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U Thome

Publications and source records attributed to U Thome.

17 recordsLinked to original sources
PubMed2001

Na,K-ATPase gene transfer mitigates an oxidant-induced decrease of active sodium transport in rat fetal ATII cells.

We investigated whether adenovirus-mediated transfer of genes encoding for subunits of the Na,K-ATPase increases transepithelial Na(+) transport in rat fetal distal lung epithelial (FDLE) monolayers and renders them more resistant to hydrogen peroxide injury. FDLE cells, isolated from rat fetuses at a gestational age of 19 to 20 d (22 d = term), were seeded on filters and infected with replication-incompetent human type 5 adenoviruses containing complementary DNAs encoding for rat Na,K-ATPase alpha(1) or beta(1) subunits (ad alpha(1) and ad beta(1), respectively). Once confluent monolayers were formed, the filters were mounted in Ussing chambers and short circuit currents (I(SC)) were measured. Increased levels of alpha(1) or beta(1) subunit proteins after infection with ad alpha(1) and ad beta(1), respectively, were confirmed by Western blot analysis. Baseline I(SC) increased after transfection with 2 plaque-forming units (pfu) of ad beta(1) from 5.1 +/- 0.3 to 6.1 +/- 0.3 microA/cm(2) (mean +/- SEM; P < 0.05). Permeabilization of the apical membrane with amphotericin B caused a large increase in I(SC); the ouabain-sensitive component of the amphotericin B-elicited I(SC) (ouab(max)) was increased from 4.0 +/- 0.2 (n = 69) in controls to 4.8 +/- 0.2 (n = 15), 5.9 +/- 0.3 (n = 53), 6.9 +/- 0.4 (n = 25), 7.7 +/- 0.9 (n = 16) in monolayers infected with 1, 2, 11, and 22 pfu of ad beta(1), respectively; transfection with ad alpha(1) had no effect on any measured variables. Further, transfection with ad beta(1) in comparison to noninfected monolayers resulted in higher baseline and ouab(max) I(SC) after injury with 500 microM H(2)O(2). We conclude that overexpression of the beta(1) subunit of the Na,K-ATPase may help maintain normal levels of vectorial Na(+) transport across ATII cell monolayers in pathologic conditions.

Amphotericin B↗
PubMed2001

Spontaneous breathing during partial liquid ventilation in animals with meconium aspiration.

Partial liquid ventilation (PLV) has been shown to improve gas exchange in paralyzed animals and humans with lung disease. The present study tests the hypothesis that PLV improves gas exchange in spontaneously breathing animals with meconium aspiration supported by proportional assist ventilation. Twenty-five adult anesthetized intubated rabbits with experimental meconium aspiration were randomized to gas ventilation (GV) or PLV while being supported by proportional assist ventilation. Minute ventilation, tidal volume, respiratory rate, mean airway pressure, heart rate, and mean arterial and pulmonary arterial pressure were recorded continuously. Every 30 min, arterial blood gases were obtained, and lung compliance, airway resistance, work of breathing, and cardiac output were measured. Animals were sacrificed after 5 h to obtain lung histology. More PLV animals survived until the end of the study period. PaO(2) (14.5 +/- 4.5 versus 25.6 +/- 6.7 kPa; p < 0.01; GV versus PLV) and lung compliance (4.3 +/- 0.4 versus 6.1 +/- 1.2 mL.kPa(-1).kg(-1); p < 0.001) were improved during PLV, resulting in a lower work of breathing (5.3 +/- 2.8 versus 3.5 +/- 1.5 mL.kPa.kg(-1); p < 0.05) and less need for ventilatory support. Minute ventilation and respiratory rate were higher during GV versus PLV, resulting in a slightly lower PaCO(2) (3.9 +/- 0.5 versus 4.5 +/- 0.7 kPa; p < 0.05). Histologic evaluation showed more atelectasis, inflammatory changes, and hemorrhage in GV animals. Other parameters measured were similar. We conclude that PLV improves oxygenation, lung compliance, and survival and results in less lung injury in spontaneously breathing animals with meconium aspiration when supported by proportional assist ventilation.

