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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↗
PubMed1979

Demonstration of alpha-adrenoceptors in the rabbit heart by [3H]-dihydroergocryptine binding.

For direct identification of alpha-adrenoceptors in a membrane fraction of the rabbit heart the potent alpha-adrenoceptor antagonist [3H]-dihydroergocryptine ([3H]-DHE) was used. 1. The binding of [3H]-DHE was saturable with 80 fmol of [3H]-DHE bound/mg protein and of high affinity with an equilibrium dissociation constant (KD) of 11.5 nM. Binding of [3H]-DHE (6 nM) was rapid (t 1/2 = 2 min) and readily reversible. From the ratio of the rate constants for forward (K1 = 1.97 X 10(7) M-1 min-1) and reverse (K2 = 0.206 min-1) reactions a KD-value of 10 nM was calculated, which is in good agreement with that obtained by equilibrium studies. 2. Adrenergic agonists compete for [3H]-DHE binding in an order to potency: (-)adrenaline greater than (-)phenyleprine greater than (-)isoprenaline and adrenergic antagonists in the order: phentolamine greater than yohimbine greater than (-)propranolol. Binding is stereospecific as indicated by the greater potency of (-)adrenaline than (+/-)adrenaline in displacing [3H]-DHE from the binding sites. 3. For comparison the binding of the potent beta-adrenoceptor antagonist (-)[3H]-dihydroalprenolol ((-)[3H]-DHA) was measured in the same membrane fraction. The number and affinity of beta-adrenoceptors amounted to 115 fmol of (-)[3H]-DHA bound/mg protein at saturation and KD = 7.9 nM. Adrenergic agonists compete for (-)[3H]-DHA binding in an order of potency: (-)isoprenaline greater than (-)adrenaline greater than (-)phenylephrine; and adrenergic antagonists in the order: (-)prapranolol greater than phentolamine. 4. It is concluded that in a membrane fraction of the rabbit heart there exist binding sites for [3H]-DHE which have characteristics indistinguishable from alpha-adrenoceptors. Thus the present results are in agreement with previously reported data on the existence of cardiac alpha-adrenoceptors in the rabbit heart (Schümann et al., 1974; Endoh et al., 1976b).

Adrenergic alpha-Agonists↗
PubMed1979

Relationship between histamine-induced changes of cyclic AMP and mechanical activity on smooth muscle preparations of the guinea-pig ileum and the rabbit mesenteric artery.

On guinea-pig ileum and rabbit mesenteric artery contracted by high potassium (100 mM) histamine produced relaxations which were inhibited by the H2-receptor antagonist metiamide. These results are thus indicative for the role of H2-receptors in mediating relaxation and for H1-receptors in mediating contraction on smooth muscle. Time course studies for the relaxing and cyclic AMP responses to histamine showed that the cyclic AMP increase preceded the H2-receptor mediated relaxation. The cyclic AMP increase in response to histamine was prevented by metiamide, but remained unaffected by mepyramine on both the guinea-pig ileum and the rabbit mesenteric artery. In addition, dose-response curves obtained on the mesenteric artery demonstrated that the H2-receptor mediated depressor responses coincided with cyclic AMP increases. Thus, these results gave clear-cut evidence that cyclic AMP is an intracellular metabolic event only implicit in the H2-receptor mediated relaxation, but not in the H1-receptor mediated contraction on smooth muscle preparations.

Animals↗
PubMed1979

Changes of adrenoceptor-mediated responses in the pithed rat during propylthiouracil-induced hypothyroidism.

Adrenoceptor-mediated responses of the cardiovascular system during propylthiouracil-induced hypothyroidism were investigated. Interfering nervous reflexes could be circumvented by using pithed rats. Cardiac beta-adrenoceptor-mediated acceleration of heart rate following electrical stimulation or injection of noradrenaline and isoprenaline was markedly diminished even after 2 weeks of treatment. This loss of beta-sensitivity prevented the study of possible changes of presynaptic regulatory adrenoceptors in this test model. Taking the increase in diastolic blood pressure after application of alpha-agonists as index of the sensitivity of vascular alpha-adrenoceptors we found these to have been desensitized in the hypothyroid state. According to these results the lack of thyroid hormones exerted a similar effect on cardiac beta- and on vascular alpha-adrenoceptors.

Animals↗
PubMed1978

The role of cyclic AMP in temperature-dependent changes of contractile force and sensitivity ot isoprenaline and papaverine in guinea-pig atria.

Right and left guinea-pig atria responded to decreasing temperatures (42-27 degrees C) with elevation for force of contraction and concomitant increases in cAMP. When atria were rapidly cooled from 42 to 27 degrees C the increase in cAMP occurred prior to the onset of the inotropic responses. Papaverine (3 X 10(-5) M) potentiated the effects of temperature on cAMP and force of contraction on left atria driven at 0.5 Hz. On right atria beating spontaneously at frequencies above 2 Hz papaverine only potentiated the effect of decreasing temperatures on the response of cAMP but not on that of force of contraction. Time course studies of the effects of isoprenaline (3 X 10(-8) M) on right atria at 27 degrees C showed large inotropic responses to isoprenaline which were accompanied by increases in cAMP. At 42 degrees C the responses of force of contraction and cAMP to isoprenaline occurred faster and were only short-lasting. As with the time courses for isoprenaline, dose-response curves for the effect of isoprenaline and papaverine on cAMP content and force of contraction also appeared to be shifted towards higher levels at hypothemia. However, pD2 values reflected increases in affinity for inotropic, but not for the cAMP responses to isoprenaline and papaverine at hypothermia. These results show that cyclic AMP is involved in the inotropic responses to hypothermia, but not in the supersensitivity of heart to isoprenaline and papaverine as observed at low temperatures.

