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Erland Erdmann - One of the best experts on this subject based on the ideXlab platform.

  • Effect of Epinine on tension of human renal arteries
    Naunyn-Schmiedeberg's Archives of Pharmacology, 1996
    Co-Authors: Robert H. G. Schwinger, Christian Schulz, Klara Brixius, Michael Böhm, J. Müller-ehmsen, Erland Erdmann
    Abstract:

    Background: The present study aimed to characterize the effects of Epinine, the active metabolite of ibopamine on tension development in human renal arteries. Methods and results: Experiments were performed on isolated human renal arteries rings obtained during surgery due to kidney tumors ( n = 12). Epinine concentration-dependently relaxed isolated precontracted (PGF_2α) human renal artery rings ( P < 0.05) in the presence of phentolamine, as effectively (Epinine − 30 +/− 4 mN, dopamine − 31 +/− 5 mN) and with the same potency as dopamine (Epinine EC_50 0.7 μmol/l (0.4−1.2 μmol/l), dopamine 0.5 μmol/l (0.2−1.7 μmol/l)). This effect was antagonized by the specific D_1-receptor-antagonist SCH 23390. Effective β-adrenoceptor antagonistic concentrations of propranolol did not affect Epinine-induced vasorelaxation. In the absence of α-and β-adrenoceptor-antagonists the potency of Epinine to contract renal artery rings was significantly higher compared to dopamine indicating a higher affinity of Epinine to α-adrenoceptors. Conclusion: The present study provides evidence for direct vasodilatory effects of Epinine via activation of D_1-receptors on human renal arteries.

  • Effect of Epinine on tension of human renal arteries.
    Naunyn-Schmiedeberg's archives of pharmacology, 1996
    Co-Authors: Robert H. G. Schwinger, Christian Schulz, Klara Brixius, Michael Böhm, J. Müller-ehmsen, Erland Erdmann
    Abstract:

    Background: The present study aimed to characterize the effects of Epinine, the active metabolite of ibopamine on tension development in human renal arteries.

  • Cardiac inotropic as well as coronary and pulmonary artery actions of Epinine in human isolated tissues.
    The Journal of pharmacology and experimental therapeutics, 1993
    Co-Authors: R. H. G. Schwinger, Michael Böhm, C. Schulz, Ulrich Schmidt, Bernhard Schmid, H. Dienemann, B. Reichart, Erland Erdmann
    Abstract:

    The present study was aimed to characterize the effects of Epinine, the metabolite of the p.o. active dopamine derivate ibopamine in human cardiovascular tissues such as myocardium, coronary artery and pulmonary artery. Isometric force of contraction was studied in electrically driven papillary muscle strips from nonfailing (brain death), moderately failing (New York Heart Association class II-III, mitral valve replacement) and terminally failing human myocardium (New York Heart Association class IV, heart transplants) as well as in auricular trabeculae (aortocoronary bypass operation). Epinine increased force development in a concentration-dependent manner. In comparison to isoprenaline, Epinine had a significantly lower potency but a similar efficacy to enhance force of contraction. Depending on the degree of myocardial failure, the effectiveness of Epinine was reduced, whereas the potency was similar. Only in nonfailing myocardium, Epinine increased force of contraction as effectively as Ca++. Prestimulation with forskolin or milrinone enhanced the potency of the Epinine-mediated inotropic effect. In contrast, the beta-1-selective antagonist CGP 207.12A [2-hydroxy-5-(2-(hydroxy-3-(4-((1-methyl-4-trifluoromethyl)-1-H-imidazol -2-yl)-phenoxy)-propyl)-aminoethoxyl)-benzamide] and the beta-2-selective antagonist ICI 118.551 [erythro-(+-)-1-(7-methylindan-4-yloxy)-3- isopropylaminobutan-2-ol-hydrochloride] shifted the concentration-response curve of Epinine significantly to the right, indicating action at both beta-2 and beta-1 adrenoceptors. Epinine exerted higher affinity at beta-2 compared to beta-1 adrenoceptors in radioligand binding experiments ([125I]iodocyanopinodolol). In human coronary artery rings and pulmonary artery rings Epinine alone as well as Epinine in the presence of propranolol initiated a concentration-dependent increase in tension development in precontracted (prostaglandin F2 alpha, 0.3 mumol/l) as well as in non-precontracted rings. These results suggest that Epinine exerts no direct vasodilatory activity in human coronary and pulmonary arteries at concentrations which are capable to produce positive inotropic activity. The supposed beneficial effects of ibopamine in the treatment of heart failure may not be due to positive inotropic actions as the concentrations producing positive inotropy are much higher than the clinically observed plasma concentrations.

