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M Zabel

Publications and source records attributed to M Zabel.

At least 109 records · Page 6Linked to original sources
PubMed1996

Synthesis and X-ray crystal structure of trans,cis-[Pt(OAc)2I2(en)]: a novel type of cisplatin analog that can be photolyzed by visible light to DNA-binding and cytotoxic species in vitro.

An original approach intended to facilitate the intratumoral activation of Pt(IV) diamines by illumination with visible light to form photolysis products that irreversibly bind to DNA and are cytotoxic to human cancer cells is reported. The novel Pt(IV) complex trans,cis-[Pt(OAc)2I2-(en)] was prepared by the acetylation of trans,cis-[Pt(OH)2I2(en)] with acetic anhydride in CH2-Cl2; trans,cis-[Pt(OH)2I2(en)] was synthesized by oxidation of [PtI2(en)] with 30% aqueous H2O2. trans,cis-[Pt(OAc)2I2(en)] crystallized from methanol as deep-red needles with a = 9.029(4) A, b = 11.443(2) A, c = 12.822(2) A, beta = 95.48(3) degrees, monoclinic space group Cc, and Z = 4. The conformation of the acetato groups around the O-Pt-O axis deviated significantly from the conformation of the acetato groups in the X-ray crystal structure reported for the cis-dichloro analog, which may explain the very different aqueous solubilities of the two compounds. trans,-cis-[Pt(OAc)2I2(en)] and trans,cis-[Pt(OH)2I2(en)] displayed broad ligand-to-metal charge-transfer bands centered at lambda = 389 and 384 nm, respectively (epsilon = 1372 and 1425 M-1 cm-1, respectively), with tailing out to ca. 550 nm. When trans,cis-[Pt(OAc)2I2(en)] was incubated with calf thymus DNA in the absence of light, no covalent binding of Pt to DNA was measurable after 6 h; however, irradiation with light of wavelengths > 375 nm resulted in 63 +/- 13% of the platinum being covalently bound to DNA after 6 h, suggesting that a photoreduction to Pt(II) species took place. Although trans,cis-[Pt(OH)2I2(en)] was also labile to visible light, only 10 +/- 2% DNA platination was observed after 6 h of illumination; however, covalent binding of Pt to DNA took place quantitatively when a reducing agent such as glutathione was added to the photolyzed incubations. These results provide evidence that the photolysis of the trans-dihydroxo analog resulted predominately in the substitution of the iodide ligands for water rather than a reduction of Pt(IV) to Pt(II). When protected from light, trans,cis-[Pt(OAc)2I2-(en)] and trans,cis-[Pt(OH)2I2(en)], both at a concentration of 10 microM, had half-lives of 6.6 +/- 0.5 and 46.8 +/- 8.8 h, respectively, at 37 degrees C in Eagle's minimum essential medium (EMEM) containing 5% fetal calf serum. When irradiated with light lambda(irr) > 375 nm, the half-lives were decreased by 24- and 53-fold for the diacetato- and dihydroxoplatinum(IV) complexes, respectively. Compared to the "dark" control, the in vitro treatment of TCCSUP human bladder cancer cells with trans,cis-[Pt(OAc)2I2(en)] resulted in 35% greater growth inhibitory activity when during the first 1.5 h of drug exposure the cells were irradiated with light lambda irr > 375 nm. The photolysis of trans,cis-[Pt(OH)2I2(en)] with visible light resulted in a 22% enhancement of antiproliferative activity.

Antineoplastic Agents↗
PubMed1996

Effect of sustained load on dispersion of ventricular repolarization and conduction time in the isolated intact rabbit heart.

