Biomedical subjects
A Schwartz
Publications and source records attributed to A Schwartz.
Characterization of the ternary complexes formed in the reaction of cis-diamminedichloroplatinum (II), ethidium bromide and nucleic acids.
The purpose of this study was to characterize the ternary complexes formed in the reaction of cis-diamminedichloroplatinum (II) (cis-DDP) and nucleic acids, in the presence of the intercalating compound ethidium bromide (EtBr). In these ternary complexes, some EtBr is tightly bound to the nucleic acids. Tight binding is defined by resistance to extraction with butanol, assayed by filtration at acid pH or thin layer chromatography at basic pH. These ternary complexes are formed with double stranded but not with single stranded nucleic acids. They are not formed if cis-DDP is replaced by transdiamminedichloroplatinum(II). The amount of tightly bound EtBr depends upon the sequence of the nucleic acid, being larger with poly (dG-dC).poly(dG-dC) than with poly(dG).poly(dC). Spectroscopic results support the hypothesis that the tight binding of the dye is due to the formation of a bidentate adduct (guanine-EtBr)cis-platin. The visible spectrum of the ternary complexes is blue-shifted as compared to that of EtBr intercalated between the base pairs of unplatinated DNA and it depends upon the conformation of the ternary complex. The fluorescence quantum yield of the ternary complexes is lower than that of free EtBr in water. Tightly bound EtBr stabilizes strongly the B form versus the Z form of the ternary complex poly(dG-dC)-Pt-EtBr and slows down the transition from the B form towards the Z form. The sequence specificity of cis-DDP binding to a DNA restriction fragment in the absence or presence of EtBr is mapped by means of the 3'----5' exonuclease activity of T4 DNA polymerase. In the absence of the dye, all the d(GpG) sites and all the d(ApG) sites but one in the sequence d(TpGpApGpC) are platinated. The d(GpA) sites are not platinated. In the presence of EtBr, some new sites are detected. These results might help to explain the synergism for drugs used in combination with cis-DDP and in the design of new chemotherapeutic agents.
Receptor pharmacology of calcium entry blocking agents.
The mechanism of action of calcium channel modulators, a class of drugs that includes 3 chemical groups--1,4-dihydropyridines, phenylalkylamines and benzothiazepines--has been extensively reviewed. The best known representatives of these 3 groups are nifedipine, verapamil and diltiazem, respectively. These drugs bind reversibly, stereospecifically and with high affinity to both the membrane-bound and the purified receptor complex. Non-dihydropyridines allosterically regulate dihydropyridine binding. This has been shown by using (-) [3H]202-791 and (+) [3H]PN200-110 as labeled ligands. The purified receptor complex that possesses binding sites for all 3 chemical groups is likely to be related to the voltage-dependent calcium channel. As the result of a drug-receptor interaction, voltage-dependent calcium channels are either activated or inactivated. The drugs that activate channels act by promoting long-lasting channel openings. The drugs that inhibit calcium channels, the calcium entry-blocking agents, act by preventing channel openings upon membrane depolarization. A complex pharmacologic, electrophysiologic, biochemical, immunologic and molecular genetic approach is required to determine the molecular mechanism of action of calcium channel modulators. Clinically, calcium entry-blocking agents are recommended for the treatment of angina pectoris, hypertension, posthemorrhagic cerebral vasospasm, supraventricular tachycardia, migraine and asthma and the protection of the ischemic myocardium.
[Is Wegener's granulomatosis really a rare and incurable disease?].
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Suppression of charge movement by calcium antagonists is not related to calcium channel block.
The calcium channel-inhibiting drugs nitrendipine and diltiazem represent two important classes of organic calcium antagonists. In the present study, the effect of these drugs on calcium currents and charge displacement currents in bullfrog semitendinosus muscle fibers was examined using a vaseline gap voltage clamp. Nitrendipine (10 microM) reduced the quantity of charge that moved both during the ON phase (QON) and the OFF phase (QOFF) of charge movement. This action appeared to be most selective for QON. However, at this same concentration, nitrendipine had no blocking action on inward calcium currents. In contrast to these findings, diltiazem blocked calcium currents in a concentration-dependent manner, while slightly increasing the quantity of charge moved during QON and QOFF. The enhancement of charge movement by diltiazem resulted from two actions. First, diltiazem shifted the voltage-dependence of charge movement to more negative potentials. Second, diltiazem increased the maximum amount of charge moved.
