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G Engel

Publications and source records attributed to G Engel.

At least 55 records · Page 3Linked to original sources
PubMed1985

Characterization of the 5-HT1B recognition site in rat brain: binding studies with (-)[125I]iodocyanopindolol.

(-)[125I]Iodocyanopindolol ([125I]CYP) labels rat brain membrane sites which display high affinity for several serotonergic and beta-adrenergic compounds. The binding of [125I]CYP to these serotonergic recognition sites was evaluated in the presence of 30 microM (-)isoprenaline in order to suppress binding to beta-adrenoceptors. [125I]CYP binds in rat cortex membranes rapidly, reversibly and stereoselectively to a finite number of recognition sites: Bmax = 180 fmol/mg, KD = 230 pM. Similar affinity values of [125I]CYP were obtained in membranes from rat hippocampus and striatum. Kinetic, saturation and competition experiments suggest that under these conditions [125I]CYP binds to a single serotonergic recognition site named 5-HT1B. The pharmacological profile of 5-HT1B sites is characteristic of a 5-HT1 binding site and shows the following rank order of affinity for agonists: RU 24969, (5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]1H-indole) greater than 5-CT, (5-carboxamidotryptamine) greater than 5-HT, (5-hydroxytryptamine, serotonin) greater than 5-OCH3-T, (5-methoxytryptamine) much greater than 2-CH3-5-HT, (2-methylserotonin) greater than 8-OH-DPAT, (8-hydroxy-2-(di-n-pro-pylamino)-tetralin). The rank order of affinity for antagonists is: (+/-)ICYP, ((+/- )-3-I-cyano-pindolol) greater than (-)21-009, (4-[3-ter-butyl-amino-2-hydroxy-propoxy]-indol-2-carbonic acid isopropyl ester) greater than (+)21-009 greater than (-)propranolol greater than metitepin greater than (-)pindolol much greater than ketanserin greater than spiroperidol greater than mesulergine. 5-HT1B recognition sites display low affinity for selective beta 1- and beta 2-adrenoceptor antagonists, e.g. atenolol, betaxolol, ICI 89-406 and ICI 118-551. The low affinity of 5-HT1B recognition sites for some 5-HT1A, 5-HT1C and 5-HT2 selective compounds (e.g. 8-OH-DPAT, mesulergine, ketanserin) suggests that 5-HT1B recognition sites are pharmacologically different from 5-HT1A, 5-HT1C and 5-HT2 recognition sites.

Animals↗
PubMed1985

Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes: radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (-)[125I]iodocyanopindolol, [3H]mesulergine and [3H]ketanserin.

The pharmacological characteristics of the binding of [3H]8-OH-DPAT ([3H]8-hydroxy-2(di-n-propylamino)tetralin, [125I]CYP ((-)[125I]iodocyanopindolol) (in the presence of 30 microM (-)isoprenaline) and [3H]mesulergine to 5-HT1 recognition sites were studied in rat and pig brain membranes. [3H]8-OH-DPAT bound in rat and pig cortex to the 5-HT1A recognition site characterized by high affinity for 5-CT (5-carboxamido-tryptamine), 8-OH-DPAT, 5-HT (5-hydroxytryptamine, serotonin) and low affinity for pirenperone, ketanserin and mesulergine. [125I]CYP bound in rat but not in pig cortex to the 5-HT1B site which shows high affinity for (-)21-009 (4[3-ter-butyl-amino-2-hydroxy-propoxy]indol-2-carbonic acid isopropyl ester), (+/-)ICYP (3-I-cyanopindolol), 5-HT, RU 24969 (5-methoxy-3-[1,2,3,6-tetrahydropyridon-4-yl]1H-indole) and low affinity for 8-OH-DPAT, mesulergine and pirenperone. [3H]Mesulergine bound in pig choroid plexus and in rat cortex (besides binding to 5-HT2 sites in rat cortex) to the 5-HT1C recognition site characterized by high affinity for metergoline, mesulergine, 5-HT and methergine and low affinity for (-)21-009, ICYP, 8-OH-DPAT and spiroperidol. The pharmacological profile of 5-HT1A sites in rat and pig cortex appears to be identical; 5-HT1C sites in pig choroid plexus and rat cortex show no differences. In contrast, it was not possible to label 5-HT1B sites with [125I]CYP in pig brain membranes indicating that like 5-HT2 receptors, 5-HT1 recognition sites show species differences. The pharmacological profiles of the three 5-HT1 recognition sites are clearly different from one another. Furthermore, the pharmacological profile of each individual 5-HT1 recognition site is also different from that of the 5-HT2 receptors labelled with [3H]ketanserin in rat cortex membranes although some similarities exist between 5-HT2 and 5-HT1C sites. Finally, the beta-adrenoceptor antagonist (-)21-009 which has different affinities for 5-HT1A, 5-HT1B and 5-HT1C recognition sites, yielded triphasic competition curves for [3H]5-HT binding in rat cortex membranes providing evidence that [3H]5-HT labels three distinct 5-HT1 sites in these membranes.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

beta-Adrenoceptor blocking agents recognize a subpopulation of serotonin receptors in brain.

