Biomedical subjects

Mika Scheinin

Publications and source records attributed to Mika Scheinin.

44 records · Page 3Linked to original sources

PubMed2003

Effects of common polymorphisms in the alpha1A-, alpha2B-, beta1- and beta2-adrenoreceptors on haemodynamic responses to adrenaline.

Common naturally occurring polymorphisms have been identified in the coding regions of the alpha(1A)-, alpha(2B)-, beta(1)- and beta(2)-adrenoceptor (AR) genes [alpha(1A)-AR R492C, alpha(2B)-AR insertion/deletion (I/D), beta(1)-AR R389G, beta(2)-AR G16R and beta(2)-AR Q27E] and are associated with modified in vivo and in vitro functionality. We tested their possible effects on the haemodynamic responses to intravenous adrenaline (20, 40, 80 and 160 ng/kg of body weight per min; 5 min for each infusion rate) before and after beta-blockade (propranolol) in 16 young healthy men. We monitored changes in heart rate, blood pressure (BP), ECG, coronary flow velocity and plasma adrenaline and noradrenaline. The Cys/Cys (CC) genotype of the alpha(1A)-AR R492C polymorphism was associated with a longer ECG PR interval before and during the adrenaline infusions. The deletion/deletion (D/D) genotype of the alpha(2B)-AR I/D polymorphism was associated with blunted coronary blood flow increases during the adrenaline infusion before beta-blockade. The beta(1)-AR R389G polymorphism was not associated with modified responses to infused adrenaline. Subjects carrying the Gly/Gly (GG) genotype of the beta(2)-AR G16R polymorphism demonstrated increases in diastolic BP upon adrenaline infusion, whereas diastolic BP was decreased in the other genotype groups. These results suggest that, upon acute adrenaline infusion, the alpha(2B)-AR D/D genotype confers increased vasoconstriction and that the beta(2)-AR GG genotype confers reduced vasodilatation.

Adrenergic beta-Antagonists↗

PubMed2003

Agonist-dependent trafficking of alpha2-adrenoceptor subtypes: dependence on receptor subtype and employed agonist.

Many G protein-coupled receptors (GPCRs) are internalized from the plasma membrane after agonist exposure. Previously, marked agonist-induced internalization of human alpha2A- and alpha2B-adrenergic receptors (AR) was observed in transfected neuronal rat pheochromocytoma (PC12) cells; alpha2A- and alpha2B-AR were internalized into partly distinct intracellular vesicles (Olli-Lähdesmäki et al., J. Neurosci. 19, 9281-9288, 1999). In this paper, the extent of alpha2-AR internalization was quantitated in human embryonic kidney (HEK-293) and PC12 cells by combined application of cell surface biotinylation and ELISA methods, which allow measurement of protein trafficking in intact, differentiated and undifferentiated cells. Significant subtype-specific (but not cell type-dependent) trafficking of human alpha2-AR was observed by quantitation and immunocytochemistry. Agonist-induced sequestration of alpha2B-AR was markedly reduced after blocking the formation of clathrin-coated vesicles by hyperosmotic sucrose pretreatment. The sequestration of alpha2A-AR was partly inhibited after sucrose pretreatment but could be further reduced after inhibiting the formation of both clathrin-coated and caveolin vesicles by combined pretreatment with hyperosmotic sucrose and filipin. Differences were also observed in the recycling of alpha2A- and alpha2B-AR. The extent of maximal agonist-induced sequestration in PC12 cells was not directly dependent on relative agonist efficacy.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2003

Nonradioactive GTP binding assay to monitor activation of g protein-coupled receptors.

