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Biomedical subjects

R Düsing

Publications and source records attributed to R Düsing.

At least 91 records · Page 5Linked to original sources
PubMed1993

Effects of carbamazepine on action potentials and calcium currents in rat spinal ganglion cells in vitro.

The effects of carbamazepine (CBZ) on action potentials and calcium currents in cultured rat sensory spinal ganglion cells were investigated. CBZ was found to reversibly suppress the calcium-dependent components of action potentials and to reduce the amplitude of the after-hyperpolarizations, while the rising phase and the peak amplitude were hardly changed. Furthermore, CBZ caused a marked reduction in the calcium currents, which in some cells was reversible. The present findings confirm that CBZ has calcium-antagonistic properties.

Action Potentials↗
PubMed1993

Membrane sodium-proton exchange and primary hypertension.

Recent studies have revealed that an enhancement of sodium-proton exchange is a frequently observed ion transport abnormality in essential hypertension. An altered antiport activity not only is measurable in blood cells of hypertensive subjects ex vivo but also is detectable in skeletal muscle in vivo. Several lines of argument suggest that the altered antiport activity is not an epiphenomenon of hypertension: 1) the increased activity is found only in a subgroup of patients with high blood pressure, 2) it is not tightly correlated to the severity or duration of hypertension, and 3) high sodium-proton exchange activity persists over time and is not affected by antihypertensive treatment. Available evidence suggests that enhanced sodium-proton exchange is associated with or a cause for the structural alterations found in resistance vessels of hypertensive individuals (media hypertrophy) and left ventricular hypertrophy. This review summarizes some of the physiological properties and roles of the sodium-proton exchanger and discusses its kinetic properties in essential hypertension. Furthermore, the reasons for the enhanced antiport activity and its potential implications regarding the pathogenesis of hypertension are discussed.

Animals↗
PubMed1993

Action of dihydropyridine calcium antagonists on early growth response gene expression and cell growth in vascular smooth muscle cells.

OBJECTIVE: Evidence suggests that calcium antagonists may suppress vascular smooth muscle cell (VSMC) growth and proliferation, which may be a crucial step in the pathogenesis of hypertension and atherosclerosis. DESIGN: The effects of the dihydropyridine calcium antagonists nifedipine, nitrendipine, nisoldipine, nimodipine and isradipine on cell growth induced by platelet-derived growth factor (PDGF)-AB and angiotensin II (Ang II), and expression of the transcription factors c-fos and early-growth response gene 1 (egr-1) were investigated. METHODS: Proliferation of VSMC in culture was measured by [3H]-thymidine incorporation into cell DNA and by cell count. Expression of c-fos and egr-1 messenger RNA (mRNA) was determined by the Northern blot technique. RESULTS: All of the calcium antagonists blunted the PDGF-induced rise in VSMC DNA synthesis. The inhibitory potency of isradipine on PDGF-stimulated DNA synthesis was approximately 10-fold that of the other calcium antagonists used, isradipine having a half-maximal inhibitory concentration (IC50) of (4.2 +/- 0.16) x 10(-7) mol/l. The calcium antagonists investigated also inhibited Ang II-induced DNA synthesis. Isradipine (10(-6) mol/l) completely abolished the PDGF-induced cell proliferation. Both PDGF (50 ng/ml) and Ang II (10(-7) mol/l) induced c-fos and egr-1 mRNA expression, having maximum effect after 30 min. In the case of c-fos, pre-incubation with 5 x 10(-6) mol/l isradipine led to a decrease in both Ang II- and PDGF-induced expression of this immediate-early gene. The expression of egr-1 was not affected by pre-incubation with 5 x 10(-6) mol/l isradipine. CONCLUSIONS: All calcium antagonists investigated in the present study inhibited cell growth. Isradipine was more potent in blocking growth factor-induced cell growth than the other calcium antagonists studied. The inhibitory effect of the dihydropyridine calcium antagonists appears to be dependent on the expression of c-fos.

Animals↗
PubMed1992

Losartan inhibits the angiotensin II-induced stimulation of the phosphoinositide signalling system in vascular smooth muscle cells.