Effect of a sustained release formulation of diltiazem on the development of atherosclerosis in cholesterol-fed rabbits.
Cholesterol-fed rabbits were used to test potential anti-atherosclerotic effects of diltiazem, a calcium antagonist of the benzothiazepine type. Two groups of 7 rabbits each were fed standard laboratory chow supplemented with 1% cholesterol. One group received a 60 mg sustained release diltiazem capsule twice a day and the other group received a placebo capsule twice a day. A third group of control animals were fed an unmodified basal diet under conditions exactly the same as the experimental groups. All groups were studied over a period of 16 weeks. The cholesterol-fed animals showed a marked increase in plasma total cholesterol which was not significantly different for the diltiazem and placebo groups. Plasma calcium levels, blood pressure, and heart rate were also unchanged from the control animals. In the diltiazem-treated animals, 47.5 +/- 10.5% of the aortae showed atherosclerotic lesions; the value for the placebo group was 43.1 +/- 8.1%. Similar results were obtained for the coronary arteries. These results show that diltiazem treatment in the doses employed in this study had no effect on the reduction of atherosclerosis in this animal model.
Transcranial Doppler ultrasound for the assessment of intracranial arterial flow velocity--Part 2. Evaluation of intracranial arterial disease.
Transcranial (TC) pulsed Doppler ultrasound was used to evaluate flow velocity within the intracranial basal cerebral arteries in 71 patients with cerebrovascular disease as revealed by arteriography. Abnormalities of the fast-Fourier transformed (FFT) Doppler spectra were used to detect and classify obstructive lesions as well as dilative arteriopathy of the carotid siphon, the middle, anterior, and posterior cerebral arteries, and the basilar artery. Functional stenosis due to large shunting volumes in patients with arteriovenous malformations and in the presence of significant collateralization of extracranial obstructive lesions were similarly diagnosed.
Transcranial Doppler ultrasound for the assessment of intracranial arterial flow velocity--Part 1. Examination technique and normal values.
We present the examination technique and normal values of flow velocity from intracranial basal cerebral arteries for a recently developed pulsed Doppler system operating at 2 MHz emitting frequency. Peak systolic, peak diastolic, and mean flow velocity values are analyzed from fast-Fourier transformed (FFT) Doppler spectra at selected depths for 50 presumed normal subjects ranging in age from 22 to 79 years. Interindividual variation is high for peak flow but moderate for mean flow velocity values, which hence are more likely to discriminate normal from abnormal. Flow velocity values within the posterior cerebral artery (PCA) and the basilar artery (BA) are significantly lower than in the anterior cerebral artery (ACA) and the middle cerebral artery (MCA), which is also unique in showing significantly decreasing values with increasing age: calculated mean flow velocities are 47.3 +/- 13.6 and 45.3 +/- 13.5 cm/sec in the ACA, and 58.4 +/- 8.4 and 44.7 +/- 11.1 cm/sec in the MCA in patients less than 40 years and greater than 60 years, respectively, but 34.2 +/- 7.8 and 29.9 +/- 9.3 (PCA) (patients less than 40 years and patients greater than 60 years), and 34.9 +/- 7.8 and 30.5 +/- 12.4 (BA) (patients less than 40 years and patients greater than 60 years). A new scanning system is introduced, which we suggest will reduce interindividual variations and improve the accurate separation of nearby vessels, which are major causes for the comparatively large standard deviations at present.
Studies on mechanisms of calcium channel modulators.
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Absorbable polydioxanone suture for venous anastomoses: experimental studies using venography and transluminal angioscopy.
