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Biomedical subjects

H J Schümann

Publications and source records attributed to H J Schümann.

At least 19 recordsLinked to original sources
PubMed1989

Amplifying effects of several vasoconstrictor agents of alpha 1-adrenoceptor-mediated contraction of isolated thoracic aortae of the guinea pig.

In guinea-pig aorta phenylephrine and noradrenaline induced concentration-dependent contractions when beta-adrenoceptors were blocked. The contractile response to phenylephrine was amplified by previous application of subthreshold concentrations of 5-hydroxytryptamine, ouabain, B-HT 920, Bay K 8644, phorbol-12-myristate-13-acetate and arachidonic acid. Bay K 8644 also enhanced the contractile response to noradrenaline. The amplification was not substantially altered by removing the endothelium of the aorta. The increase in cytosolic calcium availability induced by the vasoconstrictor agents investigated may be responsible for the enhancement of the alpha 1-adrenoceptor-mediated contractions.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1987

Influence of cyclooxygenase inhibitors and of lithium on the positive inotropic effect mediated by alpha 1-adrenoceptors in guinea-pig left atrium.

In experiments on the isolated guinea-pig left atrium we tried to get more information about the intracellular signal transmission of the alpha 1-adrenoceptor. We were able to demonstrate that the cyclooxygenase inhibitors indometacin and acetylsalicylic acid enhance the positive inotropic effect of relatively low phenylephrine concentrations at an extracellular calcium concentration of 1.22 mmol/l. Preincubation with prazosin as well as an increased calcium concentration of 2.5 mmol/l abolished this effect. These observations led us to suppose that an elevated level of receptor-generated arachidonic acid, whose degradation is inhibited by the cyclooxygenase inhibitors, caused the increased contractility by releasing more calcium from the sarcoplasmic reticulum. Under these conditions also lithium caused a distinct enhancement of the positive inotropic effect evoked by alpha 1-adrenergic agonists, probably by inhibiting the degradation of the second messenger inositol trisphosphate.

Animals↗
PubMed1987

Alpha 1-adrenoceptors in guinea-pig heart ventricles. [3H]prazosin and [125I]IBE 2254 are bound specifically to a receptor population with high affinity and low density.

In membrane preparations of guinea-pig heart ventricles [3H]prazosin ([3H]PRAZ) and [125I]-2-[beta-(4-hydroxy-3-iodophenyl)ethylaminoethyl]tetralone ([125I]IBE 2254) were used to determine the quantity and the characteristics of the small number of alpha 1-adrenoceptors. The amount of alpha 1-adrenoceptors was compared with the quantity of beta-adrenoceptors which were determined by [3H]dihydroalprenolol ([3H]DHA) binding. Equilibrium binding of all radioligands was found to be of high affinity, high specificity and saturable. A single homogeneous population of binding sites was labelled with the radioligands. The results of kinetic experiments with [3H]PRAZ and [125I]IBE 2254 confirmed the equilibrium binding results. In competition experiments, the rank order of potency for antagonists and agonists to compete with both radioligands was consistent with the well-established rank order at the alpha 1-adrenoceptor. In competition experiments, (-)-noradrenaline was more potent in inhibiting specific binding of [3H]PRAZ and [125I]IBE 2254 than (+)-noradrenaline by a factor of more than 50. The number of beta-adrenoceptors exceeded those of alpha 1-adrenoceptors by a factor of 4.4. According to our results in ventricles of the guinea-pig heart there exists a small population of alpha 1-adrenoceptors. Therefore, the determination of their number even by an adapted method and by means of radioligands with high specific activity and high selectivity as [3H]PRAZ and [125I]IBE 2254 is difficult.

Animals↗
PubMed1986

The effect of urapidil on cardiac alpha- and beta-adrenoceptors.