2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bip hen yl-4-yl)methyl]imidazole, potassium salt (Losartan) (previous name, DuP 753 or MK 954) is a nonpeptide angiotensin II receptor antagonist. This study was performed to investigate the ability of Losartan to inhibit the angiotensin II-induced stimulation of the phospoinositide signalling system and the angiotensin II-induced hypertrophy in aortic vascular smooth muscle cells of normotensive Wistar-Kyoto rats. 10(-7) M Losartan abolished the angiotensin II-induced formation of inositol 1,4,5-trisphosphate in vascular smooth muscle cells. 10(-6) M Losartan completely abolished the angiotensin II-induced elevation of the intracellular free Ca2+ concentration ([Ca2+]i). 10(-6) M Losartan lacked effects on the [Arg8]vasopressin-induced elevation of [Ca2+]i. In addition, 10(-6) M completely inhibited the angiotensin II-induced stimulation of Na+/H+ exchange in the vascular smooth muscle cells. 10(-10) to 10(-6) M Losartan inhibited the angiotensin II-induced cell protein synthesis in a concentration-dependent manner, yielding to an effective concentration (ED50) of 6.2 +/- 1.8 x 10(-8) M (n = 4). Losartan did not affect the platelet-derived growth factor-BB-induced increase in cell protein. These results show that Losartan is a highly specific angiotensin II receptor antagonist which inhibits angiotensin II-induced cell growth and thus may have beneficial effects on the development and regression of vascular hypertrophy.

Angiotensin II↗
PubMed1992

Inhibition of angiotensin II and platelet-derived growth factor-induced vascular smooth muscle cell proliferation by calcium entry blockers.

Structural changes within the blood vessel wall such as hyperplasia and hypertrophy of vascular smooth muscle cells are important factors in the pathogenesis of hypertension. Humoral growth factors such as angiotensin II (AII) and platelet-derived growth factor BB (PDGF-BB) may participate in the remodelling of the blood vessel wall. Whether and by which mechanisms antihypertensive treatment is capable of influencing the structural blood vessel alterations to date remains unclear. In the present study, the effect of nifedipine and diltiazem on AII- and PDGF-BB-induced vascular smooth muscle cell proliferation was examined. Nifedipine and diltiazem at a concentration of 10 microM did not affect baseline DNA synthesis in isolated vascular smooth muscle cells in culture. AII (final concentration 100 nM) and PDGF-BB (50 ng/ml) stimulated DNA synthesis by approximately 9.0- and 4.6-fold, respectively. Both AII- and PDGF-BB-induced DNA synthesis was significantly blunted by diltiazem and nifedipine in a concentration of 10 microM, while no significant influence was seen with concentrations from 10 nM up to 1 microM. In contrast, no significant influence of these drugs could be observed on fetal calf serum 5%-induced DNA synthesis. The findings indicate that calcium antagonists possess antimitogenic potential and that they may thus contribute to the regression of structural changes of the blood vessels associated with hypertension.

Angiotensin II↗
PubMed1992

Inhibition of cyclooxygenase attenuates baroreceptor function and increases the pressor response to norepinephrine in man.

The possible influence of prostaglandins on baroreceptor function in man has been investigated. Baroreceptor reflex was activated by intravenous infusion of norepinephrine and the pressor response was measured, both before and after administration of indomethacin. Resting blood pressure remained unchanged after indomethacin while resting heart rate was significantly decreased as compared to placebo and the norepinephrine-induced rise in mean arterial blood pressure was significantly more pronounced. The baroreceptor-mediated decrease in heart rate tended to be smaller. Baroreceptor sensitivity (delta heart rate/delta blood pressure) was significantly reduced by indomethacin to about half of the control value. In addition to attenuation of sensitivity, the findings represent resetting of the baroreceptor setpoint and a more pronounced pressor response to norepinephrine after cyclooxygenase inhibition. Thus, eicosanoids originating via the cyclooxygenase pathway of arachidonate metabolism may modulate the vascular response to adrenergic stimulation and may participate in the regulation of baroreceptor reflex setpoint and sensitivity.

Adult↗
PubMed1992

Calcium antagonistic effects of carbamazepine as a mechanism of action in neuropsychiatric disorders: studies in calcium dependent model epilepsies.