Animals↗
PubMed2000

Postnatal changes of extracellular volume, atrial natriuretic factor, and diuresis in a randomized controlled trial of high-frequency oscillatory ventilation versus intermittent positive-pressure ventilation in premature infants <30 weeks gestation.

OBJECTIVES: High-frequency oscillatory ventilation (HFOV) with a high lung volume strategy is an experimental mode of ventilating preterm infants aimed at achieving maximal alveolar recruitment Higher mean airway pressures are used during HFOV than during intermittent positive-pressure ventilation (IPPV), and the intrathoracic volume increase is relatively constant. Both factors increase the risk to depress organ blood flow and diuresis. Our objective was to test the hypothesis that high lung volume HFOV attenuates the postnatal reduction of extracellular volume in preterm infants by reducing plasma atrial natriuretic factor and diuresis. DESIGN: Prospective, randomized, controlled clinical trial. SETTING: University hospital, Level III neonatal intensive care unit. PATIENTS: Premature infants <30 wks gestation requiring intubation for respiratory distress syndrome within the first 6 hrs of life; 15 infants (gestational age, 26 [24-29] wks, birth weight 814 [452-1340] g) were randomized to HFOV, 19 infants (gestational age 27 [24-39] wks, birth weight 930 [644-1490] g) to IPPV. INTERVENTIONS: The randomized mode of ventilation was assigned within 1 hr after intubation. During HFOV mean airway pressure was increased as long as oxygenation improved and no lung overinflation was seen on chest radiograph. IPPV rates were > or =60/min. MEASUREMENTS AND MAIN RESULTS: We measured extracellular volume (sucrose dilution) and atrial natriuretic factor on Day 1 and Day 3. Mean airway pressure, body weight, diuresis, and fluid intake were measured daily. During HFOV mean airway pressure was higher at 12 hrs (median 7 cm H2O vs. 4 cm H2O; p = .001) and 24 hrs (median 6 cm H2O vs. 3 cm H2O; p = .01). In both groups, extracellular volume decreased between Day 1 and Day 3 (HFOV from 428 +/- 126 mL to 344 +/- 145 mL [p = .003], IPPV from 466 +/- 108 mL to 414 +/- 124 mL [p = .01]) and diuresis increased (HFOV, from 2.5 +/- 1.7 to 4.6 +/- 0.9 mL/kg/hr [p = .001]; IPPV, from 2.8 +/- 1.6 to 4.2 +/- 1.0 mL/kg/hr [p = .01]). Plasma atrial natriuretic factor was not decreased in the HFOV group. CONCLUSIONS: High lung volume HFOV as primary mode of ventilation in preterm infants <30 wks gestation did not result in unwanted fluid retention and a decrease in diuresis in the first days of life.

Atrial Natriuretic Factor↗
PubMed2000

Syntaxin 1A is expressed in airway epithelial cells, where it modulates CFTR Cl(-) currents.

The CFTR Cl(-) channel controls salt and water transport across epithelial tissues. Previously, we showed that CFTR-mediated Cl(-) currents in the Xenopus oocyte expression system are inhibited by syntaxin 1A, a component of the membrane trafficking machinery. This negative modulation of CFTR function can be reversed by soluble syntaxin 1A peptides and by the syntaxin 1A binding protein, Munc-18. In the present study, we determined whether syntaxin 1A is expressed in native epithelial tissues that normally express CFTR and whether it modulates CFTR currents in these tissues. Using immunoblotting and immunofluorescence, we observed syntaxin 1A in native gut and airway epithelial tissues and showed that epithelial cells from these tissues express syntaxin 1A at >10-fold molar excess over CFTR. Syntaxin 1A is seen near the apical cell surfaces of human bronchial airway epithelium. Reagents that disrupt the CFTR-syntaxin 1A interaction, including soluble syntaxin 1A cytosolic domain and recombinant Munc-18, augmented cAMP-dependent CFTR Cl(-) currents by more than 2- to 4-fold in mouse tracheal epithelial cells and cells derived from human nasal polyps, but these reagents did not affect CaMK II-activated Cl(-) currents in these cells.