In the present study the effects of the antihypertensive drug urapidil on cardiac adrenoceptors in various regions of the heart were analyzed. On the isolated rabbit papillary muscle urapidil was found to produce a competitive antagonism against the alpha 1-agonist phenylephrine with a pA2-value of 6.4 in the presence of the beta-antagonist sotalol (5 X 10(-5) mol/l). In the same preparation urapidil also antagonized the positive inotropic effects evoked by the beta-adrenoceptor agonist isoprenaline yielding a pA2-value of 5.9. An antagonism against the positive inotropic effect of isoprenaline with the same pA2-value could also be demonstrated in guinea pig left atria. For further characterization of urapidil its effect against the beta 2-adrenoceptor agonist fenoterol on the carbachol contracted tracheal chain of the guinea pig was investigated. A weak antagonism with a pA2-value of 4.9 was observed. Thus the beta 1-adrenolytic potency of urapidil was found to be about 10 times higher than the beta 2-adrenolytic one. On the isolated perfused rabbit heart urapidil inhibited the electrically evoked increase in heart rate by 27 and 63% in a concentration of 10(-6) and 10(-5) mol/l, respectively, whereas the stimulation induced noradrenaline release was increased by 25 and 51%. This rise in noradrenaline release by urapidil was antagonized by clonidine 10(-7) and 10(-6) mol/l. From these results it can be concluded that urapidil acts not only as an antagonist at cardiac alpha 1- and beta-adrenoceptors, but also on alpha 2-adrenoceptors located presynaptically. The antagonism at these receptors against endogenous noradrenaline leads to an enhanced transmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗
PubMed1984

Facilitating interaction between rauwolscine and angiotensin in the mesenteric artery of the rabbit.

The interaction between rauwolscine and angiotensin II was investigated in the isolated mesenteric artery of the rabbit. Rauwolscine, known as an antagonist at alpha 2-adrenoceptors, did not induce contraction itself but interacted with angiotensin to produce a facilitated response of the vascular tissue. In the presence of rauwolscine, the contractile response of the tissue to angiotensin was markedly enhanced. The degree of facilitation appeared to be dependent on the rauwolscine concentration used rather than that of angiotensin. Moreover, rauwolscine induced a concentration-dependent increase in tension (pD2 = 6.8) in the presence of even subcontractile concentrations of angiotensin (10(-10) mol/l). This effect was not attributable to an indirect action involving presynaptic catecholamines, as revealed by the use of tissue strips from animals pretreated with reserpine or after chemical sympathectomy. Furthermore, an interaction via the prostaglandin system was excluded by negative results obtained with indomethacin. The 'agonistic effect' of rauwolscine was significantly attenuated by phentolamine (alpha 1/alpha 2) but not by prazosin (alpha 1) or phenoxybenzamine when applied for only a short time. The alpha 2-antagonist BDF 6143 behaved like rauwolscine whereas the alpha 1-antagonist corynanthine, a stereoisomer of rauwolscine, did not. The results indicate that the 'rauwolscine effect' is mediated by a receptor with alpha 2-characteristics. In general, angiotensin appears to interfere with some process which determines the expression of a drug's intrinsic effect.

Adrenergic alpha-Antagonists↗
PubMed1984

B-HT 920 acts as an alpha 1-adrenoceptor agonist in the rabbit aorta under certain in vitro conditions.

We have investigated the interaction of the alpha 2-adrenoceptor agonist B-HT 920 with the alpha-adrenoceptors in the rabbit aorta using various experimental conditions. In standard Krebs-Henseleit solution B-HT 920 behaved as an antagonist when tested against the alpha 1-agonist phenylephrine. However, it behaved as a partial agonist at alpha-receptors when subcontractile concentrations of various spasmogens (angiotensin II, serotonin, prostaglandin F2 alpha) were applied, although no change in the affinity of the receptor to B-HT 920 was observed. By means of the selective antagonists prazosin and rauwolscine it was established that B-HT 920 activated alpha 1-receptors. The same agonistic effects of B-HT 920 were obtained after pretreatment of the animal with reserpine or in the presence of ouabain. The various treatments used (except reserpine) did not influence the contractile response to phenylephrine. The contractile response to B-HT 920 was found to be highly susceptible to the calcium entry blocker nitrendipine whereas the response to phenylephrine was not. It is concluded that spasmogens modulate the responsiveness of alpha-receptors to certain agonists, possibly by causing a depolarization of the cell membrane and, thereby, sensitization of a mechanism involved in excitation-contraction coupling, conceivably a calcium gating mechanism.

Adrenergic alpha-Agonists↗
PubMed1984

Effect of removing the endothelial cells on the reactivity of rat aortic segments to different alpha-adrenoceptor agonists.

