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Biomedical subjects

A Geisler

Publications and source records attributed to A Geisler.

At least 37 records · Page 2Linked to original sources
PubMed1989

The effects of lithium in vitro and ex vivo on adenylate cyclase in brain are exerted by distinct mechanisms.

The effects of lithium on basal and forskolin-stimulated activity of adenylate cyclase in membrane preparations from cerebral cortex of the rat have been studied. Chronic treatment with lithium, yielding a level of lithium in serum of 0.71 +/- 0.18 mmol/l, reduced forskolin-stimulated activity in total homogenates but exerted no effect on the basal activity. Lithium in vitro, at 2 and 10 mM, did not influence the basal enzyme activity in membranes from either control or lithium-treated animals. The sensitivity of forskolin-stimulated adenylate cyclase to lithium in vitro was unaltered after chronic treatment and the in vitro and ex vivo effects of lithium on this parameter were additive. The inhibitory ex vivo effect of lithium was not antagonized by increasing concentrations of magnesium and the inhibitory effect of lithium ex vivo was still persistent after washing of the membranes. The present results indicate that lithium exerts its ex vivo effect on the activated cyclase, independently of the in vitro effect. Both effects may, however, contribute to the in vivo effect of lithium during chronic treatment.

Adenylyl Cyclases↗
PubMed1989

Calmodulin-dependent adenylate cyclase activity in rat cerebral cortex: effects of divalent cations, forskolin and isoprenaline.

The role of calcium-calmodulin (Ca2+-CaM) in the modulation of beta-adrenergic adenylate cyclase activity in rat cerebral cortex has been studied. In addition, the effects of manganese (Mn2+) and forskolin on CaM-dependent enzyme activity were investigated. At 2 mM magnesium (Mg2+) low concentrations of Ca2+ stimulated the enzyme activity (Ka 0.25 +/- 0.08 microM), whereas higher Ca2+ levels (greater than 2 microM) inhibited the activity. No activating effect of Ca2+ was observed in CaM-depleted membranes, but the inhibitory effect persisted and the stimulatory action of Ca2+ could be restored by addition of exogenous CaM. The ability of Ca2+ to activate the enzyme was reduced by increasing concentrations of Mg2+. At 10 mM Mg2+ the apparent Ka of Ca2+ was 0.55 +/- 0.16 microM and half-maximal inhibition was observed at 80-120 microM Ca2+. A synergistic effect was observed between Ca2+ and isoprenaline on the adenylate cyclase activity. Calcium did not alter the apparent Ka of isoprenaline (0.9 +/- 0.27 microM) and isoprenaline did not change the apparent Ka of Ca2+. However, isoprenaline decreased the apparent Ka of CaM; 0.11 +/- 0.07 micrograms vs. 0.32 +/- 0.1 micrograms (0.5 ml assay mixture)-1, with and without isoprenaline, respectively. A synergistic effect was also observed between Ca2+ and forskolin, but no change in their apparent Ka values was found. Furthermore, Mn2+ was found to activate the enzyme through CaM. These data demonstrate that Ca2+ -CaM potentiates beta-adrenergic adenylate cyclase activity and thus is able to modulate neurotransmitter stimulation in cortex. Furthermore, both forskolin and Mn2+ affect CaM-dependent enzyme activity. Forskolin potentiates Ca2+-CaM stimulation, while Mn2+ increases the activity by activating the enzyme through CaM.

Adenylyl Cyclases↗
PubMed1989

Electrocardiographic criteria of left atrial enlargement: do they correlate with atrial size?

In the past, M-mode echocardiography, the "gold standard" for determining left atrial dimension (LAD), has been used to examine the validity of the New York Heart Association criteria for left atrial enlargement (LAE). When the authors used two-dimensional echocardiography to determine LAD in 91 patients, they found no significant correlation between any of these criteria, either alone or together, and actual LAE. They propose that if the diagnosis of LAE is made using these criteria alone, that it be qualified at all times with the word "possible."

American Heart Association↗
PubMed1987

Effects of lithium on calmodulin-stimulated adenylate cyclase activity in cortical membranes from rat brain.