O E Brodde - One of the best experts on this subject based on the ideXlab platform.

  • Dose-dependent separation of dopaminergic and adrenergic effects of Epinine in healthy volunteers
    Naunyn-Schmiedeberg's Archives of Pharmacology, 1995
    Co-Authors: A. Daul, M. Elter-schulz, U. Poller, F. Jockenhövel, K. Pönicke, F. Boomsma, A. J. Man In't Veld, R. F. Schäfers, O E Brodde
    Abstract:

    Epinine (N-methyl-dopamine, the active metabolite of ibopamine), is a full agonist at dopamine (DA)-receptors and α- and \-adrenoceptors. To study whether in vivo DA-receptor mediated effects can be separated from α- and \-adrenoceptor effects we compared in 10 male volunteers the effects of i.v. Epinine (0.5; 1; 2; 4 μg/kg/min for 15 min each) on DA-receptor (changes in serum prolactin)- and α- and \-adrenoceptor (changes in systolic [P_syst] and diastolic blood pressure [P_diast] and heart rate)-mediated effects with those of dopamine before and after propranolol (5 mg i.v. 45 min pre-infusion), bisoprolol (15 mg p.o. 2 h preinfusion) and domperidone (10 mg p.o. 1 h pre-infusion). At the 0.5 and 1 μg doses dopamine and Epinine did not affect P_syst P_diast and heart rate but significantly decreased prolactin levels. At the higher dose both dopamine and Epinine significantly increased P_syst and heart rate, while only Epinine significantly increased P_diast. In addition both dopamine and Epinine significantly increased diuresis and natriuresis; in contrast, only dopamine, but not Epinine, dose-dependently increased plasma noradrenaline levels. Domperidone did not affect dopamine- and Epinine-evoked blood pressure-and heart rate-changes, but antagonized their prolactin-effects (at least at the lower doses). Bisoprolol and propranolol significantly reduced dopamine-induced P_syst- and heart rate-increases to about the same extent. Propranolol enhanced Epinine-induced P_syst-and P_diast-increases while bisoprolol reduced Epinine-evoked P_syst-increase but not P_diast-increase. Epinine-induced heart rate-increase was abolished by bisoprolol and was converted into a heart rate-decrease by propranolol. We conclude that in 0.5 and 1 μg doses (plasma levels of 20–80 nmol/1) Epinine acts only at DA-receptors. Thus, ibopamine in therapeutically recommended doses (3 × 100 mg/day with peak plasma Epinine-levels of 50–80 nmol/1) very likely activates only DA-receptors. In higher doses, however, Epinine -like dopamine - activates α- and \-adrenoceptors whereby Epinine has a stronger α-adrenoceptor agonistic activity than dopamine. Moreover, part of the dopamine-effects are indirect via release of endogenous noradrenaline whereas Epinine-effects do not appear to include an indirect component.