INTRODUCTION: It is well known that myocardial stretch can elicit ventricular arrhythmias in experimental models. However, previous reports have predominantly documented stretch-induced arrhythmias during short, pulsatile stretch. The arrhythmogenic mechanism of sustained static stretch is incompletely understood. METHODS AND RESULTS: To examine the influence of sustained load on several electrophysiologic parameters, a latex balloon was placed into the left ventricle of ten isolated Langendorff-perfused rabbit hearts and filled with a neutral volume of fluid. The heart was paced from a catheter inside the right ventricle (apicoseptal endocardial position), and the following parameters were studied during steady-state pacing with a cycle length of 500 msec (S1) and during extrastimulation (S2, base drive of 8 beats): monophasic action potential (MAP) durations at 90% repolarization (APD90) from 5 to 6 epicardial electrodes located on both ventricles and one right ventricular endocardial contact electrode; dispersion of APD90 (range of MAP durations from all electrodes); effective refractory period (ERP) and longest activation time (pacing stimulus to MAP upstroke). After baseline recordings, the balloon inside the left ventricle was filled with a volume of 1.0 mL of fluid by means of a servo-controlled pump. The ERP was significantly shortened from 198 +/- 9 msec at baseline to 183 +/- 8 msec during sustained load (P < 0.03). Similarly, the average APD90 was shortened from 180 +/- 5 msec at baseline to 175 +/- 6 msec during sustained load (P < 0.006) with steady-state pacing and from 178 +/- 6 msec to 170 +/- 8 msec during premature extrastimulation (P < 0.03). At the same time, dispersion of APD90 was increased from 27 +/- 5 msec to 38 +/- 6 msec (P < 0.002) during steady-state pacing and from 28 +/- 4 msec to 38 +/- 6 msec (P = 0.013) during premature extrastimulation. The longest activation time among all MAP recordings was increased from 39 +/- 2 msec to 43 +/- 3 msec (P = 0.003) during steady-state pacing and from 56 +/- 6 msec to 69 +/- 6 msec during premature extrastimulation (P < 0.003). CONCLUSIONS: Sustained load shortens the ERP and the mean APD90, and at the same time increases dispersion of APD90 and prolongs activation times. These findings provide additional insight into the arrhythmogenic mechanisms of sustained mechanical load.

Action Potentials↗
PubMed1996

Myocardial vulnerability to T wave shocks: relation to shock strength, shock coupling interval, and dispersion of ventricular repolarization.

INTRODUCTION: Induction of ventricular fibrillation (VF) by T wave shocks is of clinical interest due to the correlation between the upper limit of vulnerability (ULV) and the defibrillation threshold (DFT). However, the ULV has not yet been defined precisely in reference to the entire "area of vulnerability" (AOV), which is defined bifunctionally by both shock strengths and shock coupling intervals, nor has it been related to the dispersion of ventricular repolarization, considered to be an important determinant of vulnerability. METHODS AND RESULTS: In 11 isolated perfused rabbit hearts immersed in a tissue bath containing a 3-lead ECG recording system and two opposite plate electrodes for field shock administration, 7 monophasic action potentials (MAPs) were recorded simultaneously from different epicardial and endocardial regions of the right and left ventricles. An average of 90 +/- 25 monophasic waveform shocks of varying shock strengths and coupling intervals were delivered to each heart to determine the horizontal and vertical boundaries of the AOV. The AOV approximated a rhomboid with homogenous VF inducibility. The ULV and lower limit of vulnerability (LLV) represented discrete corners of the AOV with significant changes in VF inducibility if either shock coupling intervals or shock strength were changed by only 10 msec or 10 V, respectively (P < 0.001). The ULV occurred at 7 +/- 10 msec shorter coupling intervals than the LLV (P < 0.05), and VF-inducing shock strengths at the left corner of the AOV were 50 +/- 67 V higher as compared to the right corner (P < 0.01). The maximal range of VF-inducing coupling intervals coincided (within < 2 msec) with the dispersion of MAPs at 70% repolarization, and the ULV coupling interval coincided (within < 4 msec) with the longest repolarization at 50%. CONCLUSIONS: (1) VF vulnerability to monophasic T wave shocks is defined by an AOV that has the shape of a leftward tilted rhomboid. (2) Both the ULV and LLV are sharply defined upper and lower corners of the AOV rhomboid. (3) The width of the AOV corresponds to the dispersion of ventricular repolarization at the 70% level. (4) Considering the dispersion of ventricular repolarization may yield more precise ULV determinations and a better understanding of the correlation between the ULV and DFT.

