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H D Smith

Publications and source records attributed to H D Smith.

At least 19 recordsLinked to original sources
PubMed1995

4-(Heteroarylthio)-2-biphenylyltetrazoles as nonpeptide angiotensin II antagonists.

A series of 4-(heteroarylthio)-2-biphenylyltetrazoles was prepared, and the compounds were examined for their ability to displace [3H]AII from angiotensin II receptors. Analogues that exhibited significant receptor binding affinities at less than 10 microM were investigated further for potential antagonism of angiotensin II-mediated contraction of rabbit isolated aortic rings. Three 4-(heteroarylthio)-2-biphenylyltetrazoles were identified that exhibited sub-micromolar angiotensin II receptor binding affinities. These compounds and two reference agents, saralasin and losartan (DUP-753), exhibited concentration-dependent reversal of angiotensin II contraction in isolated aortic rings parallel to their receptor binding affinities. Molecular modeling studies were conducted to examine the conformational effects of the novel sulfide bridging unit contained in these 4-(heteroarylthio)-2-biphenylyltetrazoles. The biological effects of the sulfide bridge as well as alterations in the heteroaromatic moiety were investigated, and the resulting structure--activity relationships are discussed.

Angiotensin II↗
PubMed1995

A 60 Hz electric and magnetic field exposure facility for nonhuman primates: design and operational data during experiments.

A unique exposure facility was designed and constructed to generate large-scale vertical electric fields (EF) of up to 65 kV/m and horizontal magnetic fields (MF) of up to 100 microT (1G), so that the behavioral and neuroendocrine effects of 60 Hz EF or combined electric and magnetic field (E/MF) exposure could be examined using nonhuman primates as subjects. Facility design and operational problems and their solutions are presented, and representative operational data from four sets of experiments are provided. A specially designed, optically isolated, 4 cm spherical-dipole EF probe and a commercially available MF probe were used to map the EF and MF within the fiberglass animal cages. In addition, amplifiers, signal conditioners, and A/D converters provided EF, MF, and transformer signals to a microcomputer at 15 min intervals. The apparatus produced homogeneous, stable E/MF at the desired intensities, and the fiberglass cages did not produce appreciable distortion or attenuation. Levels of recognized EF artifacts such as corona and ozone were negligible. The facility worked as intended, providing a well-characterized and artifact-controlled environment for experiments with baboons (Papio cynocephalus).

Animals↗
PubMed1995

Detection thresholds for 60 Hz electric fields by nonhuman primates.

Because responses of animals to detection of the presence of an electric field (EF) are a possible mechanism for production of biological effects, it is important to know what EF intensities are detectable. Operant methods were used to train six baboons (Papio cynocephalus) to perform a psychophysical task involving detection of EF presence. During the response phase of a trial, a subject responded on one push button to report the presence of the EF and on a different push button to report the absence of the EF. Correct reports of EF presence of absence produced delivery of food rewards. The subjects became proficient at performing this psychophysical detection task; during 35 days of testing, false alarm rates averaged 9%. The average EF detection threshold was 12 kV/m; the range of means among subjects was 5-15 kV/m. Two special test procedures confirmed that the subjects were responding directly to EF presence of absence and not to artifacts that might be associated with EF generation. The EF detection threshold of nonhuman primates is similar to thresholds reported for rats and humans.

Animals↗
PubMed1995

Initial exposure to 30 kV/m or 60 kV/m 60 Hz electric fields produces temporary cessation of operant behavior of nonhuman primates.

In two separate experiments, we examined the effects of a 60 Hz electric field (EF) on performance of an operant schedule consisting of two signaled components: fixed-ratio (FR30) and differential reinforcement of low-rate (DRL20). In each experiment, 12 naive baboons (Papio cynocephalus) were assigned randomly to either an EF-exposed experimental group or a sham-exposed control group. A homogeneous vertical EF of 30 kV/m was used in one experiment; 60 kV/m was used in the other. The experimental design for both experiments included 6 week preexposure, exposure, and postexposure periods. The planned analyses indicated no evidence of statistically significant (P < .05) effects of EF exposure. However, exploratory analyses comparing performance during the last week of preexposure and the first week of exposure revealed statistically significant acute effects (work stoppage): The mean response rates of the EF-exposed groups were greatly reduced on day 1 of exposure but were normal by the end of day 2 of EF exposure. We hypothesize that introduction of a highly unusual stimulus, the EF, temporarily interfered with normal operant behavior to produce a primary work stoppage. Supplementary cross-over experiments added at the end of each main experiment indicated that work stoppage occurred again when formerly EF-exposed subjects served as sham-exposed controls, while other subjects received their first EF exposure. Presumably, reoccurrence of other stimuli correlated with initial exposure to the EF became sufficient to subsequently cause secondary work stoppage in the absence of direct EF exposure. The primary and secondary work-stoppage effects were reproducible.