The interaction of beta-adrenoceptor blocking agents with serotonin receptors in rat brain was analyzed by quantitative light microscopic autoradiography using (-) [125I]cyanopindolol (ICYP) as a ligand. In some brain areas such as the globus pallidus and dorsal subiculum, binding of ICYP was blocked with high affinity by some serotoninergic ligands, RU-24969 and serotonin, but not by lysergic acid diethylamide and 8-hydroxy-2-(N,N-di-n-propylamino)tetralin. Some beta-blockers also showed high affinity for these sites. These results supply direct evidence for the labeling of a subclass of serotonin receptors, the 5-HT-1B class, providing anatomical and pharmacological basis for some known serotonin-related effects of beta-adrenoceptor drugs.

Adrenergic beta-Antagonists↗
PubMed1985

Lesioning of serotoninergic and noradrenergic nerve fibres of the rat brain does not decrease binding of 3H-clonidine and 3H-rauwolscine to cortical membranes.

alpha 2-Adrenoceptors located presynaptically on nerve terminals are known to modulate the release of neurotransmitters from noradrenergic and serotoninergic neurons. The pre- and/or postsynaptic localization of binding sites for alpha 2-adrenergic radioligands, the agonist 3H-clonidine and the antagonist 3H-rauwolscine, was investigated in the rat cerebral cortex by the use of specific neurotoxins. Intracerebroventricular injections of 6-hydroxydopamine (6-OH-DA) and 5,7-dihydroxytryptamine (5,7-DHT) were used to destroy the noradrenergic and serotoninergic neurons, respectively, and the success of the treatment was controlled by measurement of tritium accumulation in cortex slices incubated with 3H-noradrenaline or 3H-serotonin. In cortical membranes, 3H-rauwolscine bound to a single site (KD about 5 nmol/l; Bmax 217-247 fmoles/mg protein), whereas 3H-clonidine bound to a high affinity site (KD 0.6-1.4 nmol/l) and a low affinity site (KD 6-10 nmol/l). The total number of high plus low affinity 3H-clonidine binding sites was about two thirds of the number of 3H-rauwolscine binding sites. 6-OH-DA treatment significantly increased the number of high affinity 3H-clonidine binding sites without reducing the number of high plus low affinity binding sites, indicating a denervation supersensitivity. KD- as well as Bmax-values for 3H-rauwolscine remained unaltered after 6-OH-DA-treatment. Since an increase in postsynaptic alpha 2-adrenoceptors due to 6-OH-DA-administration might have masked a loss of presynaptic alpha 2-adrenergic binding sites, rats were chronically treated with high doses of clonidine in order to prevent a possible supersensitivity of postsynaptic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

5,7-Dihydroxytryptamine↗
PubMed1985

beta-Adrenoceptor subtypes in sections of rat and guinea-pig kidney.

The present autoradiographical study examines the distribution of the two beta-adrenoceptor subtypes in sections of rat and guinea-pig kidney. The radioligand [125Iodo]-(--)-cyanopindolol was used for the labelling of beta-adrenoceptors and the selective beta-adrenoceptor blocking agents ICI 89-406 (beta 1-antagonist) and ICI 118-551 (beta 2-antagonist) were utilized to differentiate both subclasses unequivocally. beta-Adrenoceptors in rat kidney were found to be almost exclusively beta 1. They were located mainly on glomeruli and to a lesser extent on the straight part of the distal tubules and on the cortical portion of the collecting ducts. Some beta 2-adrenoceptors were localized around the corticomedullary junction. Grain localization in the auto-radiograms was absent in the inner medulla and papilla. Glomeruli and distal tubules of the guinea-pig kidney also possess only beta 1-adrenoceptors, but, in contrast to the rat, extremely high concentrations of beta 2-adrenoceptors were associated with the straight part of the proximal tubules in the cortex and possibly with the cortical portion of the collecting duct. Labelling was not detected on the proximal convoluted tubule in either species.

Adenylyl Cyclases↗
PubMed1985

Study of the contractile effect of 5-hydroxytryptamine (5-HT) in the isolated longitudinal muscle strip from guinea-pig ileum. Evidence for two distinct release mechanisms.