  • Lack of desensitization of α-and β-adrenoceptor function during chronic treatment of healthy volunteers with ibopamine, an orally active dopamine receptor agonist
    European Journal of Clinical Pharmacology, 1993
    Co-Authors: O E Brodde, F. Boomsma, A. J. Man In't Veld, I. Klusmann, M. Wojcik, M. C. Michel
    Abstract:

    In 18 healthy volunteers, in a double-blind placebo-controlled study, we investigated of whether 14 days treatment with a therapeutic dose of ibopamine (3×100 mg/day p.o.), respectively its active metabolite Epinine, would desensitize lymphocyte β_2- or platelet α_2-adrenoceptors, or α_1- and β-adrenoceptor mediated (phenylephrine-and isoprenaline infusions, respectively), changes in systolic and diastolic blood pressure and heart rate. Ibopamine-treatment, which resulted in peak plasma Epinine concentrations of 4–5 nmol·l^−1, neither affected resting heart rate or blood pressure, nor any of the α- or β-adrenoceptor parameters measured. Since in man in general long-term administration of α- and β-adrenoceptor agonists desensitizes α- and β-adrenoceptors, the lack of any α- and β-adrenoceptor desensitizing effect of ibopamine suggests that, in the dose employed (3×100 mg per day), ibopamine does not exert α- or β-adrenoceptor agonistic effect in humans.

Frans Boomsma - One of the best experts on this subject based on the ideXlab platform.

  • Effects of ibopamine on postural hypotension in pure autonomic failure.
    Journal of cardiovascular pharmacology, 1993
    Co-Authors: P. L. Rensma, A. H. Van Den Meiracker, Frans Boomsma, Arie J. Man ʼt Veld, M. A. D. H. Schalekamp
    Abstract:

    We wished to determine whether ibopamine, a dopaminergic prodrug with weak agonist activity on alpha- and beta-adrenoceptors, improves orthostatic tolerance in autonomic insufficiency. Three subjects with severe orthostatic hypotension resulting from pure autonomic failure (PAF) were studied. Direct arterial blood pressure (ABP) and heart rate (HR) were recorded continuously. Orthostatic tolerance was evaluated by 60 degrees passive head-up tilting. Tilting was performed before and after a single oral 100-mg dose of ibopamine. Blood samples for measurement of plasma catecholamines, free Epinine (the active metabolite of ibopamine), and conjugated Epinine were taken at regular intervals. In all 3 subjects, orthostatic tolerance was greatly improved by ibopamine. This improvement occurred as soon as 10-30 min after administration of ibopamine and lasted 20-50 min. alpha-Adrenoceptor blockade with phentolamine abolished the effect of ibopamine. The interindividual pharmacokinetics of ibopamine varied considerably: Peak plasma concentrations of ibopamine in the three subjects were 2.8, 4.5, and 35.4 ng/ml, respectively. The high level of Epinine in one patient was associated with severe hypertension and tachycardia. Ibopamine may be a valuable new pharmacologic treatment for orthostatic hypotension in PAF, but in light of the highly variable interindividual pharmacokinetics further studies must be performed before use of the compound can be advocated in this disorder.

  • differential cardiovascular and neuroendocrine effects of Epinine and dopamine in conscious pigs before and after adrenoceptor blockade
    British Journal of Pharmacology, 1992
    Co-Authors: L J Van Woerkens, Frans Boomsma, A Man In J T Veld, M M Bevers, P D Verdouw
    Abstract:

    1. The effects of Epinine or dopamine (both 1-10 micrograms kg-1 min-1) on systemic haemodynamics and plasma concentrations of catecholamines and prolactin were studied in conscious pigs before and after combined non-selective alpha- and beta-adrenoceptor blockade. 2. The plasma concentrations of the two compounds did not differ from each other over the entire dose-range. 3. Epinine increased aortic blood flow (AoBF, 24 +/- 6%), which was due to an increase in heart rate (HR) for doses less than 10 micrograms kg-1 min-1. At 10 micrograms kg-1 min-1, HR decreased slightly (10 +/- 3%, as compared to the value obtained at 5 micrograms kg-1 min-1) and stroke volume increased up to 15% (P < 0.05). Mean arterial pressure (MAP, 99 +/- 3 mmHg at baseline) decreased dose-dependently (14 +/- 2%, P < 0.05) up to the infusion rate of 5 micrograms kg-1 min-1, but increased by 4.0 +/- 1.8 mmHg during infusion of 10 micrograms kg-1 min-1. Systemic vascular resistance (SVR) decreased up to 23 +/- 3% for doses less than 10 micrograms kg-1 min-1, but did not change further during infusion of the highest dose. LVdP/dtmax increased during the two highest infusion rates up to 22 +/- 6% (P < 0.05). After the infusion was stopped there was an abrupt increase in HR (18 +/- 4%, P < 0.05) and a further decrease in SVR before all parameters returned to baseline.4. Dopamine caused increases in AoBF (27 +/- 3%) similar to Epinine, the only difference being that HR continued to increase (32 +/- 5%) and MAP (13 +/- 3%) and SVR continued to decrease (31 +/- 3%) over the entire dose-range. The increase in LVdP/dt,,,, at the highest dose (48 +/- 4%, P <0.05) was more pronounced than with Epinine.5. Adrenoceptor blockade inhibited all Epinine-induced changes, but did not affect the dopamineinduced changes in AoBF, SVR and MAP, but attenuated the increases in HR and LVdP/dtmax.6. Noradrenaline (NA) and adrenaline (Ad) concentrations did not change during infusion of Epinine or dopamine, but NA increased by 50% within 2.5 min after stopping the infusion of Epinine. After adrenoceptor blockade NA and Ad concentrations did not change during infusion of dopamine, which contrasted with a decrease of 55 +/- 5% (P<0.05) in NA during infusion of Epinine.7. Prolactin concentrations decreased gradually from 480 +/- 40 pg ml-' to 270 +/- 50 pg ml1' (P<0.05) during infusion of Epinine, but did not change significantly during dopamine infusion.8. The differential effects of Epinine and dopamine on MAP, SVR, plasma NA (before and after adrenoceptor blockade) and prolactin, leads us to conclude that in conscious pigs, Epinine is a more potent a, P2 and D2-receptor agonist, but a weaker D,-receptor agonist than dopamine.

  • Simultaneous determination of free catecholamines and Epinine and estimation of total Epinine and dopamine in plasma and urine by high-performance liquid chromatography with fluorimetric detection.
    Journal of chromatography, 1992
    Co-Authors: Frans Boomsma, Gooitzen Alberts, F.a.j. Van Der Hoorn, A. J. Man In 't Veld, M. A. D. H. Schalekamp
    Abstract:

    Abstract Epinine (N-methyldopamine) is the pharmacologically active hydrolysis product of the prodrug ibopamine, which is currently being widely studied for the treatment of congestive heart failure. This paper reports a sensitive and reliable method for the simultaneous determination of free catecholamines and Epinine in plasma and urine. The compounds are isolated from plasma or urine by a specific liquid—liquid extraction, derivatized with the selective fluorogenic agent 1,2-diphenylethylenediamine, and quantitated by high-performance liquid chromatography with gradient elution and fluorimetric detection. The limits of detection for the derivatized catecholamines and Epinine are 0.3–0.6 pg of injected compound. Intra- and inter-assay coefficients of variation of all four compounds are good (1–8%), as are the accuracy and linearity. A method is also reported for the determination of total dopamine and Epinine in plasma and urine based on the same principle. This method, in which deconjugation is accomplished by acid hydrolysis at 95°C, also shows good sensitivity and reproducibility.

  • Effect of Epinine on systemic hemodynamics and regional blood flow in conscious pigs.
    Journal of cardiovascular pharmacology, 1992
    Co-Authors: Van Woerkens Lj, Van Der Giessen Wj, Van Meegen J, Frans Boomsma
    Abstract:

    Intravenous (i.v.) infusions (1, 2.5, 5, and 10 micrograms/kg/min for 10 min) were used to evaluate the cardiovascular effects of Epinine (N-methyl-dopamine) in 8 conscious pigs. Epinine is a nonselective and nonspecific dopamine (DA) agonist, that also stimulates alpha- and beta-adrenoceptors. Epinine (1-5 microgram/kg/min) increased cardiac output (CO) by up to 15 +/- 5% (p less than 0.05), owing to an increase in heart rate (HR, 24 +/- 6%), but an increase in stroke volume (SV, 16 +/- 4%) caused the further increase in CO at 10 micrograms/kg/min. Mean arterial blood pressure decreased gradually from 100 +/- 5 mm Hg to 84 +/- 4 mm Hg during infusions up to 5 microgram/kg/min, but increased to 89 +/- 4 mm Hg during infusion of 10 micrograms/kg/min (p less than 0.05). Systemic vascular resistance had decreased from 36.5 +/- 2.8 to 27.5 +/- 3.0 mm Hg/L/min after infusion of 5 micrograms/kg/min but did not change further during infusion of 10 micrograms/kg/min. LV dP/dtmax increased only at 10 micrograms/kg/min. Myocardial blood flow did not change at any dose, owing to metabolically regulated coronary vasodilatation (myocardial work did not change). Flow to the adrenals (up to 110 +/- 37%) and the spleen (up to 95 +/- 13%) increased dose dependently. Cerebral blood flow increased only at the highest dose (15 +/- 5%, p less than 0.05); flow to the kidneys, liver, small intestine, and skeletal muscle did not change. Flow decreased to the stomach (21 +/- 5%) and skin (for doses less than 2.5 micrograms/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

  • Differential cardiovascular and neuroendocrine effects of Epinine and dopamine in conscious pigs before and after adrenoceptor blockade.
    British journal of pharmacology, 1992
    Co-Authors: L J Van Woerkens, Frans Boomsma, M M Bevers, A. J. Man In 't Veld, P D Verdouw
    Abstract:

    1. The effects of Epinine or dopamine (both 1-10 micrograms kg-1 min-1) on systemic haemodynamics and plasma concentrations of catecholamines and prolactin were studied in conscious pigs before and after combined non-selective alpha- and beta-adrenoceptor blockade. 2. The plasma concentrations of the two compounds did not differ from each other over the entire dose-range. 3. Epinine increased aortic blood flow (AoBF, 24 +/- 6%), which was due to an increase in heart rate (HR) for doses less than 10 micrograms kg-1 min-1. At 10 micrograms kg-1 min-1, HR decreased slightly (10 +/- 3%, as compared to the value obtained at 5 micrograms kg-1 min-1) and stroke volume increased up to 15% (P < 0.05). Mean arterial pressure (MAP, 99 +/- 3 mmHg at baseline) decreased dose-dependently (14 +/- 2%, P < 0.05) up to the infusion rate of 5 micrograms kg-1 min-1, but increased by 4.0 +/- 1.8 mmHg during infusion of 10 micrograms kg-1 min-1. Systemic vascular resistance (SVR) decreased up to 23 +/- 3% for doses less than 10 micrograms kg-1 min-1, but did not change further during infusion of the highest dose. LVdP/dtmax increased during the two highest infusion rates up to 22 +/- 6% (P < 0.05). After the infusion was stopped there was an abrupt increase in HR (18 +/- 4%, P < 0.05) and a further decrease in SVR before all parameters returned to baseline.4. Dopamine caused increases in AoBF (27 +/- 3%) similar to Epinine, the only difference being that HR continued to increase (32 +/- 5%) and MAP (13 +/- 3%) and SVR continued to decrease (31 +/- 3%) over the entire dose-range. The increase in LVdP/dt,,,, at the highest dose (48 +/- 4%, P

A. K. Hsieh - One of the best experts on this subject based on the ideXlab platform.

Michael Böhm - One of the best experts on this subject based on the ideXlab platform.