Animals↗
PubMed2000

Dynamics of breathing during partial liquid ventilation in spontaneously breathing rabbits supported by elastic and resistive unloading.

Partial liquid ventilation (PLV) has been shown to improve gas exchange in paralyzed animals and in humans with lung disease. This study tests the hypothesis that PLV combined with respiratory mechanical unloading results in stable ventilation and gas exchange in spontaneously breathing animals. Ten adult anesthetized, intubated, and spontaneously breathing rabbits received ventilatory support by respiratory mechanical unloading (Fi(O2) 1.0). Minute ventilation, respiratory rate, esophageal pressure, heart rate, and arterial blood pressure were recorded continuously during gas ventilation for 1 h. Next, 30 mL/kg of perfluorocarbon was instilled into the endotracheal tube. Thereafter, data were recorded again for 1 h (PLV). Arterial blood gases were obtained at the end of each period. Variability of recorded data was assessed by calculating coefficients of variation using data obtained each minute. Compared with gas ventilation, minute ventilation was larger during PLV (275 +/- 93 versus 368 +/- 89 mL/kg/min.; p < 0.01). This was because of a higher respiratory rate during PLV (58 +/- 23 versus 74 +/- 18 breaths/min; p < 0.05), while tidal volume was similar. Compared with gas ventilation, Pa(O2) was lower during PLV (61.31 +/- 5.32 versus 47.35 +/- 8.38 kPa; p < 0.05). Pa(CO2), peak esophageal pressure deflections, heart rate, mean arterial blood pressure, and coefficients of variation for minute ventilation, tidal volume, respiratory rate, and peak esophageal pressure were not significantly different between modes. Compliance was decreased and resistance and work of breathing were increased during PLV. We conclude that stable ventilation and gas exchange may be achieved during PLV combined with mechanical unloading in spontaneously breathing animals without lung disease.

Animals↗
PubMed1999

Randomized comparison of high-frequency ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure.

OBJECTIVE: In a randomized, controlled, multicenter trial, we tested the hypothesis that high-frequency ventilation (HFV) with a high lung volume strategy results in fewer treatment failures than intermittent positive pressure ventilation (IPPV) with high rates and low peak inspiratory pressures. STUDY DESIGN: Infants with a gestational age between >/=24 weeks and <30 weeks, requiring mechanical ventilation within 6 hours of birth, were randomly assigned to receive either IPPV or HFV until 240 hours after randomization, extubation, or meeting treatment failure criteria. Treatment failure, the primary end point, was determined when air leaks, an oxygenation index >35 to 45 (depending on gestational age), death, or chronic lung disease occurred. Chronic lung disease was defined as persistent requirement of mechanical ventilation, continuous positive airway pressure, or supplemental oxygen at a postmenstrual age of 36 weeks. Secondary end points included the incidence of intracranial hemorrhage. RESULTS: The third scheduled interim analysis led to termination of the trial after recruitment of 284 infants. Treatment failure criteria were met by 46% of infants receiving IPPV and 54% of infants receiving HFV (1-tailed primary hypothesis, P =.92; 2-tailed chi2 test, P =.15). Air leaks occurred in 31% and 42% (P =.042), CLD in 23% and 25%, and grade 3-4 intracranial hemorrhage in 13% and 14% of IPPV-treated and HFV-treated patients, respectively. The mortality rate before discharge was 10% in both groups. CONCLUSION: HFV with a high lung volume strategy did not cause less lung injury in preterm infants than IPPV with a high rate and low peak inspiratory pressures.