Action Potentials↗
PubMed1996

The vulnerable period for low and high energy T-wave shocks: role of dispersion of repolarisation and effect of d-sotalol.

INTRODUCTION: The induction of ventricular fibrillation (VF) by T-wave shocks has been related to dispersion of repolarisation, but only indirect evidence of this hypothesis exists. The effects of drugs prolonging repolarisation like d-sotalol on the vulnerability to T-wave shocks remain unknown. METHODS: In 9 isolated rabbit heart, 7 monophasic action potentials (MAPs) and an ECG were recorded simultaneously. Vulnerable periods were determined using two different shock strengths, one close to the fibrillation threshold and the other close to the upper limit of vulnerability, at baseline and after action potential prolongation by d-sotalol. RESULTS: The vulnerable period had a duration of 30 +/- 14 ms for the lower and 34 +/- 12 ms for the higher shock strength (P = NS). Coupling intervals of the vulnerable periods were 13 +/- 10 ms shorter for higher shock strengths as compared to lower shock strengths (P < 0.005). The vulnerable period for low shock strengths coincided with dispersion of MAPs at 90% repolarisation (r = 0.87-0.92, P < 0.005), and the vulnerable period for high shock strengths coincided with dispersion at 70% repolarisation (r = 0.82-0.93, P < 0.005). ECG parameters predicted the vulnerable periods less precisely than MAP repolarisation (r < or = 0.72). d-Sotalol prolonged MAP durations by an average of 33 ms at 70% and 39 ms at 90% repolarisation but did not alter the described relations, nor did it reduce dispersion of repolarisation or duration of the vulnerable periods. CONCLUSIONS: Dispersion of repolarisation determines vulnerable periods and might be part of the arrhythmogenic substrate promoting induction of VF by T-wave shocks. The coupling intervals of the vulnerable periods depend on the applied shock strength as well as repolarisation, with shock strengths close to the fibrillation threshold inducing VF during dispersion at 90% repolarisation and shock strengths close to the upper limit of vulnerability inducing VF during dispersion at 70% repolarisation. d-Sotalol reduces neither vulnerability to T-wave shocks nor dispersion of repolarisation in this isolated heart model.

Action Potentials↗
PubMed1996

Stretch-induced voltage changes in the isolated beating heart: importance of the timing of stretch and implications for stretch-activated ion channels.

OBJECTIVES: It is now well recognized that myocardial stretch can cause arrhythmias due to stretch-induced depolarizations. The effects of transient stretch applied during the various phases of the cardiac action potential have not been investigated. This study (1) examined the effects of short stretch pulses and sustained stretch on the monophasic action potential (MPA) repolarization time course and diastolic potential, (2) examined the arrhythmic response to differently timed stretch pulses, and (3) tested by comparison with computer simulations whether these effects are compatible with stretch-activated channel characteristics known from patch-clamp studies. METHODS: We studied the MAP changes elicited by short transient stretch pulses applied at different times during the cardiac cycle to 8 isolated Langendorff-perfused rabbit hearts. The left ventricle (LV) was instrumented with a fluid-filled balloon, the volume of which was altered rapidly and precisely by means of a computer-controlled linear motor-driven piston. MAPs were recorded simultaneously from one right ventricular (RV) and two LV sites while short volume pulses of increasing amplitude were applied to the LV at variable delays after the last of 8 regular electrical pacing stimuli. The effect of pulsatile volume pulses applied at different phases of electrical systole and diastole was compared to the effect of sustained stretch pulses (60 s duration) of the same amplitude. The experimental results were compared with computer simulations of stretch-induced effects on the action potential to further validate the experimentally measured effects with theoretical predictions based on the Oxford Heart model with added stretch channel terms. RESULTS: Stretch pulses applied during early systole caused a brief transient repolarization during the LV MAP plateau phase, with a maximal amplitude of 24 +/- 10% of the total MAP amplitude. Stretch pulses at the end of the MAP caused a transient depolarization, with a maximal amplitude of 13 +/- 5%. These oppositely polarized stretch effects crossed over during a transitional range of repolarization (mean 65 +/- 9% of repolarization) when stretch produced neither transient repolarizations nor depolarizations. Only stretch pulses applied at a mean repolarization level of 77 +/- 5% or later led to arrhythmias, preceded by transient depolarizations. No corresponding de- or repolarizations were seen in MAPs recorded simultaneously from the unstretched RV. The effects of long pulses on the MAP waveform were nearly identical to an overlay plot of the effects of many differently timed short transient pulses. When the stretch-induced voltage changes in the MAP were plotted against the repolarization level at which they were produced, a linear relationship was found (mean correlation coefficient r = 0.97; P < 0.0001) with a reversal at approximately half the total MAP amplitude. The computer simulations of the influence of stretch-activated channels reproduced both the effects of short and sustained stretch seen in the MAP recordings. CONCLUSIONS: We demonstrated in the isolated beating heart that the electrophysiologic effects of sudden myocardial stretch depend on the timing of the stretch relative to electrical systole or diastole. These findings are in agreement with patch clamp studies on stretch-activated ion channels which showed a linear current/voltage relation with a reversal potential between -20 and -30 mV. Only stretch pulses applied at the end of the action potential or during diastole elicit ectopic beats as a result of transient depolarizations, while stretch pulses applied during phase 2 and 3 cause transient repolarizations or no effect, respectively.