Animals↗
PubMed1978

Demonstration in human atrial preparations of alpha-adrenoceptors mediating positive inotropic effects.

In isolated, electrically driven right auricular strips of the human heart the inotropic effect of phenylephrine was studied. 1. First, the influence of the driving rate on the tension developed (i.e., the frequency-force relationship) was determined by stimulation of the preparations at 0.1, 0.5, 1, 2 and 3 HZ. The force of contraction was lowest at a stimulation rate of 0.1 HZ (36.9 g/g dry weight). The maximally developed force of contraction observed at frequencies of 0.5, 1 and 2 HZ amounted to about 200 g/g dry weight. The values did not significantly differ from each other. 2. The negative log of the EC50 (-log EC50) for the positive inotropic effect of phenylephrine determined at a frequency of 0.5 and 1.0 HZ amounted to 5.28 +/- 0.08 and 5.34 +/- 0.11, respectively. The alpha-adrenolytic drug phentolamine (3 x 10(-6) M) diminished significantly the -log EC50 to 5.01 +/- 0.04 and 4.89 +/- 0.10, respectively. 3. At a frequency of 1 HZ a shift of the concentration-response curve to the right was observed after treatment with the beta-adrenolytic drug pindolol (3 x 10(-8) M); the -log EC50 of phenylephrine decreased significantly to 4.08 +/- 0.07. 4. From these results it is concluded that alpha-adrenoceptors are present in human atria; they mediate positive inotropic effects and are stimulated by phenylephrine.

Heart↗
PubMed1978

No evidence for involvement of dopaminergic receptors in the positive inotropic action of dopamine on the isolated rabbit papillary muscle.

Experiments were carried out on the isolated rabbit papillary muscle driven at 0.5 Hz in order to further elucidate the mechanism of the positive inotropic effect evoked by dopamine. The dose-response curve for dopamine was not affected by the antagonists pimozide (10(-6) M), yohimbine (10(-5) M) pindolol (3 x 10(-8) M) and phentolamine (10(-6) M) when these agents were given separately. Only the simultaneous administration of yohimbine plus pindolol and phentolamine plus pindolol, respectively, shifted the entire curve to the right. This shift was not further influenced by pimozide. Dopamine (10(-4) M) increased the cyclic AMP content of the papillary muscle by about 50%; this increase was not affected by pimozide, but was markedly elevated by yohimbine and completely depressed by pindolol. From the present results it is concluded, that dopamine produces its positive inotropic effect through stimulation of myocardial alpha-as well as beta-adrenoceptors to about the same degree; stimulation of specific dopaminergic receptors, however, is not involved. The stimulation of beta-adrenoceptors is accompanied by an increase of the cyclic AMP level, while that of alpha-adrenoceptors is not.

Animals↗
PubMed1978

Influence of frequency of stimulation on the toxicity of digoxin on isolated guinea-pig atria in different extracellular Ca2+.

In isolated guinea-pig left atria driven by rates of 0.5, 1,2, 3 and 4 Hz digoxin was infused continuously until cardiac arrest occurred. The experiments were performed in Tyrode solution with normal and twice the calcium content. Calculated was the toxic concentration of digoxin as that concentration which caused arrest of the preparation. In normal Ca2+-content (1.8 mM) an increase of the driving frequency decreased significantly the toxic concentration of digoxin, i.e. elevated the toxicity of this cardiac glycoside. The elevation of the Ca2+-content of the Tyrode caused a further diminution of the toxic concentrations of digoxin in dependence of the driving rate, thus demonstrating a synergism of Ca2+ and digoxin with regard to its toxicity.

Animals↗
PubMed1977

Effect of papaverine on the frequency-force relationship in guinea-pig left atria.

Contractile responses of guinea-pig atria to papaverine were analyzed under different stimulation frequencies. Atria, driven at 2 Hz, showed positive inotropic responses to papaverine which were maximal within 10-15 min. These responses were maintained for 60 min in the presence of low concentrations of papaverine (up to 10(-5) M), but reversed into marked negative inotropic effects under the influence of higher concentrations. The well-known frequency-force relationship was reversed by papaverine. At low stimulation rates papaverine elicited positive inotropic responses, which gradually decreased with increasing frequencies until strong cardiodepression occurred. A frequency-force curve obtained in the presence of both the Ca2+-antagonistic drug D 600 and the inhibitor of the phosphodiesterase theophylline was similar to that obtained under the influence of papaverine. Theophylline alone evoked positive inotropic effects at all frequencies studied and left the character of the ascending staircase unchanged. In contrast, D 600 was ineffective at low, but cardiodepressive at high stimulation frequencies. In the presence of D 600 or papaverine high external Ca2+ could not restore a normal frequency-force relationship. The reversal of the frequency-force relationship as produced by D 600 and papaverine could not be obtained by lowering of the external Ca2+. The present results show that papaverine is able to evoke marked positive inotropic effects at low stimulation frequencies by inhibition of phosphodiesterase. At high frequencies, however, these effects are masked by negative inotropic responses due to the inhibitory action of papaverine on Ca2+-exchange of the cardiac muscle cell.

Animals↗