Bronchopulmonary Dysplasia↗
PubMed1998

Comparison of lung volume measurements by antero-posterior chest X-ray and the SF6 washout technique in mechanically ventilated infants.

While anterior/posterior chest x-rays (CXR) are routinely performed to estimate lung volume (LV) and adjust ventilator settings, the precise measurement of LV requires additional sophistication. In 31 infants ventilated because of surfactant deficiency (n=23), bronchopulmonary dysplasia (n=7), or pulmonary hypoplasia (n=1) with either intermittent positive pressure (n=18) or high frequency oscillation (n=13) (gestational age 23-39 weeks (median 26 weeks); birthweight 550-2780 g (median 840 g); age at measurement 1-91 days (median 6 days); weight at study time (WST) 675-3000 g (median 938 g)), we investigated whether LV, as measured by the sulfur hexafluoride (SF6) washout technique, could by estimated from CXR by: 1) the sum (A+B) of the right (A) and left (B) lung fields areas; 2) the product (LxW) of the distances from the right apex to the right costophrenic angle (L) and between both costophrenic angles (W); 3) the diaphragm position relative to the posterior parts of the ribs (DP); and 4) the lung radiolucency (RL, grades 0-4). Correlations between A+B (r=0.44) or LxW (r=0.37) and LV were poor, but improved when A+B, LxW, and LV were normalized to WST: (A+B)/WST vs. LV/WST (r=0.74), and LxW/WST vs. LV/WST (r=0.67). DP (r=0.13) and RL (Spearman's rho=0.17) did not correlate with LV/WST. A multiple linear regression analysis led to the following best-fit equation: LV/WST=2.58 (A+B)/WST - 5.47 DP + 42.2 (r=0.83). We concluded that an estimate of LV from CXR lacked sufficient accuracy. DP and RL did not correlate with LV measured by SF6 washout.

Bronchopulmonary Dysplasia↗
PubMed1998

The effect of positive endexpiratory pressure, peak inspiratory pressure, and inspiratory time on functional residual capacity in mechanically ventilated preterm infants.

UNLABELLED: In mechanical ventilation of preterm infants, positive endexpiratory pressure (PEEP) is widely used to prevent alveolar collapse, maintain functional residual capacity (FRC) and improve oxygenation. Prolongation of inspiratory time (ti) and increase of peak inspiratory pressure (PIP) are also used for this purpose. We investigated the effect of variations of PEEP, PIP and ti on FRC in ten infants with hyaline membrane disease and onset of bronchopulmonary dysplasia (BPD, n = 7), pulmonary hypertension (n = 1), pulmonary hypoplasia (n = 1) or severe BPD (n = 1) (gestational age 24-39 weeks, median 26 weeks; birth weight 590-2960 g, 785 g; chronological age 7 84 days, 19 days; weight 689-4650 g, 1185 g). FRC, measured using the sulphur hexafluoride washout technique, was between 6.2 and 48.3 ml/kg (median 21.5 ml/kg). PEEP was changed stepwise 2-5 times in each patient (median 3) and mean airway pressure (MAP) was modified independently of PEEP by changing PIP 0 2 times (median 1) and ti 0(2 times (median 2). Changes of FRC correlated well with modifications of PEEP in each patient (r = 0.90, range 0.71 0.99). The slope factors of linear correlations had a median value of 2.94 ml/cm H20 per kg, which was significantly different from zero (P < 0.01) and significantly higher than the slope factors of linear correlations between FRC and MAP after modifications of PIP or ti (P < 0.01). The latter two were statistically not different from zero. The quotients deltaFRC/deltaMAP were significantly higher after adjustments of PEEP than after adjustments of PIP or ti (P < 0.01). The time lag between the change of PEEP and the stabilization of FRC on a new level ranged from 2 to 14 min (median 5). CONCLUSION: FRC is mainly determined by PEEP but not by PIP or ti. Stabilization of FRC after a change of PEEP can last up to 14 min. Its duration is unpredictable and has to be waited for when testing pulmonary function in ventilated preterm infants.