The influence of removing the endothelial cells on the alpha-receptor-mediated contractile response in segments of rat aorta was investigated using agonists with a range of affinity for alpha 1- and alpha 2-receptors. The preferential alpha 1-agonists were methoxamine, cirazoline, ST 587, and Sgd 101/75 and the preferential alpha 2-agonists were B-HT 920, clonidine, and guanfacine. When the endothelium was intact, the intrinsic activity (compared to noradrenaline) varied widely (0.0-0.7) for both groups of agonists. After removal of the endothelium the intrinsic activity was increased in each case to that of noradrenaline, or close to it. Furthermore, an increase in potency was obtained for each agonist, although to different degrees. No correlation, however, was found between the selectivity of the agonists and the degree of enhancement caused by the removal of the endothelium, in terms of either the intrinsic activity or the potency. Moreover, the use of the selective alpha 2-receptor antagonist rauwolscine on intact tissues did not mimic the effect of removing the endothelium. Therefore, the alpha-receptors of the endothelium could not be classified as either of the alpha 1- or alpha 2-subtype.

Adrenergic alpha-Agonists↗
PubMed1983

Postjunctional alpha-adrenoceptors in the isolated saphenous vein of the rabbit. Characterization and influence of angiotensin.

Experiments on the isolated saphenous vein of the rabbit have been performed in order to determine whether a coexistence of postjunctional alpha 1- and alpha 2-adrenoceptor subtypes can be demonstrated also under in vitro conditions. Prazosin, selective for alpha 1-receptors, and rauwolscine, selective for alpha 2-receptors, were used to antagonize the contractile response of the agonists phenylephrine (alpha 1), B-HT 920 (alpha 2) and noradrenaline (alpha 1/alpha 2). Each of the antagonists was equipotent against all three agonists; the effect of neither antagonist fulfilled the criteria for a competitive antagonism. The preferential alpha 1-receptor antagonist phenoxybenzamine, applied for irreversible blockade of alpha-receptors, reduced the effect of phenylephrine and B-HT 920 to the same degree. Thus, the results obtained with alpha-receptor antagonists cannot be reconciled with the coexistence of alpha 1- and alpha 2-receptors or the existence of only one of them. Contractile responses induced by alpha 1- and alpha 2-receptor agonists, respectively, could be differentiated by the calcium entry blocker nitrendipine. The effect of B-HT 920 was decreased whereas that of phenylephrine was hardly affected. Furthermore, we investigated the influence of angiotensin II on the effects of the alpha-adrenoceptor agonists as well as the antagonists. We observed firstly, that angiotensin, acting postsynaptically, potentiates the contractile response of certain alpha 2-receptor agonists and secondly, that in the presence of angiotensin the characteristics of the receptors as revealed by B-HT 920 are converted to typical alpha 2-adrenoceptors. It is concluded that the postjunctional alpha 2-receptors of the saphenous vein require the blood borne substance angiotensin for their expression.

Adrenergic alpha-Agonists↗
PubMed1983

What role do alpha- and beta-adrenoceptors play in the regulation of the heart?

Ahlquist described the existence of beta-adrenoceptors as structures mediating the positive effects of sympathetic nerve stimulation in the heart. Recently, the role of alpha-adrenoceptors has also been investigated by both biological and radioligand binding studies. The presence of alpha-adrenoceptors has now been demonstrated in the hearts of various mammalian species including man. Stimulation of beta-adrenoceptors causes positive ino-, chrono-, dromo- and bathmotropic effects while that of alpha-adrenoceptors is restricted to positive inotropic effects. Analysis of the effects mediated by alpha-stimulation as carried out in our department showed a clear-cut difference between the mechanisms underlying stimulation of beta- and of alpha-adrenoceptors: that evoked by beta-adrenoceptors is connected to an increase in cAMP, whereas that by alpha-adrenoceptors is not. Moreover, the effect of alpha-stimulation is evidently more dependent on heart rate and on the presence of Ca2+ than that of beta-stimulation. The nature of cardiac alpha-adrenoceptors is apparently distinct from that of other organs as they are stimulated by dopamine and adrenaline but not by the transmitter noradrenaline. Since the alpha-receptor-mediated increase in force of contraction is obviously less energy consuming than that via beta-receptors the heart gains a greater adaptability in adrenergic regulation especially in emergency situations such as myocardial infarction.

Animals↗
PubMed1982

Effect of long term treatment with atypical neuroleptic drugs on beta adrenoceptor binding in rat cerebral cortex and myocardium.

