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Biomedical subjects

D Hoyer

Publications and source records attributed to D Hoyer.

At least 217 records · Page 12Linked to original sources
PubMed1981

[125I]BE 2254, a new high affinity radioligand for alpha 1-adrenoceptors.

[125I]BE 2254 (IBE 2254), a new iodinated radioligand of high specific radioactivity (2175 Ci/mmol) was developed and used to characterize alpha 1-adrenoceptors in rat cerebral cortex membranes. IBE 2254 possessed a high affinity, KD 78 +/- 14 pM with a Bmax of 210 +/- 26 fmol/mg and 90% specific binding at KD value. alpha-Adrenergic antagonists competed for IBE 2254 binding in the following order: prazosin greater than or equal to WB 4101 greater than phentolamine greater than corynanthine greater than yohimbine greater than rauwolscine, a strong indication that IBE 2254 binds to alpha 1-adrenoceptors. IBE 2254 appears to be a very useful tool for studying alpha 1-adrenoceptors.

Animals↗
PubMed1981

(+/-)[125Iodo] cyanopindolol, a new ligand for beta-adrenoceptors: identification and quantitation of subclasses of beta-adrenoceptors in guinea pig.

(+/-)[125Iodo] cyanopindolol (ICYP) is a radioligand which binds with an extraordinarily high affinity and specificity to beta-adrenoceptors. In contrast to (+/-) [125Ido]-hydroxybenzylpindolol (IHYP), the new ligand has neither affinity to alpha-nor to 5-HT-receptors. The dissociation constants of ICYP for beta- adrenoceptors in various tissues range from 27 to 40 pM, thereby exceeding the affinity of IHYP by a factor of approximately 3. ICYP does not discriminate between beta 1- and beta 2-adrenoceptors. Therefore, the densities of the two receptor subtypes can be determined from competition curves of ICYP by drugs previously found to show in vitro selectivity for beta 1-adrenoceptors. The guinea pig left ventricle contains only beta 1-adrenoceptors, whereas in a lung tissue, the ratio of beta 1-to beta 2-adrenoceptors is 1 to 4. The calculated affinities of five beta 1-selective antagonists for beta 1-adrenoceptors were nearly identical in the ventricle and the lung. Kinetic studies of ICYP binding to guinea pig lung membranes indicated that the dissociation reaction consists of two components, a fast process (t 1/2 = 9 min) and a slower process (t 1/2 = 8.8 h). A mathematical treatment revealed two possibilities of interpretation: 1. Two forms of the receptor exist which are interconvertible. 2. The (+)- and (-)- enantiomers of ICYP dissociate with different rate constants. The low dissociation constant of ICYP in combination with its high specific radioactivity (2175 Ci mmole -1) allows binding studies to be carried out with small protein and ligand concentrations, e.g. 3 microgram protein per assay in guinea pig lung membranes.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Localization of 5-HT1B, 5-HT1D alpha, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain.

In situ hybridization histochemistry (ISHH) was used to study the distribution of various 5-HT1 receptor messenger RNAs (mRNA) in the mammalian nervous system. Since the cDNAs encoding the different 5-HT1 receptors, have not been cloned in one single species, brains of the species appropriate for the 5-HT1 receptor messenger RNA (mRNA) have been used. Thus, 5-HT1B and 5-HT1D alpha mRNA were determined in rat and mouse brain, while 5-HT1E and 5-HT1F mRNA were studied in human (and monkey) and guinea-pig brain, respectively. 5-HT1B and 5-HT1D alpha hybridization signals were predominantly present in caudate-putamen and cortical areas; in addition, 5-HT1B mRNA was also detected in hippocampus, cerebellum and cerebral arteries. In general, the distribution of 5-HT1B mRNA was characterized by high densities, whereas 5-HT1D alpha mRNA was expressed at very low levels. Comparison of the localization of the mRNAs to the regional distributions of the 5-HT1B and 5-HT1D binding sites in rat brain (described in a previous study), revealed that both receptor subtypes could be putative presynaptic heteroreceptors, modulating the release of various neurotransmitters in the central nervous system. The mRNA encoding the recently cloned 5-HT1E receptor, which has low affinity for the 5-HT1 receptor ligand 5-carboxamidotryptamine (5-CT), was localized in human brain. It was found to be present in cortical areas, caudate, putamen and amygdala, areas known to contain 5-CT insensitive 5-HT1 binding sites. The regional distribution of the 5-HT1F mRNA was determined in guinea-pig brain: high densities were observed in various cortical areas, the hippocampal formation and claustrum, which are regions known to contain 5-CT insensitive 5-HT1 or non 5-HT1A/1B/IC/ID [3H]5-HT binding sites. Altogether, this ISHH study describes the distribution of mRNAs of recently cloned 5-HT1 receptors in rodent and primate brain and compares these results to the distribution of the heterogeneous population of 5-HT1 binding sites.