Functional Residual Capacity↗
PubMed1998

Effect of the TI/TE ratio on mean intratracheal pressure in high-frequency oscillatory ventilation.

In high-frequency oscillatory ventilation (HFOV), an adequate mean airway pressure is crucial for successful ventilation and optimal gas exchange, but air trapping cannot be detected by the usual measurement at the y piece. Intratracheal pressures produced by the high-frequency oscillators HFV-Infantstar (IS), Babylog 8000 (BL), and the SensorMedics 3100A (SM) [the latter with either 30% (SM30) or 50% (SM50) inspiratory time] were investigated in four anesthetized tracheotomized female piglets that were 1 day old and weighed 1.6-1.9 kg (mean 1.76 kg). The endotracheal tube was repeatedly clamped while the piglets were ventilated with an oscillation frequency of 10 Hz, and the airway pressure distal of the clamp was recorded as a measure of average intrapulmonary pressure during oscillation. Clamping resulted in a significant decrease of mean airway pressure when the piglets were ventilated with SM30 (-0.86 cmH2O), BL (-0.66 cmH2O), and IS (-0.71 cmH2O), but airway pressure increased by a mean of 0.76 cmH2O with SM50. Intratracheal pressure, when measured by a catheter pressure transducer at various oscillation frequencies, was lower than at the y piece by 0.4-0.9 cmH2O (SM30), 0.3-3 cmH2O (BL), and 1-4.7 cmH2O (IS) but was 0.4-0.7 cmH2O higher with SM50. We conclude that the inspiratory-to-expiratory time (TI/TE) ratio influences the intratracheal and intrapulmonary pressures in HFOV and may sustain a mean pressure gradient between the y piece and the trachea. A TI/TE ratio < 1:1 may be useful to avoid air trapping when HFOV is used.

Animals↗
PubMed1998

Effects of mean airway pressure on lung volume during high-frequency oscillatory ventilation of preterm infants.

Measurement of mean lung volume (MLV) in high-frequency oscillatory ventilation (HFO) may be useful for optimizing the high lung volume strategy, but has not been available until now. We have measured MLV by means of the sulfur hexafluoride (SF6) washout method in 13 premature infants ventilated with HFO because of respiratory distress syndrome (gestational age, 23 to 31 wk [median, 25 + 6/7 wk]; birthweight, 630 to 1,140 g [790 g]; age at measurement, 2 to 10 d [4 d]; weight, 675 to 1,250 g [850 g]). To evaluate the relationship between MLV and mean airway pressure (MAP), the latter was systematically varied between the measurements. With clinically selected MAP, MLV was between 23.3 and 41.9 ml/kg (median, 33.5 ml/kg) and was strongly dependent on MAP in each patient; linear regression analyses resulted in slope factors between 1.0 and 6.9 ml/cm H2O/kg (median, 2.83 ml/cm H2O/kg), with correlation coefficients between 0.77 and 0.99 (median, 0.94). Stabilization of MLV after modification of MAP took 2 to 25 min (median, 9 min). We conclude that the selection of MAP on a clinical basis leads to a wide range of different MLVs. Despite the strong dependence of MLV on MAP, the prediction of MLV solely based on MAP was impossible because of large patient to patient variability of linear regressions. Alveolar recruitment and derecruitment may take up to 25 min after MAP changes.

Airway Resistance↗
PubMed1998

Comparison of pulmonary inflammatory mediators in preterm infants treated with intermittent positive pressure ventilation or high frequency oscillatory ventilation.