The contractile effect of 5-HT in the isolated longitudinal ileal muscle of adult guinea-pigs was studied over a large concentration range. 5-HT produced a biphasic concentration-response curve indicative of an interaction with at least two independent populations of receptors. The concentrations which elicited half-maximal effects for the first and the second phases of the concentration-response curve were estimated as 1.5 +/- 1.2 X 10(-8) mol/l and 1.3 +/- 0.4 X 10(-6) mol/l respectively. The maximal response produced by the interaction of 5-HT with the high affinity receptor (i.e. first phase) was calculated as 27 +/- 9.3% of the total response. The biphasic concentration-response was not influenced by methysergide (10(-6) mol/l). The effect of low concentrations of 5-HT (less than 3 X 10(-7) mol/l) was antagonised by atropine (10(-7) mol/l), tetrodotoxin (TTX) (10(-6) mol/l), morphine (10(-5) mol/l), the substance P antagonist, D-Pro4,D-Trp7,9-SP4-11 (3 X 10(-5) mol/l) and capsaicin (10(-5) mol/l). Physostigmine (10(-7) mol/l) augmented the effect. The response to high concentrations of 5-HT (3 X 10(-7)-3 X 10(-6) mol/l) was antagonised by ICS 205-930 and D-Pro4,D-Trp7,9-SP4-11 in a competitive manner and was inhibited by TTX, morphine and capsaicin in an insurmountable way. The effect of very high concentrations of 5-HT (greater than 10(-5) mol/l) could be partially antagonised by methysergide (10(-7) mol/l) in the presence of ICS 205-930 (10(-7) mol/l) and totally by a combination of methysergide and TTX.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

5-Hydroxytryptamine receptor antagonism by metoclopramide and ICS 205-930 in the guinea-pig leads to enhancement of contractions of stomach muscle strips induced by electrical field stimulation and facilitation of gastric emptying in-vivo.

Contractions induced by electrical field stimulation of isolated circular muscle strips, taken from the guinea-pig stomach, were enhanced by metoclopramide, ICS 205-930 and MDL 72222 at concentrations similar to those shown to antagonize at neuronal 5-hydroxytryptamine receptor sites in a variety of preparations. Metoclopramide, MDL 72222 and ICS 205-930 also facilitated gastric emptying in-vivo. The abilities of metoclopramide, MDL 72222 and ICS 205-930 to enhance stomach muscle contraction processes and to facilitate gastric emptying may be the consequence of 5-hydroxytryptamine receptor antagonism.

Animals↗
PubMed1985

Acute tubular necrosis after inhalation exposure to methylene chloride. Report of a case.

Nephrotoxic reaction occurred after inhalation exposure to methylene chloride. This exposure is associated with acute renal failure, myoglobinuria, hypocomplementemia, and liver enzyme elevations. Pathologic specimens, both light and electron microscopic, demonstrate renal tubular damage. We conclude that methylene chloride may have potential as both a hepatotoxic and nephrotoxic agent when inhaled at high concentrations over an extended period of time.

Acute Kidney Injury↗
PubMed1984

2-[125Iodo]LSD, a new ligand for the characterisation and localisation of 5-HT2 receptors.

LSD was iodinated with Na125I and chloramine T, to get the radioligand [125I]LSD ( 125IOL ) and with N-I-succinimide to obtain the nonradioactive compound 2-I-LSD (IOL) for comparative pharmacological studies. The introduction of iodine in position 2 of LSD leads to an increase in selectivity for 5HT2 receptors. In rat cortex membranes, 125IOL possesses a KD = 0.9 +/- 0.1 nmol/l, Bmax = 240 +/- 20 fmoles/mg, and a nonspecific binding of 30-40% in presence of 100 nmol/l ketanserin. In competition experiments, 5HT antagonists showed monophasic displacement curves. Their KI-values correlate well with pD'2-values for inhibition of 5HT-induced contraction of canine basilar artery. It can be concluded that the sites labelled by 125IOL have pharmacological properties in common with central 5HT2 receptors, which are identical with vascular postjunctional 5HT receptors. The high specific radioactivity of 125IOL permits detection of even small 5HT2 receptor densities which exist in the guinea pig ileum. These 125IOL binding sites are pharmacologically different to those found in the brain or on the vessels and might be a special subpopulation of 5HT2 sites. For example, ketanserin has a high affinity to the sites labelled by 125IOL in the brain and a 100 times lower affinity to the sites labelled in the ileum. In a routine binding screen with various ligands, the inhibition constants of IOL for alpha 1, alpha 2, beta, histamine and muscarinic receptors are greater than 100 nmol/l with the exception for dopamine receptors, 40 nmol/l. 125IOL was employed for the autoradiographic localisation of its binding sites after in vitro labelling of microtome rat brain sections. 125IOL labelled 5HT2 sites in the cortex and dopamine receptors in the nucleus caudatus. The exposure times required were very short, compared to those of other 5HT2 ligands available.