Animals↗
PubMedDate not supplied

5-HT receptor classification and nomenclature: towards a harmonization with the human genome.

Molecular biology has dramatically advanced our knowledge and understanding of receptors for 5-hydroxytryptamine (5-HT). The existence of multiple 5-HT receptors defined using traditional pharmacological and biochemical approaches has now been amply confirmed, but gene products encoding putative "new" 5-HT receptors have also been discovered. In some cases, the absence of suitably selective agonists and antagonists has hampered determination of a physiological role for these gene products. This makes their classification as formally recognised receptors premature.

Animals↗
PubMedDate not supplied

Inhibition of cAMP accumulation via recombinant human serotonin 5-HT1A receptors: considerations on receptor effector coupling across systems.

Inhibition of forskolin-stimulated cyclic AMP accumulation was measured in two stable HeLa cell lines HA6 and HA7 expressing different levels of recombinant human 5-HT1A receptors. These cells were studied previously to characterize another second messenger system activated by 5-HT1A receptors, i.e. calcium mobilization. The pharmacological characterization of the inhibition of cyclic AMP accumulation was made using agonists (5-HT, 8-OH-DPAT, buspirone, MDL 73005) and putative antagonists (SDZ 216-525, NAN-190, WAY-100135, pindolol, propranolol, WAY 100635). It is shown that 5-HT, 8-OH-DPAT, buspirone, MDL 73005 behaved as full (or nearly full) and potent agonists, whereas SDZ 216-525, NAN-190 and WAY-100135 displayed a limited (and similar) degree of intrinsic activity at human 5-HT1A receptors; on the other hand pindolol, propranolol and WAY 100635 behaved as "silent" antagonists. The effects were quantitatively and qualitatively very similar in both cells lines for all drugs tested, suggesting that the coupling between 5-HT1A receptors and inhibition of cyclic AMP accumulation in HeLa cells is very tight. There were, however, significant variations in both the level of agonism and the potency of a number of compounds when calcium mobilization and the inhibition of cyclic AMP accumulation were compared. Especially in HA7 cells which express lower receptor levels, a number of drugs failed to display agonism (e.g. buspirone or MDL 73005), whereas in HA6 cells they acted as partial agonists. Together, the data show that functional responses mediated by the same receptor can vary rather dramatically depending on receptor density and/or on the effector system involved. Interestingly, 5-HT1A receptor-mediated inhibition of adenylate cyclase activity measured in calf hippocampal membranes shows very similar degrees of potency and intrinsic activity for a number of compounds that have been tested on the inhibition of cyclic AMP accumulation in HeLa cells, suggesting that the very tight coupling observed in the recombinant system may apply to native 5-HT1A receptors.

Adenylyl Cyclases↗
PubMedDate not supplied

Distribution and characterisation of somatostatin receptor mRNA and binding sites in the brain and periphery.