  • Effect of Epinine on tension of human renal arteries
    Naunyn-Schmiedeberg's Archives of Pharmacology, 1996
    Co-Authors: Robert H. G. Schwinger, Christian Schulz, Klara Brixius, Michael Böhm, J. Müller-ehmsen, Erland Erdmann
    Abstract:

    Background: The present study aimed to characterize the effects of Epinine, the active metabolite of ibopamine on tension development in human renal arteries. Methods and results: Experiments were performed on isolated human renal arteries rings obtained during surgery due to kidney tumors ( n = 12). Epinine concentration-dependently relaxed isolated precontracted (PGF_2α) human renal artery rings ( P < 0.05) in the presence of phentolamine, as effectively (Epinine − 30 +/− 4 mN, dopamine − 31 +/− 5 mN) and with the same potency as dopamine (Epinine EC_50 0.7 μmol/l (0.4−1.2 μmol/l), dopamine 0.5 μmol/l (0.2−1.7 μmol/l)). This effect was antagonized by the specific D_1-receptor-antagonist SCH 23390. Effective β-adrenoceptor antagonistic concentrations of propranolol did not affect Epinine-induced vasorelaxation. In the absence of α-and β-adrenoceptor-antagonists the potency of Epinine to contract renal artery rings was significantly higher compared to dopamine indicating a higher affinity of Epinine to α-adrenoceptors. Conclusion: The present study provides evidence for direct vasodilatory effects of Epinine via activation of D_1-receptors on human renal arteries.

  • Effect of Epinine on tension of human renal arteries.
    Naunyn-Schmiedeberg's archives of pharmacology, 1996
    Co-Authors: Robert H. G. Schwinger, Christian Schulz, Klara Brixius, Michael Böhm, J. Müller-ehmsen, Erland Erdmann
    Abstract:

    Background: The present study aimed to characterize the effects of Epinine, the active metabolite of ibopamine on tension development in human renal arteries.

  • Cardiac inotropic as well as coronary and pulmonary artery actions of Epinine in human isolated tissues.
    The Journal of pharmacology and experimental therapeutics, 1993
    Co-Authors: R. H. G. Schwinger, Michael Böhm, C. Schulz, Ulrich Schmidt, Bernhard Schmid, H. Dienemann, B. Reichart, Erland Erdmann
    Abstract:

    The present study was aimed to characterize the effects of Epinine, the metabolite of the p.o. active dopamine derivate ibopamine in human cardiovascular tissues such as myocardium, coronary artery and pulmonary artery. Isometric force of contraction was studied in electrically driven papillary muscle strips from nonfailing (brain death), moderately failing (New York Heart Association class II-III, mitral valve replacement) and terminally failing human myocardium (New York Heart Association class IV, heart transplants) as well as in auricular trabeculae (aortocoronary bypass operation). Epinine increased force development in a concentration-dependent manner. In comparison to isoprenaline, Epinine had a significantly lower potency but a similar efficacy to enhance force of contraction. Depending on the degree of myocardial failure, the effectiveness of Epinine was reduced, whereas the potency was similar. Only in nonfailing myocardium, Epinine increased force of contraction as effectively as Ca++. Prestimulation with forskolin or milrinone enhanced the potency of the Epinine-mediated inotropic effect. In contrast, the beta-1-selective antagonist CGP 207.12A [2-hydroxy-5-(2-(hydroxy-3-(4-((1-methyl-4-trifluoromethyl)-1-H-imidazol -2-yl)-phenoxy)-propyl)-aminoethoxyl)-benzamide] and the beta-2-selective antagonist ICI 118.551 [erythro-(+-)-1-(7-methylindan-4-yloxy)-3- isopropylaminobutan-2-ol-hydrochloride] shifted the concentration-response curve of Epinine significantly to the right, indicating action at both beta-2 and beta-1 adrenoceptors. Epinine exerted higher affinity at beta-2 compared to beta-1 adrenoceptors in radioligand binding experiments ([125I]iodocyanopinodolol). In human coronary artery rings and pulmonary artery rings Epinine alone as well as Epinine in the presence of propranolol initiated a concentration-dependent increase in tension development in precontracted (prostaglandin F2 alpha, 0.3 mumol/l) as well as in non-precontracted rings. These results suggest that Epinine exerts no direct vasodilatory activity in human coronary and pulmonary arteries at concentrations which are capable to produce positive inotropic activity. The supposed beneficial effects of ibopamine in the treatment of heart failure may not be due to positive inotropic actions as the concentrations producing positive inotropy are much higher than the clinically observed plasma concentrations.