Action Potentials↗
PubMed1996

Neuropeptide Y-related peptides and hypothalamo-pituitary-adrenal axis function.

Current data on the localization of neuropeptide Y-related peptides in the hypothalamo-pituitary-adrenal gland (HPA) axis as well as the effects of these peptides on the function of cells comprising HPA axis are presented and discussed. The action of neuropeptide Y, peptide YY, and pancreatic polypeptide on HPA axis are evaluated. Moreover, we report the presence of pancreatic polypeptide immunoreactivity in subset of chromaffin cells in the medulla of rat adrenal gland.

Adrenocorticotropic Hormone↗
PubMed1995

Electrocardiographic indexes of dispersion of ventricular repolarization: an isolated heart validation study.

OBJECTIVES: This study tested the correlation of QT and JT dispersion and other potentially useful electrocardiographic (ECG) indexes with dispersion of repolarization and recovery time. BACKGROUND: Dispersion of ventricular repolarization is currently being assessed noninvasively from the surface ECG by means of QT and JT dispersion, although their correlation with dispersion of repolarization as measured directly from the myocardium is not well established. METHODS: Multiple monophasic action potentials were recorded simultaneously with a 12-lead ECG from isolated Langendorff-perfused rabbit hearts. The QT and JT dispersion was compared with the dispersion of monophasic action potential duration at 90% repolarization (APD90) and with dispersion of recovery time. As new ECG indexes, total T wave area, T wave area after the peak (late T wave area) and T peak to T end interval were also tested. RESULTS: The QT and JT dispersion showed a significant correlation with the dispersion of APD90 and the dispersion of recovery time (r values between 0.58 and 0.64, respectively, p < 0.001). However, total T wave area showed better correlation, respectively, with dispersion of APD90 and recovery time (r = 0.79 and r = 0.82, p < 0.0001), as did late T wave area (r = 0.81 and r = 0.81, p < 0.0001) and T peak to T end interval (r = 0.81 and r = 0.82, p < 0.0001). CONCLUSIONS: The JT and QT dispersion correlate significantly with dispersion of APD90 and recovery time. The ECG assessment of dispersion of repolarization can be improved by three new ECG dispersion indexes: T peak to T end interval, total T wave area and late T wave area. These new indexes should be tested clinically.

Action Potentials↗
PubMed1995

Computer analysis of monophasic action potentials: manual validation and clinically pertinent applications.