Ventilated preterm infants prone to the development of bronchopulmonary dysplasia have been shown to have increased inflammatory mediators in their tracheal aspirates. High frequency oscillatory ventilation (HFOV) is thought to be less traumatic than intermittent positive pressure ventilation (IPPV) in premature infants with surfactant deficiency, and therefore may reduce the inflammatory response in tracheobronchial aspirates. We randomized 76 premature infants requiring mechanical ventilation (birth weight 420-1830 g, median 840 g, gestational age 23 3/7 to 29 2/7 wk, median 26 4/7 to receive either an IPPV with a high rate (60-80/min) and low peak pressures, or an HFOV aiming at an optimization of lung volume, within 1 h of intubation. Tracheal aspirates were systematically collected during the first 10 d of life and analyzed for albumin, IL-8, leukotriene B4 (LTB4), and the secretory component (SC) for IgA as a reference protein. Bacterially colonized samples were excluded. On the treatment d 1, 3, 5, 7, and 10, the resulting median values of albumin (milligrams/mg of SC) were 28, 23, 24, 18, and 10, in IPPV-ventilated infants, and 33, 28, 18, 25, and 39 in HFOV-ventilated infants, respectively. Median IL-8 values (nanograms/mg of SC) were 671, 736, 705, 1362, and 1879 (IPPV) and 874, 1713, 1029, 1426, and 1823 (HFOV), respectively, and median LTB4 values (nanograms/mg of SC) were 26, 13, 27, 22, and 11 (IPPV) and 15, 12, 7, 12, and 16 (HFOV), respectively. Values were similar in IPPV- and HFOV-ventilated infants, and no significant differences were noted. We conclude that HFOV, when compared with a high rate low pressure IPPV, does not reduce concentrations of albumin, IL-8, and LTB4 in tracheal aspirates of preterm infants requiring mechanical ventilation.

Albumins↗
PubMed1997

Modulation of pacemaker activity in sheep cardiac Purkinje fibers by stimulation of beta-adrenoceptor subtypes.

The electrophysiological effects mediated by beta 1- and beta 2-adrenoceptors in spontaneously active sheep cardiac Purkinje fibers were investigated using the non-selective agonist (-)-isoproterenol (IPN) and the selective agonists (-)-noradrenaline (beta 1) and procaterol (beta 2) in the absence and presence of the selective antagonists bisoprolol (beta 1) and ICI 118,551 (beta 2). IPN (0.01 mumol/l) increased the spontaneous rate by 54% and the slope of diastolic depolarization by 68% of the respective control values. Further, IPN increased the action potential duration at -20 mV (APD -20 mV) from 96 to 154 ms, reduced the APD-70 mV by 17% and the duration of the diastole by 39% and slightly hyperpolarized the maximum diastolic potential. These effects were partially inhibited by ICI 118,551 (0.03 mumol/l), diminished by bisoprolol (0.1 mumol/l) and almost completely blocked by the combination of both antagonists. Concentration response curves of IPN were influenced by the selective antagonists as follows: ICI 118,551 (0.03 mumol/l) shifted the curves to the right by 0.2-0.4 log units and increased the slope factor. Bisoprolol (0.1 mumol/l) induced a greater shift to the right by 1.1-1.5 log units. Combination of bisoprolol with ICI 118,551 shifted the curves to the right by 1.5-1.7 log units. Noradrenaline (0.3 mumol/l) elicited similar actions as IPN. Bisoprolol (0.1 mumol/l) shifted the concentration response curves of noradrenaline to the right by 1.1-1.9 log units. Actions of procaterol (0.1 mumol/l) were weak, attained only 15-35% of the maximal effects of IPN and could be blocked by ICI 118,551 (0.03 mumol/l). These results show that the increase of pacemaker activity induced by catecholamines in sheep cardiac Purkinje fibers is predominantly mediated by stimulation of beta 1-receptors. However, contribution of beta 2-receptor mediated effects could be demonstrated.

Adrenergic alpha-Agonists↗
PubMed1997

Tissue toxicity of doxorubicin in first and second hyperthermic isolated limb perfusion--an experimental study in dogs.