The influence of lithium on calmodulin-stimulated adenylate cyclase activity has been studied in vitro and after chronic treatment. Chronic lithium treatment decreased calcium-calmodulin-stimulated adenylate cyclase activity in rat cortical membranes, while no effect was observed on GTP-stimulated activity. Lithium in vitro inhibited adenylate cyclase activity stimulated by isoprenaline, GTP or calcium-calmodulin. Calcium-calmodulin-stimulated activity was more sensitive to lithium (2 mM) than isoprenaline- and GTP-stimulated activities (5 mM) and activities by these agents combined. Lithium had no effect on the unstimulated enzyme activity. The inhibitory effect of lithium in vitro on calcium-calmodulin-stimulated adenylate cyclase activity was antagonized by magnesium. The inhibition induced by lithium in vitro on the GTP-stimulated adenylate cyclase activity was increased by substituting manganese for magnesium in the assay media. Furthermore, the manganese-stimulated activity was also reduced by lithium. The latter effect was not observed in calmodulin-depleted membranes, but the inhibitory effect of lithium could be restored by addition of exogenous calmodulin. The present results suggest that lithium might influence the interaction of calmodulin with the enzyme and/or interfere with the divalent cation site(s) on the adenylate cyclase system.

Adenylyl Cyclases↗
PubMed1987

Mode of action of lithium on the catalytic unit of adenylate cyclase from rat brain.

The action of lithium on calcium-calmodulin-activated and forskolin-activated catalytic unit of adenylate cyclase has been studied. The catalytic unit was solubilized from rat brain and separated from the guanine nucleotide binding protein by gel filtration. Calcium-calmodulin-stimulated and forskolin-stimulated catalytic unit activities were inhibited in the presence of 2 mM and 1 mM of lithium, respectively. No inhibitory effect was observed on the basal activity. The inhibitory effect of lithium on the stimulated activities was antagonized by magnesium. Lithium did not influence the interaction of the enzyme substrate (ATP) with the catalytic unit. The present results indicate that lithium interacts directly with the catalytic unit of the adenylate cyclase system. In the neuron, lithium might interfere with a divalent cation site on the catalytic unit.

Adenylyl Cyclases↗
PubMed1985

Characterization of human platelet beta-adrenoceptors.

The widespread use of beta-adrenoceptor antagonists against hypertension, angina pectoris and migraine or as a preventive treatment after myocardial infarction has encouraged us to investigate the effects of these drugs on platelet function. The aim of this study was to examine whether beta-blocking drugs interfere with platelet beta- adrenoceptors and whether this dependency is related to their selectivity for beta-adrenoceptor subtypes. Beta-adrenoceptor stimulation of human platelets with isoprenaline increased cyclic AMP (cAMP), which is known to inhibit platelet aggregation. Furthermore, our studies showed that cAMP formation in vitro was stimulated by non-selective and beta 2-selective agonists, but not by the predominant beta 1-agonist prenalterol. Isoprenaline- stimulated cAMP formation was blocked by the non- selective beta-adrenoceptor antagonists propranolol, timolol, and alprenolol, while the beta 1-selective antagonists atenolol and metoprolol had no influence on an isoprenaline-induced cAMP formation. Receptor binding studies using (3H)-dihydroalprenolol revealed an IC50 value for propranolol of 85 nM, while metoprolol only displaced the bound (3H)-dihydroalprenolol at far higher concentrations (IC50, 20 microM). We conclude that the human platelet beta-adrenoceptors are mainly of the beta 2- subtype and that beta-adrenoceptor antagonists, especially the non-selective antagonists interfere with platelet function assessed as platelet cAMP formation.

Adult↗
PubMed1985

3,4-O-diacetylisoproterenol. Preparation, structure proof, and beta-receptor effect.

Direct acetylation of isoproterenol by selective O-acetylation using CH3COCl/CF3COOH was shown to lead to the formation of 2-(3,4-diacetoxyphenyl)-2-chloro-N-isopropyl-1-ethanamine and not to 3,4-O-diacetylisoproterenol. The latter was prepared by reduction of 3,4-diacetoxy(2-isopropylamino)acetophenone and its structure confirmed by IR, 1H, 13C NMR, mass spectral, and elemental analysis. The two compounds were tested for activity on beta-receptors. Efficacy and affinity on beta 1-receptors were found identical with the effect of isoproterenol. So was efficacy on beta2-receptors, while affinity was lower for the chloro compounds than for isoproterenol and diacetylisoproterenol which exhibited identical affinity.

Acetylation↗
PubMed1985

The effect of lithium in vitro and in vivo on dopamine-sensitive adenylate cyclase activity in dopaminergic areas of the rat brain.

Lithium (5 and 20 mM) was found to inhibit the dopamine-stimulated cyclic AMP formation in homogenates from rat striatum and olfactory tubercle, leaving basal and fluoride-stimulated activities unaffected. The inhibition of dopamine-stimulated adenylate cyclase was non-competitive and dose-dependent. However, in rats treated with lithium for four weeks, no alterations were found in basal, fluoride- and dopamine-stimulated adenylate cyclase activities. It is suggested that lithium interferes with hormonal stimulation of adenylate cyclase activity by an interaction with the process regulating the transfer of the receptor-hormone stimulus to the adenylate cyclase enzyme.