GPCRs represent important targets for drug discovery because GPCRs participate in a wide range of cellular signaling pathways that play a role in a variety of pathological conditions. A large number of screening assays have been developed in HTS laboratories for the identification of hits or lead compounds acting on GPCRs. One type of assay that has found relatively widespread application, due to its at least in part generic nature, relies on the use of a radioactive GTP analogue, [(35)S]GTPgammaS. The G-protein alpha subunit is an essential part of the interaction between receptor and G proteins in transmembrane signaling, where the activated receptor catalyzes the release of GDP from Galpha, thereby enabling the subsequent binding of GTP or a GTP analogue. [(35)S]GTPgammaS allows the extent of this interaction to be followed quantitatively by determining the amount of radioactivity associated with cell membranes. However, with the increased desire to move assays to nonradioactive formats, there is a considerable need to develop a nonradioactive GTP binding assay to monitor ligand-induced changes in GPCR activity. The Eu-GTP binding assay described here is based on TRF that exploits the unique fluorescence properties of lanthanide chelates, and provides a powerful alternative to assays using radioisotopes. In this article, we have used the human alpha(2A)-AR as a model GPCR system to evaluate the usefulness of this Eu-GTP binding assay.

Animals↗

PubMed2003

Electroencephalographic burst suppression versus loss of reflexes anesthesia with propofol or thiopental: differences of variance in the catecholamine and cardiovascular response to tracheal intubation.

UNLABELLED: The electroencephalographic burst suppression pattern (BSP) might indicate the brain's effect-site concentration of anesthetics more precisely than clinical signs and thus eliminate bias from studies on the reaction to tracheal intubation after different induction drugs. To test this hypothesis, we compared the catecholamine and cardiovascular responses and their variances to tracheal intubation when either BSP was induced by infusion of propofol (30 mg x kg(-1) x h(-1); n = 14) or thiopental (75 mg x kg(-1) x h(-1); n = 14) or anesthesia by repeated bolus doses until loss of reflexes (LR), initially of propofol 2.5 mg/kg (n = 15) or thiopental 5 mg/kg (n = 15). The standard deviations were more often smaller in the BSP than in the LR groups, but the results of Levene's test for differences of variance were insignificant. At the LR level, propofol attenuated catecholamine, arterial blood pressure, and heart rate responses to intubation better than thiopental, but at the BSP level, only the norepinephrine response was better attenuated. Cp50 concentrations of propofol and thiopental at the onset of BSP were 9.65 and 31.60 micro g/mL, respectively. IMPLICATIONS: Our results did not support the hypothesis that the responses to tracheal intubation can be more accurately predicted when unconsciousness is controlled with the aid of an electroencephalographic burst suppression pattern. Significant differences were found in the reactions between propofol and thiopental. At the burst suppression level, the catecholamine response was abolished with propofol.

Adult↗

PubMed2002

Alpha 2C-adrenoceptor mediated regulation of cortical EEG arousal.

Alpha2-adrenergic drugs modulate cortical arousal and EEG. However, the role of individual alpha2-adrenoceptor (alpha(2)-AR) subtypes in these functions is not clear. We investigated the role of alpha(2C)-ARs in the modulation of baseline cortical EEG activity and EEG responses to the alpha(2)-AR selective agonist, dexmedetomidine (3-300 microg/kg, s.c.), and antagonist, atipamezole (3-1000 microg/kg, s.c.), by using alpha(2C)-AR knockout (KO) and wildtype (WT) mice. The overall amplitude (1-30 Hz) was not significantly altered in KO mice although the activity of theta band (4-8 Hz) was increased in these mice. The main finding was that dexmedetomidine (30-300 microg/kg) more effectively slowed and atipamezole (30-1000 microg/kg) less effectively increased cortical EEG arousal in KO mice compared to WT controls. Importantly, autoradiographical results showed no compensatory increase in other alpha(2)-AR subtypes in cortical, thalamic or other brain structures of KO mice. Furthermore, there were no differences between the genotypes in the levels of hippocampal choline acetyltransferase, monoamines or their metabolites. Altered baseline cortical EEG activity and EEG responses to alpha(2)-AR selective drugs in KO mice indicate that alpha(2C)-ARs are involved in regulation of cortical arousal. These results suggest that alpha(2C)-ARs may antagonize the sedative effect of alpha(2)-AR agonists mediated by activation of alpha(2A)-ARs.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2002

Deletion polymorphism in the alpha2B-adrenergic receptor gene is associated with flow-mediated dilatation of the brachial artery.