Animals↗
PubMed1995

Nonhuman primates will not respond to turn off strong 60 Hz electric fields.

Using a set of six baboons (Papio cynocephalus), we conducted a series of seven experiments designed to evaluate the potentially aversive character of a 60 Hz electric field (EF). Initially, the subjects were trained, using food rewards as the reinforcer, to respond only when a cue light was illuminated. Next, an EF was presented along with the cue light; responses produced delivery of a food pellet and turned off both the cue light and the EF. Then, stimulus and reward conditions were varied. We determined that 1) presence of a strong EF does not affect operant responding for food rewards, 2) subjects will not respond at normal rates when the only reinforcer is termination of a strong EF, 3) presence of a strong EF can serve as a discriminative stimulus, 4) presence of a strong EF does not affect extinction of an appetite-motivated task, and 5) presentation of an EF can become a secondary reinforcer. The pattern of results was consistent across all experiments, suggesting that an EF of as much 65 kV/m is not aversive to nonhuman primates. Separately, we demonstrated that the average EF detection threshold for baboons in 12 kV/m. Thus, EF exposure at intensities well above the detection threshold and at species-scaled EF strengths greater than those found environmentally does not appear to be aversive.

Animals↗
PubMed1995

Exposure of baboons to combined 60 Hz electric and magnetic fields does not produce work stoppage or affect operant performance on a match-to-sample task.

We examined the effects of combined 60 Hz electric and magnetic field (EMF) exposure on performance of delayed match-to-sample (MTS) procedure involving the flash rate of a light as the stimulus. Six baboons (Papio cynocephalus) fully acquired the task; four others functioned accurately only when cued. All ten subjects were assigned to EMF-exposed or sham-exposed groups of five and were used to test for a work-stoppage effect that was previously observed with initial exposure to electric fields (EF) of 30 or 60 kV/m. Here, we report the results of two experiments, each consisting of 6 week preexposure, exposure, and postexposure periods. We found no evidence of work stoppage with fields of 6 kV/m and 50 microT (0.5 G) or with 30 kV/m and 100 microT (1.0 G). In neither experiment was there evidence of an adverse effect of 60 Hz EMF exposure on MTS performance.

Animals↗
PubMed1995

Initial studies on the effects of combined 60 Hz electric and magnetic field exposure on the immune system of nonhuman primates.

In a pilot immunology experiment, peripheral blood samples from six baboons (Papio cynocephalus) housed as a social group were collected during week 5 of preexposure, exposure, and postexposure periods that were each 6 weeks in duration. The subjects were exposed to vertical 6 kV/m and horizontal 50 microT (0.5 G) fields for 12 h per day. Lymphocytes collected during the exposure period displayed statistically significant (p < .05) reductions in CD3+ and CD4+ counts, interleukin 2 receptor expression, and proliferative response to pokeweed mitogen. A second experiment was conducted using samples from seven subjects exposed to 30 kV/m and 100 microT (1.0 G) and eight sham-exposed subjects. Statistically significant Period x Group interactions occurred for total white blood cell count and CD4+ to CD8+ ratio, but the pattern of results was not suggestive of an exposure-related effect. Although components of the nonhuman primate immune system appear to be affected by 60 Hz electric and magnetic field exposure in one of two experiments, additional experiments are required to evaluate this possibility.

Animals↗
PubMed1995

Chronically indwelling venous cannula and automatic blood sampling system for use with nonhuman primates exposed to 60 Hz electric and magnetic fields.