Adenylyl Cyclases↗
PubMed1985

A simple assay for cyclic adenosine 3':5'-monophosphate in human saliva.

Methods specially designed for the assay of cyclic adenosine 3':5'-monophosphate (cAMP) in human saliva have not previously been published. Methods for measurements in plasma or tissue preparations are inapplicable to saliva due to interference. This interference can be reduced by calibrating standard solutions with reagent blanks prepared from saliva pre-treated to remove cAMP (by charcoal adsorption). Further, human saliva contains only small amounts of cAMP (approximately 0.2 pmol/50 microliters saliva). The method presented provides the necessary sensitivity (lower detection limit: 0.02 pmol/50 microliters) obtained by adjustments of tracer and binding protein concentrations. The method is simple and has a comparatively great capacity for the number of test tubes to be assayed.

Animals↗
PubMed1984

Characterization of the beta-adrenergic receptor on the human platelet: a beta 2-subtype.

The human platelet beta-adrenergic receptor was characterized by using the ability of different drugs to stimulate the adenylate cyclase activity and the effects of various beta-antagonists to block the isoprenaline-stimulated adenylate cyclase activity. Isoprenaline was found 10 times more potent than adrenaline and 1000 times more potent than noradrenaline in stimulating the adenylate cyclase activity in these cells. Isoprenaline-stimulated activity was blocked by the non-selective beta-antagonists propranolol and alprenolol and by the beta 2-selective antagonist IPS 339 and prenalterol. Metoprolol, a beta 1-selective blocker, was without effect on the isoprenaline-stimulated adenylate cyclase activity. We conclude from our findings that the beta-adrenergic receptor type on the human platelet is mainly of the beta 2-subtype.

Adenylyl Cyclases↗
PubMed1984

No change in rat cerebral cortex calmodulin content following chronic treatment with lithium, reserpine, imipramine, and lithium combined with reserpine or imipramine.

Rats were treated 2-3 weeks with lithium, reserpine, imipramine, and combinations of lithium with reserpine or imipramine. Lithium was given in the diet, while the other drugs were dissolved in 0.9% saline and given intraperitoneally twice daily. The control and lithium groups received only vehicle injections. Twenty-four hours after the last injection the rats were decapitated and the cerebral cortex dissected. The tissue was sliced and the noradrenaline-stimulated cyclic AMP accumulation determined or the tissue was homogenized and centrifuged at 10,000 X g for 30 min. and the calmodulin content determined in the pellet and the supernatant. Reserpine treatment was found to cause an 50% increase in the noradrenaline-stimulated cyclic AMP accumulation, while treatment with imipramine and the combination lithium-imipramine decreased the noradrenaline-stimulated cyclic AMP accumulation by 40%. The tissue content of calmodulin was, however, found unaltered by all treatments.

Animals↗
PubMed1984

Forskolin-stimulated adenylate cyclase activity in rat cerebral cortex following chronic treatment with psychotropic drugs.

Rats were treated with lithium, imipramine, reserpine, and lithium combined with imipramine or reserpine. Lithium was given in the diet (40 mmol/kg) resulting in a serum-Li+ level of 0.5-0.6 mmol/l. Other drugs were dissolved in 0.9% saline and given intraperitoneally once or twice daily. After 3 weeks of treatment, forskolin-stimulated adenylate cyclase activity was measured in cerebral cortex homogenates. Reserpine did not affect the forskolin stimulation, while both imipramine and lithium caused a decrease in this activity. The combined treatments lithium-imipramine and lithium-reserpine also exhibited a clear decrease in forskolin stimulation, but the effect of concomitant lithium and imipramine treatment did not differ from the effect seen after any of the treatments alone. The unstimulated activity was unaltered by all treatments. The inhibition of lithium and imipramine on the forskolin stimulation indicates an interference of these two drugs with the forskolin-mediated activation of the adenylate cyclase.

Adenylyl Cyclases↗
PubMed1984

Lithium inhibition of forskolin-stimulated adenylate cyclase.

The lithium sensitivity of forskolin- and fluoride-stimulated adenylate cyclase activity was investigated in rat brain homogenates in vivo and in vitro. The unstimulated and fluoride-stimulated activity was not affected by lithium, while the forskolin stimulation exhibited a pronounced inhibition by this cation. Furthermore, if Mn2+ was substituted for Mg2+ in the assay media, the forskolin-stimulated activity was even more sensitive to lithium. The results indicate an action of lithium mainly on the catalytic moiety in the adenylate cyclase system. However, the effect cannot be direct on this protein, since the unstimulated activity was unaffected. The action is rather on the microenvironment surrounding this protein, thereby interfering with a possible conformational change of the adenylate cyclase of importance for the activation of this enzyme.

Adenylyl Cyclase Inhibitors↗