Animals↗
PubMed1984

Labelling of Ri adenosine receptors in rat fat cell membranes with (-)-[125iodo]N6-hydroxyphenylisopropyladenosine.

A new adenosine analogue, (-)-iodo-N6-phydroxyphenylisopropyladenosine [(-)-IHPIA], has been developed for radioligand binding studies of Ri adenosine receptors. In addition, the effects of (-)IHPIA on adenosine-mediated responses of rat fat cells have been characterized. (-)IHPIA is slightly less potent at Ri adenosine receptors than (-)N6-phenylisopropyladenosine [(-)PIA] as assessed by adenylate cyclase and lipolysis studies. (-)IHPIA inhibited basal adenylate cyclase activity with an IC50 of 60 nmol/l compared to an IC50 of 16.3 nmol/l for (-)PIA. (-)PIA and (-)IHPIA inhibited adenosine deaminase-stimulated lipolysis of intact rat fat cells with an IC50 of 0.55 and 3.6 nmol/l. The potency of (-)N6-phydroxyphenylisopropyladenosine [(-)HPIA] was intermediate. (-)HPIA has been labelled with carrier-free Na[125I] to very high specific activity (2,175 Ci/mmol) and used as agonist radioligand in binding studies of Ri adenosine receptors. The binding of (-)[125I]HPIA was saturable, reversible and stereospecific. Saturation analysis revealed two affinity states with dissociation constants (KD) of 0.7 and 7.6 nmol/l and maximal number of binding sites (Bmax) of 0.94 and 0.95 pmol/mg protein. The rate constant of association, k1, was 3.7 X 10(8) l X mol-1 X min-1. Binding was slowly reversible with a t1/2 of 88 min. In competition experiments specific binding was most potently inhibited by (-)PIA, N6-cyclohexyladenosine (CHA), (-)HPIA and (-)IHPIA, followed by 5'-N-ethylcarboxamidoadenosine (NECA) and 2-chloroadenosine. 1,3-Diethyl-8-phenylxanthine (DPX) and 8-phenyltheophylline were the most potent adenosine antagonists with Ki-values of 67 and 83 nmol/l, whereas the methylxanthines 3-isobutyl-1-methylxanthine, theophylline and caffeine had Ki-values between 1 and 21 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1984

Identification of 5HT2-receptors on longitudinal muscle of the guinea pig ileum.

In binding experiments with the radioligands [3H]Ketanserin (HKet) and [125I]LSD (ILSD) 21 compounds were investigated using rat brain cortex membranes. The pKD-values of the compounds were virtually independent of the radioligand used and their rank order was consistent with classification of the binding sites as being of the 5-HT2-type. In contrast, in the longitudinal muscle of the guinea pig ileum in the presence of 0.3 microM cinanserin, ILSD labelled sites which were quite different to those in the cortex. In a functional test antagonism of the 5HT induced contraction of the guinea-pig ileum was measured in the presence of 1 microM atropine. The pharmacological inhibition constants (IC50-values) of 8 compounds correlated well with the dissociation constants for HKet binding in the cortex and did not correlate with the data from ILSD binding in the guinea pig ileum. It is concluded that the ileum contains postjunctional 5HT2-receptors which mediate contraction. The nature of the ILSD binding sites in the ileum remains to be elucidated.

Animals↗
PubMed1984

True uterine diverticulum. A partial müllerian duct duplication?

True uterine diverticulum is an exceedingly rare entity. We report only the second case, to our knowledge, of a nulliparous uterus containing a diverticulum communicating with the endometrial cavity. True uterine diverticula probably arise from a localized duplication of the distal Müllerian duct on one side. They may be confused pathologically with uterine sacculations of pregnancy, but tend to have thicker walls. Associated conditions include "ectopic" pregnancy in the diverticulum, dysmenorrhea, and abnormal uterine bleeding.

Adult↗
PubMed1984

Three distinct subtypes of serotonergic receptors mediate the triphasic blood pressure response to serotonin in rats.