The distribution and nature of (somatostatin) SRIF receptors and receptor mRNAs was studied in the brain and periphery of various laboratory animals using in situ hybridisation, autoradiography and radioligand binding. The messenger RNA (mRNA) expression of SRIF receptors msst1, msst2, msst3, msst4 and msst5 was studied in the adult mouse brain by in situ hybridisation histochemistry using specific oligonucleotide probes and compared to that of adult rats. As observed in rat brain, sst3 receptor mRNA is prominently expressed across the mouse brain, although equivalent binding has not yet been identified in situ. Sst1 and sst2 receptor mRNA expression, was prominent and again comparable to that observed in rat brain, whereas sst4 and especially sst5 receptor mRNA show comparatively low levels, although the former appears to be widely distributed while the latter could only be identified in a few nuclei. Altogether, the data are compatible with current knowledge, i.e. sst1 and sst2 receptor mRNA is prominent (both receptors have been functionally identified in the brain and for sst2 in the periphery), sst3 mRNA is highly expressed but in the absence of any functional correlate remains elusive. The expression of sst4 mRNA is comparatively low (especially when compared to what is seen in the lung, where high densities of sst4 receptors are present) and it remains to be seen whether sst5 receptor mRNA, which is confined to a few nuclei, will play a role in the brain, keeping in mind that high levels are found in the pituitary. Radioligand binding studies were performed in CCL39 cells expressing the five human recombinant receptors and compared to binding in membranes of rat cerebral cortex with [125I]Tyr11-SRIF14 which in the presence of 120 mM labels primarily sst1 receptor as suggested by the better correlation hsst1 and similar rank order of potency. The profile of [125I]Tyr3-octreotide labelled sites in rat cortex correlates better with recombinant sst2 than sst3 or sst5 binding profiles. Finally, [125I]LTT-SRIF28-labelled sites in rat lung express a sst4 receptor profile in agreement with previous findings. SRIF receptor autoradiography was performed in the brain and peripheral tissue of rat and/or guinea-pig using a number of ligands known to label recombinant SRIF receptors: [125I]LTT-SRIF28, [125I]CGP 23996, [125I]Tyr10-CST, or [125I]Tyr3-octreotide. Although, [125I]Tyr10-CST has been shown to label all five recombinant SRIF receptors, it is apparent that this radioligand is not useful for autoradiographic studies. By contrast, the other three ligands show good signal to noise ratios in rat or guinea-pig brain, rat lung, rat pancreas, or guinea-pig ileum. In most tissues, [125I]Tyr3-octreotide represents a prominent part of the binding (when compared to [125I]LTT-SRIF28 and [125I]CGP 23996), suggesting that sst2 receptors are strongly expressed in most tissues; it is only in rat lung that [125I]LTT-SRIF28 and [125I]CGP 23996 show marked binding, whereas [125I]Tyr3-octreotide does apparently label no sites, in agreement with the sole presence of sst4 receptors in this tissue.

Animals↗
PubMedDate not supplied

Robust nonlinear autoregressive moving average model parameter estimation using stochastic recurrent artificial neural networks.

In this study, we introduce a new approach for estimating linear and nonlinear stochastic autoregressive moving average (ARMA) model parameters, given a corrupt signal, using artificial recurrent neural networks. This new approach is a two-step approach in which the parameters of the deterministic part of the stochastic ARMA model are first estimated via a three-layer artificial neural network (deterministic estimation step) and then reestimated using the prediction error as one of the inputs to the artificial neural networks in an iterative algorithm (stochastic estimation step). The prediction error is obtained by subtracting the corrupt signal of the estimated ARMA model obtained via the deterministic estimation step from the system output response. We present computer simulation examples to show the efficacy of the proposed stochastic recurrent neural network approach in obtaining accurate model predictions. Furthermore, we compare the performance of the new approach to that of the deterministic recurrent neural network approach. Using this simple two-step procedure, we obtain more robust model predictions than with the deterministic recurrent neural network approach despite the presence of significant amounts of either dynamic or measurement noise in the output signal. The comparison between the deterministic and stochastic recurrent neural network approaches is furthered by applying both approaches to experimentally obtained renal blood pressure and flow signals.

Algorithms↗
PubMedDate not supplied

[Principles and experiences for modeling chaotic attractors of heart rate fluctuations with artificial neural networks].

The aim of the present paper was, using artificial neural networks, to identify chaotic attractors presumed to be responsible for heart rate fluctuations. Chaotic behaviour is based on low-dimensional deterministic processes which are highly sensitive to initial conditions and therefore of limited predictability. Chaotic attractors produce orbits in the phase space where the points are dense. Following transformation of measured heart rate date into the phase space, such heart rate prediction characteristics were found in 6 adult rabbits. A low-dimensional deterministic model was designed by means of an artificial neural network [2*dimension of the time series +1) input neurons, 1 hidden layer, 1 output neuron and was successfully employed to predict the next 5 heart beats. Training of the neural network in terms of the prediction of the suspected chaotic orbits was dramatically improved by considering all possible prediction intervals within the prediction horizon. The trained models enabled the heart rate fluctuations to be distinguished during consciousness, under anaesthesia and additional vagal blockade.

Animals↗