Several neuroleptic drugs enhance the release and the turnover of noradrenaline in the central nervous system and in peripheral organs. The present study demonstrates the effect of long term treatment (18 days) with atypical neuroleptic drugs (clozapine, thioridazine, and sulpiride) on beta-adrenoceptor density in the cerebral cortex and in the myocardium of rats. 1. Clozapine and thioridazine significantly reduced the number of 3H-dihydroalprenolol (DHA)-binding sites by 24 and 21%, respectively, in a crude cortical membrane fraction, and by 28 and 24% in myocardial membranes. 2. Sulpiride failed to alter the maximal number of binding sites in the cortex and in the myocardium. 3. The affinity of 3H-DHA to its binding sites remained unchanged by treatment with neuroleptic drugs. 4. Desipramine, which is known to reduce cerebral beta-adrenoceptors during chronic administration, was tested as reference compound. It proved to be more effective in this regard than clozapine and thioridazine in the cortex, but failed to reduce 3H-DHA binding in the myocardium. 5. Acute treatment with desipramine, clozapine, and thioridazine had no effect on 3H-DHA binding in the cerebral cortex. The decrease in beta-adrenoceptor density after long term treatment with neuroleptics may be ascribed to an increased concentration of noradrenaline at the receptor site due to antagonism at presynaptic alpha 2-adrenoceptors and inhibition of noradrenaline reuptake.

Animals↗
PubMed1981

Regulation of alpha 1-adrenoceptors in the cerebral cortex of the rat by thyroid hormones.

The influence of thyroid hormones on the concentration and properties of alpha 1-adrenoceptors in a crude membrane fraction obtained from the rat cerebral cortex was investigated using the [3H]-WB 4101 binding assay. Animals were made hypothyroid by feeding 6-propyl-2-thiouracil for 8 weeks. Hyperthyroidism was induced by triiodothyronine injections (50 microgram/100 g body weight) for 9 days. 1. The binding of [3H]-WB 4101 was saturable and of high affinity in controls as well as in hyper- and hypothyroid animals. The maximal number of binding sites (Bmax), which amounted to 95 fmol/mg protein in control animals, was increased by 27% in cortical membranes from hyperthyroid rats and reduced by 23% in the hypothyroid group. 2. The reduction in [3H]-WB 4101 binding due to 6-propyl-2-thiouracil feeding was reversible by triiodothyronine treatment. 3. Dissociation constants (KD) calculated from saturation experiments (0.25 nM) or kinetic data (0.21 nM) remained unchanged in altered thyroid states. 4. Inhibition of [3H]-WB 4101 binding by adrenergic agonists and antagonists revealed no differences between euthyroid and hypothyroid animals. The higher affinity of prazosin to the binding sites compared with yohimbine indicated that [3H]-WB 4101 predominantly labeled alpha 1-adrenoceptors. It is concluded that thyroid hormones regulate the number of alpha 1-adrenoceptors in membranes of the rat cerebral cortex, leaving their affinities unchanged.

Animals↗
PubMed1981

A radioenzymatic method for determination of normetanephrine in blood plasma.

A radioenzymatic assay for determination of normetanephrine in blood plasma is described. It was based on N-methylation of normetanephrine by phenylethanolamine-N-methyltransferase using S-adenosyl[methyl-3]methionine as the methyl donor. 2981 +/- 85 cpm (mean +/- s mean, n = 32) were obtained from 1 ng normetanephrine. Blank values corresponded to 27 +/- 3 pg (n = 7). Normetanephrine levels measured in the blood plasma of 12 persons ranged from 1.3 to 9.6 ng/ml.

Humans↗
PubMed1981

A sensitive radioenzymatic assay for dihydroxymandelic acid, dihydroxypenylglycol and dihydroxyphenylacetic acid .

A sensitive radioenzymatic procedure for the simultaneous determination of dihydroxymandelic acid, dihydroxyphenylglycol, and dihydroxyphenylacetic acid has been developed. The catechols were methylated by catechol-O-methyltransferase using S-adenosyl[methyl-3H]methionine as methyl donor. The assay involved extraction into organic solvent, thin-layer chromatography and periodate oxidation. The applicability of the procedure was tested by measuring the amounts of deaminated metabolites of noradrenaline, adrenaline and dopamine in heart perfusion samples and plasma of rabbits.

3,4-Dihydroxyphenylacetic Acid↗