Because of their increased tendency to stenosis and spasm and thrombosis, results after venous anastomoses are often unsatisfactory. Nonabsorbable sutures and a continuous suture technique have been suggested to have a negative effect on the compliance of vascular anastomoses. Eighty venous anastomoses were performed with either an interrupted or continuous suture technique, using polypropylene or polydioxanone (PDS) sutures, according to a randomised experimental model. The anastomoses were divided in four groups: (1) Nonabsorbable suture material, continuous suture technique; (2) Nonabsorbable suture material, interrupted suture technique; (3) Absorbable suture material, continuous suture technique; and (4) Absorbable suture material, interrupted suture technique. The morphology of the anastomoses was controlled by venography directly after closure of the wound and at weekly intervals for 2 months and monthly intervals thereafter until 2 years had passed. In 10 cases venography was followed by transluminal angioscopy in the early postoperative period and after 1, 2, 4, 8 and 12 weeks. In the first 2 months moderate and high degree stenoses were found in all 4 groups by venography. After 8 weeks there was a significant decrease in the incidence of stenosis in all groups with the exception of the group, in which continuous nonabsorbable suture had been used. Using angioscopy a marked swelling of the intima at the site of the anastomoses could be detected in the early postoperative period in all experimental groups. After 2 months no significant narrowing could be identified in groups 2, 3 and 4.(ABSTRACT TRUNCATED AT 250 WORDS)
Mapping a region associated with Na channel inactivation using antibodies to a synthetic peptide corresponding to a part of the channel.
Antibodies to the synthetic peptide (carrier-coupled) corresponding to amino acids 210-223 of the primary sequence of eel Na channel (C1+ peptide) were generated. The antipeptide antibodies were used to identify functional roles as well as the accessibility from the external membrane surface of the C1+ domains. Rabbit antipeptide antibodies bound specifically to the C1+ synthetic peptide and to an eel membrane fraction bearing a high density of Na channels. When applied to the external surface of cultured dorsal root ganglion cells obtained from newborn rats, the antibodies modify Na channel inactivation by shifting the steady-state Na current-inactivation parameter, h infinity, curve to more negative potentials in fast and slow Na currents. The rate of inactivation of the slow channel is shown to be increased. The antibodies do not have a significant effect on activation of the channels. Part of the amino acid sequence corresponding to C1+ peptide is therefore accessible, in the mammalian Na channel, from the external membrane surface and is associated with the inactivation gate.
Visceral pleural thickening in asbestos exposure: the occurrence and implications of thickened interlobar fissures.
We evaluated fissural (ie, visceral pleural) thickening on radiographs in two asbestos-exposed study populations and a control group. Asbestos workers had an incidence of fissural thickening of 54.5% compared with 16.0% in the unexposed control group, with a strong positive statistical effect due to asbestos exposure beyond that attributable to age. Fissural thickening occurred in 85% of workers with parietal plaques and in 36% without pleural plaques. Fissural thickening occurred in 45% without radiographic evidence of pulmonary fibrosis, but it was very common (85%) in those with pulmonary fibrosis. Data analysis showed that fissural thickening responds more strongly to asbestos exposure than does plaque formation, with 21 years of asbestos exposure needed for a 50% chance of developing fissural thickening, while 31 years of exposure were needed for a 50% chance of forming pleural plaques. From a second group of 57 asbestos workers evaluated clinically, 8 were diagnosed as having asbestosis with radiographically clear lungs and fissural thickening. We conclude that visceral pleural thickening is common in asbestos exposure, that it is related to the years since first asbestos exposure, and that its presence may indicate the presence of pulmonary asbestosis, even with radiographically normal lungs.
Photonastic Control of Leaflet Orientation in Melilotus indicus (Fabaceae).