The aim of this experimental study in dogs was to assess the tissue toxicity of doxorubicin (DOX) and the impact of dose and pharmacokinetics after double isolated limb perfusion (ILP). Fifteen beagle dogs were assigned to three groups of five animals each. In the first ILP 0.75 mg/kg bodyweight (bw) DOX was given to all animals. In the second perfusion after an interval of 6 to 8 weeks the dosage was 0.5 mg/kg bw in group I, 0.75 mg/kg bw in group II, and 1.0 mg/kg bw in group III. At the same dosage tissue toxicity increased in comparison to the first ILP. At the second ILP there was a dose-toxicity relationship. At a dose of 0.75 mg/kg bw pharmacokinetics of DOX in the perfusate showed no significant differences between first and second perfusion. The mean muscle tissue levels during the second ILP were lower than during the first perfusion. However, in contrast to the first perfusion, they showed a further increase after perfusate eluation. A disturbed microcirculation caused by intima proliferations in arteries and arterioles fter the first ILP may impair the removal of DOX from the intravasal and interstitial compartment and can be assumed as a reason for increased tissue toxicity. Therefore, we recommend a reduction of DOX dose in the second ILP for clinical use.

Animals↗
PubMed1995

Pharmacokinetics of two different delivery regimens of doxorubicin in isolated hyperthermic limb perfusion.

Evaluation of doxorubicin (DOX) pharmacokinetics in hyperthermic isolated limb perfusion (HILP) is limited. In this study two administration regimens of DOX were compared in terms of area under the time concentration curve (AUC) in plasma. HILP was performed in 13 dogs. In group 1 (n = 7) four single doses of DOX were injected in intervals of 15 minutes, in group 2 (n = 6) DOX was administered continuously during the first 30 min. The total dose in both groups was 1 mg/kg body weight, and the perfusion lasted 60 min. Concentrations of DOX and its major metabolite doxorubicinol (DOXol) were measured in perfusate and muscle tissue by high performance liquid chromatography (HPLC). Pharmacokinetic estimates were calculated. The two investigated administration modes provided sufficient drug levels of DOX during the whole perfusion time. Maximum concentrations in the perfusate and areas under the time concentration curves were nearly the same. The tissue concentrations also did not show significant differences. Both regimens are practicable avoiding high peak levels of the drug in order to minimize toxic side effects.

Animals↗
PubMed1992

Electrophysiological characterization of histamine receptor subtypes in sheep cardiac Purkinje fibers.

The histamine-receptor-subtype-mediated effects on action potentials of electrically driven and spontaneously active isolated sheep cardiac Purkinje fibers were investigated using H1- and H2-selective agonists and antagonists. In electrically stimulated Purkinje fibers, histamine (3 mumol/l) increased the action potential plateau height, decreased the action potential duration measured at a repolarization level of -60 mV and enhanced the pacemaker activity. These effects were abolished by the H2-selective antagonist cimetidine (30 mumol/l), but were not impaired by the H1-selective antagonist dimetindene (0.3 mumol/l). In spontaneously active Purkinje fibers, histamine (10 mumol/l) increased the spontaneous rate by 24%, the slope of diastolic depolarization by 45% and shortened the duration of the diastole by 32% of the respective control measurements. These effects were blocked by 30 mumol/l cimetidine, but remained unchanged in the presence of 0.3 mumol/l dimetindene. Concentration-response curves of histamine were shifted to the right by approximately 2 logarithmic units in the presence of 30 mumol/l cimetidine, but were not influenced in the presence of 0.3 mumol/l dimetindene. The H2-selective agonist impromidine (0.001-0.3 mumol/l) had similar actions as histamine on spontaneously active Purkinje fibers, while the H1-selective agonist 2-(2-pyridyl-)ethylamine was ineffective. It is concluded that the pronounced stimulatory action of histamine on spontaneous activity in sheep cardiac Purkinje fibers is exclusively mediated by H2 receptors.

Action Potentials↗