Carbamazepine (CBZ) is used in neurology for the treatment of epilepsies and trigeminal neuralgia and in psychiatry for the prophylactic treatment of affective and schizoaffective psychoses. Since a common mechanism of epilepsies and affective psychoses might be increased intracellular calcium ion levels, CBZ action was analyzed in penicillin, caffeine and low Mg2+ induced model epilepsies which have been shown to be suppressed specifically by organic calcium antagonists. In CA3 and CA1 areas of hippocampal slice preparations of guinea pigs CBZ reduced paroxysmal depolarizations and extracellular field potentials (EFP) in a typical time and concentration dependent manner as it is known from calcium antagonists. Furthermore, subthreshold concentrations of the organic calcium antagonist verapamil intensified the action of CBZ. NMDA induced increases of the discharge rate of EFP were, however, unaffected by CBZ.

Animals↗
PubMed1992

Platelet cAMP and cGMP in essential hypertension.

Vasodilator substances released in the blood vessel wall, such as the endothelium-derived relaxing factor (EDRF) and prostacyclin (PGI2), may participate in the regulation of arterial blood pressure. However, their role in the pathogenesis of human essential hypertension to date remains unclear. For some of these factors affecting vascular smooth muscle cells, blood platelets represent a second target tissue. Thus, EDRF and PGI2 inactivate platelets by stimulation of cyclic guanosine-5'-monophosphate (cGMP) and cyclic adenosine-5'-monophosphate (cAMP) synthesis, respectively. In the present study, platelet cAMP (n = 68) and cGMP (n = 60) were determined in a control group of healthy subjects (C) and in 12 patients with untreated essential hypertension (EH). In the control group, platelet cAMP and cGMP content averaged 13.52 +/- 0.38 and 1.48 +/- 0.06 pmol/10(9) platelets and no dependence of either variable on sex or age could be established. Furthermore, cGMP levels were similar in EH as compared to the control group (1.38 +/- 0.11 pmol/10(9) platelets). However, intracellular concentrations of cAMP were significantly lower in EH as compared to C (11.22 +/- 1.37 pmol/10(9) platelets; P < .01). In addition, we investigated the stimulatory effect on cAMP of the stable PGI2 analog iloprost (10(-9), 5 x 10(-9), 10(-8), 5 x 10(-8) mol/L) in the platelets of 12 control subjects (C12) and EH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

The effect of angiotensin II on DNA synthesis varies considerably in vascular smooth muscle cells from different Wistar-Kyoto rats.

OBJECTIVE: It is well established that angiotensin II induces vascular smooth muscle cell (VSMC) growth but conflicting data exist concerning whether angiotensin II induces cell hypertrophy and/or DNA synthesis from Wistar-Kyoto (WKY) rats. DESIGN: In this study we examined the effect of 10(-7) mol/l angiotensin II on cell protein and DNA synthesis in VSMC (passages 5-30) derived from eight different WKY rats. METHODS: The mitogenic and hypertrophic effect of angiotensin II was determined by 3H-thymidine incorporation into cell DNA and by total cellular protein measurements. RESULTS: In cells derived from two cell lines, angiotensin II induced a potent mitogenic effect. In cells derived from two other cell lines it induced a weak mitogenic effect. No significant effects on DNA synthesis were observed in cells derived from the four remaining cell lines. Cells from all cell lines reacted to angiotensin II with a 30-40% increase in cell protein. The observed mitogenic effect of angiotensin II was inhibited by losartan, a non-peptide angiotensin II receptor antagonist, proving that the angiotensin II-induced mitogenic effect is directly triggered via the angiotensin II subtype AT1 receptor. The hypertrophic effect of angiotensin II was also illustrated by morphological studies showing that angiotensin II increases the cell size in all cell lines used. CONCLUSIONS: Our study shows that angiotensin II not only is a hypertrophic agent, but may also be a potent mitogenic agent for VSMC from WKY rats.

Angiotensin II↗
PubMed1992

Platelet Na(+)-H+ exchanger activity in normotensive and hypertensive subjects: effect of enalapril therapy upon antiport activity.