Leaflet orientation in Melilotus indicus (L.) All. Is under photonastic control during the day and nyctinastic control during the night, but also exhibits a diaphototropic (solar-tracking) response. Detached leaves with the two lateral leaflets excised were used to study the solar-tracking capability of the terminal leaflet. Perception of the photonastic excitation is located in the pulvinule. The lower (abaxial) and upper (adaxial) surfaces perceive photonastic excitation, which results in concomitant contraction of the side exposed to light and/or expansion of the opposite side. Steady state laminar elevation is determined by the fluence rates of the light incident simultaneously on the opposite sides. Light sensitivity of the lower side exceeds that of the upper. Response to photonastic excitation of either side is affected by angle of incidence of the light, but angular dependence is restricted to a limited range of angle of incidence, which differs for the two sides. This may be accounted for by the different topography of the two pulvinar surfaces and the localization in them of the light-sensitive tissues.
Drives, affects, behavior--and learning: approaches to a psychobiology of emotion and to an integration of psychoanalytic and neurobiologic thought.
Drawing on concepts and data from psychoanalysis, neuroscience, ethology, and experimental psychology, this paper suggests that affects are the prime movers of human motivation and have, in addition, these properties: they are neurophysiologically generated, sensationlike signals originating not in classical sensory systems, but in limbic structures; activation of the neurobiologic affect generators reliably triggers motor stereotype--like facial expression, posture, and tone of voice--which in turn transmit the physical data underlying empathy and emotional communication; and appetitively sought pleasant emotions-sensations and aversive dysphoric feelings serve respectively as the ultimate, "brain-synthesized" positive and negative reinforcers of emotional learning. The latter ideas point to derivative hypotheses: that parental nonverbal behavior and communication evoke in children the affects that guide character development and choice of defense, and that these processes are consistent with an affect-reinforced associative learning model comprising both operant and classical conditioning paradigms. Psychoanalysis as therapy, then, may mechanistically rely for its clinical effectiveness on extinctionlike processes in which new experience in the analyst-patient relationship leads to the modulation or extinction of initially crippling signal affects associatively linked to various other affects, appetites, and behaviors. Finally, the core hypotheses mesh both with recent findings from the cellular study of affect and learning mechanisms and with associative learning-unlearning assumptions variably explicit in psychoanalytic writings since the time of Freud's (1895) Project.
Role of ONO-3144, a new cardioplegic agent, in the reoxygenation injury in the anoxic myocardium.
We have investigated the effect of ONO-3144 (2-aminomethyl-4-tert-butyl-6-propionylphenol), which facilitates the conversion of prostaglandin G2 to H2 and acts as a scavenger of free radicals, on the reoxygenation injury in the anoxic heart. Rat hearts were perfused retrogradely with Krebs-Henseleit (KH) medium for 30 min (n = 8) in Group I. In Group II, the hearts which were perfused with anoxic KH medium for 40 min were reoxygenated for 30 min (n = 8). Group III hearts were similar to those in Group II except that 4 mg ONO-3144/liter was added to both anoxic and reoxygenation media (n = 8). Coronary effluent was collected for creatine kinase (CK) loss. Four rats hearts in each group were fixed for electron microscopic study and the remaining hearts were frozen in liquid nitrogen for measurement of adenosine triphosphate (ATP). A six-fold increase in CK leakage, observed after reoxygenation of anoxic heart, was prevented by ONO-3144. Tissue ATP was reduced from 22.2 +/- 0.9 mumol/g dry weight (Group I) to 5.5 +/- 1.1 mumol/g dry weight (Group II). A significant amount of ATP (9.05 +/- 1.22 mumol/g dry weight) was preserved in the treated Group III. The number of normal cells obtained by morphometrical analysis increased significantly from 56.7 +/- 7.8% (Group II) to 86.2 +/- 1.0% (Group III) and moderately injured cells were reduced to 3% in Group III as compared to 16% in the untreated Group I. Injury to the severely injured cells was not prevented by the drug treatment. At electron microscopic level, the cellular membranes, mitochondria and glycogen deposits were well preserved in Group III. Thus, ONO-3144 treatment provides a protection against reoxygenation injury in the anoxic myocardium by scavenging. .OH or other closely related species of free radicals. Therefore, free radicals generated through the conversion of prostaglandin G2 to H2 might play an important role in the reoxygenation injury of the anoxic myocardium.
The relationship between the binding site of [3H]-d-cis-diltiazem and that of other non-dihydropyridine calcium entry blockers in cardiac sarcolemma.