Monophasic action potential (MAP) recordings are increasingly being used in a variety of clinical and experimental situations but their manual measurement is cumbersome, especially when hundreds or thousands of beats must be analyzed to monitor the exact time course of action potential duration (APD) changes following heart rate alterations, during surveillance of APD alternans, or during the onset and stabilization of Class III drug effects. To facilitate this task we developed a computer program that automates programmed electrical stimulation, digitizes at 1-kHz sampling frequency MAP recordings up to 8 channels simultaneously, analyzes all APDs at repolarization levels from 10%-90% in 10% decrements (APD10-90), and automatically outputs the analyzed numerical data into spreadsheets for graphical display or statistical analysis. To validate the computer algorithm, two independent observers manually analyzed 585 concurrent MAP recordings at a paper speed of 100 mm/s. Cycle length measurements by the computer were precise to 0.4 +/- 0.5 ms as compared to the computer determined paced cycle length. Computer measurements of APD20, 50, and 90 differed from manual measurements by 2.0 +/- 8.8 ms, 0.7 +/- 7.9 ms, and 0.2 +/- 8.5 ms, respectively, for observer 1; and by 12.2 +/- 8.3 ms, 5.8 +/- 7.5 ms, and 1.4 +/- 10.1 ms, respectively, for observer 2. Inter-observer variability (IOV) was 10.3 +/- 11.1 (APD20), 5.1 +/- 9.0 ms (APD50), and 1.2 +/- 7.8 ms (APD90), which was similar to computer/observer-2 differences and significantly greater (0.001) than computer/observer-1 differences. This indicates that the computer analysis was at least as precise as manual measurements when compared to IOV, and more precise when comparing computer/observer-1 differences to IOV. While providing equal or greater precision, computer-aided analysis of 100 MAP signals took approximately 1 minute while manual analysis of the same data set took between 2.5 and 4 hours. The pacing and analysis software was subsequently applied to experiments that mimic clinically pertinent examples of MAP recordings: (1) automatic generation, analysis, and graphical display of electrical restitution curves at multiple ventricular sites simultaneously; (2) evaluation of myocardial pharmacokinetics by monitoring the progression of Class III antiarrhythmic drug effects by continuous MAP recordings, and displaying differences in drug action between multiple sites; (3) depiction of the adaptation time course of APD to abrupt changes in paced cycle length; and (4) quantitative analysis of APD alternans during myocardial ischemia. The results show that our computerized algorithm greatly facilitates the generation of cardiac electrophysiological, and clinically important, data.

Action Potentials↗
PubMed1995

Immunocytochemical studies on endocrine cells of alimentary tract of the pig in the embryonic and fetal period of life.

The study aimed at immunocytochemical analysis of alimentary tract endocrine cells between 20th day of embryonal life and 105th day of fetal life of domestic pig. In the pancreas, presence of endocrine cells was detected already in 20th day and, at the time, the cells comprised around 3/4 all cells in primordia of the organ. Starting at that time, numerous endocrine cells produced insulin and glucagon and individual cells synthesized somatostatin and pancreatic polypeptide. In the 20th day, stomach and duodenum contained single endocrine cells but hormone production was not detected until days 27 and 30. Beginning from this days, both organs manifested rapid increase in the number of gastrin-producing cells. In each of the three organs, the number of somatostatin-producing cells exhibited most extensive changes.

Animals↗
PubMed1995

Regulation of calcitonin secretion by thyroid parafollicular cells in vitro.

The studies were performed on cultured TT cells originating from human thyroid medullary carcinoma (i.e., from parafollicular cells of the thyroid). The amount of released calcitonin was dependent upon calcium level in the medium. Moreover, calcitonin secretion might be regulated by medium supplementation with polypeptide hormones. Somatostatin inhibited while glucagon and pentagastrin stimulated calcitonin secretion to t he medium. Calcitonin secretion was also influenced by biogenic amines and their precursors. Dihydroxy-1-phenylalanine and serotonin augmented while 5-hydroxy-1-tryptophan and dopamine inhibited calcium secretion. This, calcitonin secretion may be controlled by different substances present in the healthy organism. This points to a complex control of calcium ion level in the blood.

5-Hydroxytryptophan↗
PubMed1995

[Calcitonin gene related peptide].

Paper presents a recent review on the function and practical importance of CGRP in both physiology and pathology of animals and humans. The special attention was paid on CGRP role in cardiovascular, endocrine and gastrointestinal systems and in neoplasms.

Animals↗