OBJECTIVE: Primary hypertension has been reported to be associated with an enhancement of Na(+)-H+ exchange. However, details of the kinetic properties of the Na(+)-H+ exchanger in hypertensives and its dependence upon age and gender in normotensives are unknown. PARTICIPANTS: We determined the activity of the platelet Na(+)-H+ exchanger in 20 normotensives and 26 untreated primary hypertensives. INTERVENTIONS: In eight hypertensive individuals antihypertensive treatment was interrupted for 1 week. Treatment for 6 weeks with a daily single dose of 10 mg enalapril decreased mean arterial pressure to 105.7 +/- 11.6 mmHg. METHODS: Platelets were loaded with the intracellular pH (pHi) indicator 2'-7'-bis-carboxyethyl-5(6)-carboxyfluorescein (BCECF) and acidified by propionic acid. Initial velocities of pH recovery were determined and used for calculation of maximum velocity (Vmax), baseline pHi and the pHi value for half maximal activation (pH0.5) of the Na(+)-H+ exchanger in each individual. RESULTS: In normotensives, Vmax averaged 0.05 +/- 0.01 dpHi/min independently of age, gender and actual diastolic blood pressure. In hypertensives, two different subgroups were defined bearing either low or high Na(+)-H+ exchange activity. Values of pHi and pH0.5 were identical in all subgroups irrespective of Vmax. The twofold enhancement of Na(+)-H+ exchange in the second group was preserved in thrombin-stimulated platelets. Vmax values remained unaffected by enalapril treatment. CONCLUSIONS: Enhanced Na(+)-H+ exchange activity in hypertensives is primarily characterized by an increase in Vmax. This enhancement is refractory to antihypertensive treatment and therefore appears to be a relatively fixed parameter.

Age Factors↗
PubMed1992

ACE-inhibition, kinins, and vascular PGI2 synthesis.

In the present studies, ex vivo-, in vitro-, and in vivo-effects of three structurally different angiotensin I-converting enzyme (ACE) inhibitors on the kallikrein-kinin and eicosanoid systems are described. In the ex vivo- and in vitro-experiments using isolated rat aorta, vascular prostacyclin (PGI2) production is dose-dependently stimulated by the ACE inhibitors captopril, lisinopril, and ramipril. Furthermore, the ACE inhibitor-induced augmentation of vascular PGI2 synthesis observed in vitro was completely inhibited by the competitive bradykinin antagonist D-Arg[Hyp3,Thi5,8,D-Phe7]bradykinin suggesting that ACE inhibitors stimulate PGI2 generation by an enhancement of kinin activity. In the in vivo studies in healthy volunteers, we used platelet cyclic adenosine-5'-monophosphate (cAMP) and cyclic guanosine-5'-monophosphate (cGMP) as indirect parameters of the activity of prostacyclin and the endothelium-derived relaxing factor, respectively. Since platelet cAMP and cGMP were unaffected by an acute dose of 10 mg of lisinopril, our data do not support the concept that the interference of ACE inhibitors with the kallikrein-kinin-prostaglandin system observed ex vivo and in vitro participates in the haemodynamic effects of these agents in humans in vivo.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Investigation of the bioequivalence of two carbamazepine sustained-release formulations in healthy subjects.

A bioavailability study of two commercial carbamazepine sustained-release formulations was carried out in 14 healthy male subjects in order to compare plasma concentration/time profiles and to determine the relative bioavailability of carbamazepine (CBZ). This randomized study had a single-dose, crossover design and consisted of two trial periods separated by a three-week wash-out period. A sensitive, validated HPLC method was used to analyze plasma carbamazepine levels. Bioequivalence was only accepted for the test (Timonil 600 retard from Desitin Arzneimittel GmbH) and reference preparations (T and R) if the 90% confidence interval (parametric or non-parametric) for the ratios of the median values of the target variables was completely within the bioequivalence range. The following values were found for relative bioavailability: T/R: AUC = 109.6 (101.5-116.5)%, MRT = 96.4 (92.0-100.4)%, HVD = 92.4 (85.0-97.8)%. Applied to these pharmacokinetic data, the requirements for bioequivalence are met when the inclusion rule is used.

Adult↗
PubMed1992

Investigations into the relative bioavailability of carbamazepine after single oral administration of three test batches of a carbamazepine-containing sustained release formulation in healthy subjects.