An automated blood sampling system was developed for use with tethered baboons (Papio cynocephalus) during concurrent exposure to 60 Hz 30 kV/m electric fields and 0.1 mT (1.0 G) magnetic fields. The system was controlled by a FORTH-based microcomputer, which operated a pump, a fraction collector, and two pinch valves. A swivel mechanism at the end of the tether allowed the baboons to move freely in their cages. The hardware and software were designed for fail-safe operation. Heparinized saline was infused at a rate of 0.5 mL/min until a sample cycle was initiated. Then, blood was drawn from the animal into a storage tube at a rate of 12.5 mL/min, a sample of undiluted blood was taken from the end of the storage tube near the baboon, and the blood remaining in the storage tube was then flushed back into the animal. Use of the storage tube prevented the peristaltic pump rollers from pressing on tubing containing blood, and return of the blood diluted with saline limited the blood wasted per sample to less than 0.5 mL. The system functioned reliably in three experiments, collecting samples as scheduled 97% of the time. Although it was initially designed for and used successfully with primates in an electric and magnetic field environment, this type of system could be employed in many areas of biomedical research or medical treatment.

Animals↗
PubMed1995

Regularly scheduled, day-time, slow-onset 60 Hz electric and magnetic field exposure does not depress serum melatonin concentration in nonhuman primates.

Experiments conducted with laboratory rodents indicate that exposure to 60 Hz electric fields or magnetic fields can suppress nocturnal melatonin concentrations in pineal gland and blood. In three experiments employing three field-exposed and three sham-exposed nonhuman primates, each implanted with an indwelling venous cannula to allow repeated blood sampling, we studied the effects of either 6 kv/m and 50 microT (0.05 G) or 30 kV/m and 100 microT (1.0 G) on serum melatonin patterns. The fields were ramped on and off slowly, so that no transients occurred. Extensive quality control for the melatonin assay, computerized control and monitoring of field intensities, and consistent exposure protocols were used. No changes in nocturnal serum melatonin concentration resulted from 6 weeks of day-time exposure with slow field onset/offset and a highly regular exposure protocol. These results indicate that, under the conditions tested, day-time exposure to 60 Hz electric and magnetic fields in combination does not result in melatonin suppression in primates.

Animals↗
PubMed1995

Rapid-onset/offset, variably scheduled 60 Hz electric and magnetic field exposure reduces nocturnal serum melatonin concentration in nonhuman primates.

Experiments with rodents indicate that power-frequency electric field (EF) or magnetic field (MF) exposure can suppress the normal nocturnal increase in melatonin concentration in pineal gland and blood. In a separate set of three experiments conducted with nonhuman primates, we did not observe melatonin suppression as a result of 6 weeks of day-time exposure to combined 60 Hz electric and magnetic fields (E/MF) with regularly scheduled "slow" E/MF onsets/offsets. The study described here used a different exposure paradigm in which two baboons were exposed to E/MF with "rapid" E/MF onsets/offsets accompanied by EF transients not found with slowly ramped E/MF onset/offset; profound reductions in nocturnal serum melatonin concentration were observed in this experiment. If replicated in a more extensive experiment, the observation of melatonin suppression only in the presence of E/MF transients would suggest that very specific exposure parameters determine the effects of 60 Hz E/MF on melatonin.

Animals↗
PubMed1994

Kinetics of a cellular response to interleukin 6.

The stimulation of the production of haptoglobin from the human hepatoma HepG2 was used as a model to examine the kinetics of a cellular response to interleukin 6 (IL-6). It was demonstrated that IL-6 upregulated the production of haptoglobin in a time-dependent manner: using a sensitive radioimmunoassay for haptoglobin, increases were already detectable 2 hr after IL-6 treatment began. The haptoglobin level continued to rise in a linear fashion to at least 16 hr. The stimulation of haptoglobin by IL-6 was abolished in the presence of 5 micrograms/ml actinomycin D and was thus likely pretranslational. It was further demonstrated that the upregulation of haptoglobin continued well after the removal of IL-6 from the system. An 8-hr "pulse" of IL-6 gave rise to haptoglobin secretion which was above control levels for the following 4 days. The effects of IL-6 in vivo can therefore be predicted to be long-lived despite its own short half-life, especially since the products of IL-6 stimulation, e.g., immunoglobulin and acute-phase proteins, are themselves long-lived in the circulation.

Dactinomycin↗