A deletion variant of the alpha(2B)-adrenergic receptor (alpha(2B)-AR) has been associated with an increased risk of acute cardiac events in middle-aged men. Our aim was to determine the possible associations between the alpha(2B)-AR gene deletion variant and indicators of subclinical atherosclerosis in the brachial and carotid arteries. A total of 148 middle-aged men participating in an epidemiological twin study on risk factors for subclinical coronary heart disease were genotyped using PCR. Flow-mediated dilatation (FMD) of the brachial artery, carotid artery compliance and carotid intima-media thickness were measured using high-resolution ultrasound. FMD was 6.2+/-5.0% in subjects with the I/I (insertion/insertion) genotype, 5.5+/-4.1% in the I/D (insertion/deletion) group and 4.1+/-3.8% in the D/D (deletion/deletion) group ( P =0.03 for trend). In multivariate regression analysis controlling for age, presence of hypertension, smoking, use of angiotensin-converting enzyme inhibitors and plasma levels of low-density lipoprotein cholesterol and lipoprotein (a), the association between the alpha(2B)-AR genotype and FMD remained significant ( P =0.04 for trend). The alpha(2B)-AR genotype was not associated with intima-media thickness or carotid artery compliance. These findings indicate that subjects homozygous for the deletion allele of alpha(2B)-AR appear to have an increased risk of impaired endothelial function, which may provide an explanation for the previously observed increased risk of myocardial infarction in male subjects with this genotype. It is not known whether the association of the alpha(2B)-AR polymorphism with endothelial function is direct, or is mediated via altered sympathetic activation.

Adult↗

PubMed2002

Subtype-specific neuronal differentiation of PC12 cells transfected with alpha2-adrenergic receptors.

Cells of the PC12 rat pheochromocytoma cell line acquire characteristics of sympathetic neurons under appropriate treatment. Stably transfected PC12 cells expressing individual alpha2-adrenergic receptor (alpha2-AR) subtypes were used to assess the role of alpha2-ARs in neuronal differentiation and to characterise the signalling pathways activated by the alpha2-AR agonist epinephrine in these cells. The effects of alpha2-AR activation were compared with the differentiating action and the signalling mechanisms of nerve growth factor (NGF). Epinephrine induced neuronal differentiation of PC12alpha2 cells through alpha2-AR activation in a subtype-dependent manner, internalization of all human alpha2-AR subtypes, and activation of mitogen-activated protein kinase (MAPK) and the serine-threonine protein kinase Akt. Epinephrine and NGF showed synergism in their differentiating effects. The MAPK kinase (MEK-1) inhibitor PD 98059 abolished the differentiating effect of epinephrine indicating that the differentiation is dependent on MAPK activation. Activating protein-1 (AP-1) DNA-binding activity was increased after epinephrine treatment in all three PC12alpha2 subtype clones. Evaluation of the potential physiological consequences of these findings requires further studies on endogenously expressed alpha2-ARs in neuronal cells.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1985

Neurotransmission and the experience of low back pain; no association between CSF monoamine metabolites and pain.

We have investigated the possible associations between the demographic, clinical and psychological characteristics of 80 patients with low back pain and the CSF levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the principal central nervous system metabolites of serotonin, dopamine and noradrenaline, and of tryptophan, the amino acid precursor of serotonin. Neither the clinical measures nor the psychological characteristics were significantly correlated with the CSF neurochemistry. Therefore the hypothesis about an intimate relationship between monoaminergic neurotransmission and the experience of chronic low back pain was not confirmed. Among the other factors studied, body height contributed most to the variance in both 5-HIAA and HVA concentrations; the levels of MHPG increased with age.

Adult↗