In pentobarbitone- or urethane-anaesthetized normotensive rats the triphasic pressure response to serotonin (5-HT): a short-lasting depressor phase with an intense bradycardia, a pressor phase and a prolonged hypotension, was investigated. The highly selective 5-HTM antagonist ICS 205-930 (1 microgram/kg) inhibited the first but not the second or third phase. The 5-HT2 antagonist ketanserin (0.1 mg/kg) inhibited the second but not the first or third phase. Following selective blockade of the pressor component with ketanserin (0.1 mg/kg), the hypotensive potency of eight serotonin receptor agonists was quantified (-log ED50). A correlation (r = 0.75, P less than 0.05) was observed between this parameter and the displacement of the 5-HT1 ligand [3H]-5-HT. It is suggested that the three phases are due to 5-HTM-, 5-HT2- and 5-HT1-receptor activation, respectively.

Animals↗
PubMed1983

Characterization of beta-adrenergic receptor subtypes in androgen-induced mouse kidney hypertrophy using a new high-affinity ligand, [125I]iodocyanopindolol.

In fully developed androgen-induced hypertrophy of female mouse kidney, beta-adrenergic receptors per unit membrane protein were increased approx. 2.5-fold, as measured by the binding of [125I]iodocyanopindolol, with no change in apparent dissociation constants (Kd range 20-25 pM). Membrane protein relative to total kidney protein, Na+/K+-dependent ATPase (EC 3.6.1.3) and 5'-nucleotidase (EC 3.1.3.5) activities and cholesterol content per unit membrane protein did not differ significantly in preparations from control and treated animals. The binding of iodocyanopindolol to kidney membranes was characterized with respect to association and dissociation kinetics, and also in regard to the less-specific contributions of other major catecholamine or indolamine receptors, using mixtures of the corresponding specific competitors. beta 1-selective drugs, practolol and metoprolol, and beta 2-selective agents, IPS-339 and zinterol, were competed with iodocyanopindolol to assess the receptor type specificity, and the ensuing binding profiles were dissected by a nonlinear regression analysis as described by Munson, P.J. and Rodbard, D. (Anal. Biochem. (1982) 107, 220-239). Most of the androgen-induced beta-adrenergic receptors had the binding properties corresponding to beta 2-subtype. No consistent increase in the density of beta 1-adrenergic receptors could be shown.

Androgens↗
PubMed1983

Evidence for common pharmacological properties of [3H]5-hydroxytryptamine binding sites, presynaptic 5-hydroxytryptamine autoreceptors in CNS and inhibitory presynaptic 5-hydroxytryptamine receptors on sympathetic nerves.

The affinities of 16 5-hydroxytryptamine (5-HT) receptor agonists (indole derivatives) and 7 5-HT receptor antagonists for [3H]5-hydroxytryptamine [( 3H]5-HT) binding sites in rat cerebral cortex membranes were determined. In addition, the potencies of the agonists for inhibiting the electrically induced tritium overflow from rat brain cortex slices preincubated with [3H]5-HT and from canine saphenous veins preincubated with [3H]noradrenaline were measured. Furthermore, the potencies of the indole derivatives for inducing contractile responses of canine saphenous veins were recorded. In addition, the interaction of the antagonists with unlabelled 5-HT at the 5-HT autoreceptor was studied in rat brain cortex slices. There was a good correlation between the binding affinities of the indole derivatives for the [3H]5-HT sites of rat brain cortex membranes and their potencies for inhibiting the evoked tritium overflow from both rat brain cortex slices and strips of canine saphenous vein. Comparison of the inhibition constants derived from the overflow experiments in both tissues again revealed a high correlation coefficient while there was only weak correlation between the binding affinities in rat brain cortex and the contractile potencies of the drugs in canine saphenous vein strips. When 5-HT receptor antagonists were investigated, metitepin and metergoline showed moderate affinities for the 5-HT autoreceptors in rat brain cortex slices, whereas quipazine had only weak affinity, and ketanserin, metoclopramide, cinanserin and cyproheptadine exhibited no antagonistic property. In binding experiments, the competition curves of most 5-HT receptor antagonists were biphasic, suggesting that the [3H]5-HT binding sites are heterogeneous.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Affinity spectra: a novel way for the evaluation of equilibrium binding experiments.

For equilibrium binding isotherms of radioreceptor assays, the affinity spectrum is defined as a plot of the number of binding sites against their corresponding dissociation constants. A numerical procedure for direct calculation of affinity spectra from untransformed binding data is presented and illustrated with experimental values. The advantage of the new method in comparison to non-linear regression analysis is the fact that no starting values and mathematical models have to be supplied and that statistical assessment of the results is straightforward from a detailed graphical display of a likelihood function. Affinity spectra thus show directly all information formerly obtained by means of both graphical plots and regression analysis.

Animals↗