A bioavailability study with three test batches of a sustained release formulation of carbamazepine, which differed only in their in vitro dissolution profiles, was performed in 18 healthy subjects to compare the respective plasma concentration profiles and to determine the relative bioavailability of carbamazepine (CBZ). This investigation was designed to examine the extent to which these differences in dissolution properties can be determined from the results of in vivo tests. The randomized, single-dose, crossover study comprised three experimental periods, separated by washout intervals of three weeks' duration. A sensitive, validated HPLC method was used for the analysis of serum carbamazepine concentrations. Bioequivalence was only accepted if the 90% confidence interval (parametric or nonparametric) for the quotients of the mean values of the variables for each test and reference preparation was completely within the bioequivalence range. For this calculation, all three test preparations were compared with one another. The following relative bioavailability values were obtained: A/B: AUC = 87% (83%, 92%), MRT = 106% (103%, 109%), HVD = 109% (105%, 113%). C/B: AUC = 106% (101%, 110%), MRT = 98% (96%, 99%), HVD = 87% (82%, 91%). C/A: AUC = 124% (117%, 130%), MRT = 92% (89%, 94%), HVD = 79% (74%, 84%). There was a positive correlation between the in vitro dissolution rates of the different test batches and the respective degree of carbamazepine absorption as determined in vivo, while an inverse correlation existed between the in vitro dissolution rates on one side and the mean residence time (MRT) as well as the half value duration (HVD) on the other.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Pharmaceutical and biopharmaceutical quality of a sustained release carbamazepine preparation: a contribution to quality assurance.

Side effects observed during treatment with non-sustained release carbamazepine preparations are often due to the steep rise in plasma carbamazepine concentrations. To maintain plasma levels with only minor fluctuations between narrow limits, sustained release formulations have been developed which release the active constituent at a constant rate which is not too high. Bioavailability tests (single dosage, crossover design) and several investigations into the dissolution profile were carried out on three test batches of a sustained release carbamazepine preparation (Timonil 300 retard). The aim was a release model which, in the context of quality assurance, would not only facilitate reliable statements with regard to batch conformity, but would also be validated in respect of pharmacokinetic parameters such as rate of absorption and bioavailability. Correlations between mean dissolution times (MDT) and mean absorption times (MAT) at level B were found [Skelly et al. 1990]. A dissolution test differing from the pharmacopoeial tests was selected, which permitted the assessment of both batch conformity and biopharmaceutical batch quality.

Absorption↗
PubMed1991

Pharmacokinetics and converting enzyme inhibition after morning and evening administration of oral enalapril to healthy subjects.

Possible circadian changes in the pharmacokinetics and effect on serum angiotensin-converting enzyme (ACE) activity of the ACE inhibitor enalapril have been studied in 8 healthy subjects after oral ingestion of 10 mg enalapril maleate either at 08.00 h or 20.00 h. The time to peak serum concentration (tmax) of enalapril was increased after administration at 20.00 h compared to 08.00 h (2.4 h versus 1.3 h), whereas other kinetic parameters were not significantly altered. The 24 h-kinetics of the active metabolite enalaprilat did not differ significantly between the two treatments, but the area under the curve (AUC (0-24] and the peak serum concentration (Cmax) were slightly higher after intake at 20.00 h. The relationship between the measured serum enalaprilat level and the degree of inhibition of serum ACE was the same after both treatments. Overall, the evening and morning administration of enalapril did not differ markedly in the pharmacokinetics and the time course of ACE inhibition.

Administration, Oral↗
PubMed1991

Membrane transport, sodium balance, and blood pressure regulation.

Essential hypertension is characterized by polygenic inheritance and quantitative and/or qualitative abnormalities of membrane transport systems may function as intermediate phaenotypes. The present review attempts to evaluate the importance of sodium transport systems such as the sodium pump, cotransport and countertransport as aetiological or pathogenetic factors involved in primary hypertension. Furthermore, the relative importance of NaCl balance as an exogenous factor modifying these transport systems is reviewed. Controversial results exist with respect to the activity of the sodium pump and cotransport both as a function of blood pressure and NaCl balance. In contrast, accumulating evidence suggests that the activity of the counter-transport system is increased in essential hypertension and that this may be observed even before the elevation of blood pressure can be documented. In own studies performed in normotensive volunteers on a low (20 mmol/day) and high (320 mmol/day) NaCl intake, lymphocyte antiport activity was significantly higher during chronic NaCl loading. Therefore, alterations of the Na+/H+ antiport system may represent an intermediate phaenotype of gene(s) involved in the genesis of primary hypertension. Preliminary evidence suggests that NaCl balance may be an exogenous modulator of this system.

Animals↗