[3H]-d-cis-Diltiazem binds to canine cardiac sarcolemma in a specific, saturable, and reversible manner with a KD = 58.0 +/- 9.5 nM and a receptor site density (maximum binding) of 2.19 +/- 0.24 pmol/mg of protein. Bepridil and verapamil, Ca2+ channel inhibitors, can completely inhibit this binding at nM concentrations. This inhibition was determined from saturation binding data to be due to a change in affinity of the radioligand, suggesting a competitive interaction between the three drugs. However, in dissociation experiments, both bepridil and verapamil increased the dissociation rate of the radioligand. This effect is uncharacteristic of competitive inhibitors and suggests that bepridil and verapamil regulate [3H]-d-cis-diltiazem binding in a negative allosteric fashion through their own distinct binding sites.
A comparison between the binding and electrophysiological effects of dihydropyridines on cardiac membranes.
To investigate the mechanism of action of dihydropyridines on calcium channels, both receptor binding and the electrophysiological effects of optically pure enantiomers of Bay k 8644, Sandoz 202-791, nimodipine, and PN200-110 were studied in a guinea pig ventricular preparation. The radioligand binding studies are consistent with other reports that the inhibitory and excitatory dihydropyridines share a single binding site. The patch clamp method was used for recording whole cell calcium currents. (-)-Bay k 8644 and (+)-202-791 produced voltage-dependent increases in the calcium currents. The magnitude of the effect was dependent on the holding potential. At holding potentials between -40 and -90 mV these activators increased calcium currents in a concentration-dependent manner with EC50 values of 25 nM and 80 nM, respectively. The inhibitors (+)-Bay k 8644, (-)-202-791, (+)- and (-)-nimodipine, and (+)-PN200-110 blocked the calcium currents with potencies that depended upon holding potential. The IC50 values for these enantiomers measured at a holding potential of -80 mV were, respectively, 8000, 200, 2000, 450, and 400 nM, and IC50 values measured at a holding potential of -30 mV were 26, 1.0, 52, 4.0, and 4.5 nM. The dissociation constants calculated for some dihydropyridines are similar to the Kd values determined by radioligand binding. However, for other dihydropyridines, large discrepancies between the concentrations giving rise to half-maximal electrophysiological effects and the Kd values from binding studies could not be reconciled by voltage-dependent binding alone. We suggest that each dihydropyridine also produces unique effects on the voltage-dependent gating of calcium channels.
A possible role for the endothelium in porcine coronary smooth muscle responses to dihydropyridine calcium channel modulators.
The role of the endothelium in contraction and relaxation produced by the dihydropyridine calcium channel modulators was examined in porcine coronary smooth muscle. The optically pure dihydropyridine calcium agonists (+)-S202-791 and (-)-Bay k 8644 both produced greater contractions in tissues without endothelium compared with tissues with intact endothelium. In contrast, histamine produced the same degree of contraction in tissues with and without endothelium. In the presence of KCl-induced active muscle tone, the optically pure calcium antagonists (-)-R202-791 and (+)-Bay k 8644 and the nitrovasodilator isosorbide dinitrate all produced the same degree of relaxation in tissues with and without endothelium. These results suggest that the endothelium plays an inhibitory role in dihydropyridine-induced contraction. When coronary rings with intact endothelium were pretreated for 60 min with 10 or 100 nM (-)-R202-791, the contraction to subsequent addition of (+)-S202-791 was significantly greater than in control tissues pretreated with only solvent. However, in rings with denuded endothelium, pretreatment with (-)-R202-791 resulted in a rightward shift of the dose-response curve to (+)-S202-791, and a depression of the maximal contraction compared with controls. Thus, the interaction between the calcium agonist [(+)-S202-791] and antagonist [(-)-R202-791] is more complex than competitive inhibition. We suggest that the calcium agonists produce two effects, a release of endothelium-derived relaxant factor and a direct contraction of smooth muscle; the calcium antagonists can inhibit both processes.(ABSTRACT TRUNCATED AT 250 WORDS)