, but the maximal mean arterial pressure after tracheal intubation was lower in the dexmedetomidine 2.4-micrograms/kg group (104 mm Hg [SD 19]) than in the saline solution group (130 mm Hg [SD 12]). Dexmedetomidine (2.4 and 1.2 micrograms/kg) attenuated the maximal heart rate after intubation (84 [SD 11] and 101 beats/min [SD 15], respectively) compared with saline solution (116 beats/min [SD 19]). On the other hand, 40% of the patients in the dexmedetomidine 2.4-micrograms/kg group received atropine in the postanesthesia care unit for bradycardia (heart rate < or = 40 beats/min). Preoperative anxiety and sedation before and after preanesthetic medication were evaluated by the patients with the aid of a profile of mood-state questionnaire; only dexmedetomidine 2.4 micrograms/kg produced significant anxiolysis and sedation. Plasma concentrations of norepinephrine, epinephrine, 3,4-dihydroxyphenylglycol, cortisol, and beta-endorphin increased less in the dexmedetomidine 2.4-micrograms/kg group in response to tracheal intubation and surgery than in the saline solution group.

Adrenergic alpha-Agonists↗
PubMed1991

Improved high-performance liquid chromatographic method for the routine determination of unconjugated 3-methoxy-4-hydroxyphenylethyleneglycol in human plasma using solid-phase extraction and electrochemical detection.

An improved semi-automated high-performance liquid chromatographic method is described for the routine determination of unconjugated 3-methoxy-4-hydroxyphenylethyleneglycol in plasma. The 3-ethoxy analogue of the compound is used as an internal standard. The method is based on purification of 0.5-ml plasma samples with phenyl-type reversed-phase extraction columns, reversed-phase separation with an acetate-citrate-methanol mobile phase with an octadecyl-bonded column, and dual-electrode coulometric detection with oxidation at +0.44 V and reduction at -0.25 V. The precision and accuracy of the assay are satisfactory: the lower limit of reliable detection corresponds to a plasma concentration of 1.5 nM. The validity of the determination is demonstrated by an 18% mean increase in plasma levels of 3-methoxy-4-hydroxyphenylethyleneglycol during physical exercise (duration 16 min, n = 13) and a 50% mean reduction in plasma levels induced by a single dose of the monoamine oxidase inhibitor, moclobemide (n = 8). The method is suitable for routine use in pharmacological and physiological experiments.

Benzamides↗
PubMed1991

Plasma 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are insensitive indicators of alpha 2-adrenoceptor mediated regulation of norepinephrine release in healthy human volunteers.

The usefulness of the plasma concentrations of two major metabolites of norepinephrine (NE), 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG), as indicators of neuronal NE release was investigated. The potent alpha 2-adrenoceptor agonist, dexmedetomidine, induced only about 15% maximal reductions in the metabolite concentrations, in spite of almost total inhibition of neuronal NE release, as evidenced by 90% reductions in plasma NE concentrations. Similarly, administration of the alpha 2-adrenoceptor antagonist atipamezole was followed by only small increases in plasma DHPG and no change in MHPG levels, in spite of almost six-fold, albeit short-lasting, increases in plasma NE. In contrast, a single dose of the reversible monoamine oxidase type A (MAO-A) inhibitor moclobemide reduced plasma DHPG levels by 78% and MHPG levels by 51%. It is concluded that the plasma concentrations of DHPG and MHPG are largely determined by intraneuronal, MAO-A-dependent metabolism of NE, and do not accurately reflect acute alterations in neuronal NE release. The concentration of NE in venous plasma is clearly a more sensitive indicator of alpha 2-adrenoceptor-mediated regulation of NE release.

Adult↗
PubMed1991

Beta-blocking effects of timolol at low plasma concentrations.

The concentration-effect relationship of 0.25 mg intravenous timolol with and without pretreatment with 100 mg quinidine was studied in six healthy young volunteers with a randomized, double-blind, crossover study design. Blockade of cardiac beta-adrenoceptors was assessed by determining the dose ratios (DR) of isoproterenol infusions required to increase heart rate by 25 beats/min before and after timolol infusion. The logarithm of timolol concentration in plasma was linearly related to the logarithm (DR-1) of isoproterenol infusion, with a mean Pearson correlation coefficient of 0.89 +/- 0.11 (+/- SD; n = 24) at timolol concentrations well below 1 ng/ml. The increases in cyclic adenosine monophosphate (cAMP) and norepinephrine plasma levels caused by isoproterenol infusions were attenuated after timolol. Quinidine administration increased timolol plasma levels and cardiac beta-blocking effects by 10% to 40%. It was concluded that timolol at concentrations below 1 ng/ml in plasma competitively antagonizes cardiac and noncardiac effects of isoproterenol infusions. Timolol effects are augmented after quinidine administration. The beta-blockade occurring at low plasma levels can explain side effects and actions of ocularly applied timolol.

Adult↗
PubMed1991

Biochemical assessment of preoperative stress: a study with diazepam and measurement of monoamine metabolites and catecholamines in cerebrospinal fluid and plasma.

Diazepam 5 mg or an inert placebo tablet was given as preoperative hypnotic on the night before operation to two groups (n = 18 in each) of healthy women having elective Caesarean section under spinal analgesia. A third group (n = 18) received no hypnotic. The quality of the preoperative night's sleep assessed subjectively was significantly better in the diazepam-treated patients compared with those receiving no drug. The diazepam-treated patients had also smaller CSF concentrations of noradrenaline (NA) and of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC). In comparison with the two other patient groups, in the diazepam group there was no correlation between demographic, physiological or subjectively estimated variables and CSF or plasma measurements of monoamine transmitters and their metabolites. Preoperative fear and apprehension correlated most strongly with preoperative heart rate and with the increase in heart rate from the previous day. The monoamine neurotransmitters or their metabolites were of limited use in monitoring the intensity of preoperative fear and anxiety.

3,4-Dihydroxyphenylacetic Acid↗