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W P Watkinson

Publications and source records attributed to W P Watkinson.

34 records · Page 2Linked to original sources
PubMed1991

Effects of 3,4-methylenedioxymethamphetamine on autonomic thermoregulatory responses of the rat.

3,4-Methylenedioxymethamphetamine (MDMA), a substituted amphetamine analogue which stimulates serotonin release in the CNS, has been shown to induce near lethal elevations in core temperature in the rat. To characterize the effects of MDMA on temperature regulation, we measured metabolic rate (MR), evaporative water loss (EWL), motor activity (MA), and colonic temperature (Tc) in male, Long-Evans rats at 60 min following 30 mg/kg (SC) MDMA or saline at ambient temperature (Ta) of 10, 20 and 30 degrees C. MDMA caused an elevation in MR at Ta's of 20 and 30 degrees C but had no effect at 10 degrees C. At a Ta of 30 degrees C, MR of the MDMA group was double that of the saline group. EWL was elevated by MDMA, an effect which was potentiated with increasing Ta. MDMA also elicited an increase in MA at all three Ta's. MDMA led to a 3.2 degrees C increase in Tc at 30 degrees C, no change in Tc at 20 degrees C, and a 2.0 degrees C decrease in Tc at 10 degrees C. A second study found that treatment with 20 mg/kg MDMA failed to elicit an increase in blood flow to the tail in spite of a hyperthermic core temperature of 41.4 degrees C. Preliminary studies using radiotelemetry methodology suggested that MDMA lethality is preceded by precipitous elevations in heart rate and core temperature. The data suggest that, at relatively warm Ta's. MDMA-induced stimulation of serotonergic pathways causes an elevation in MR and peripheral vasoconstriction, thus producing life-threatening elevations in Tc.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Methylenedioxyamphetamine↗
PubMed1989

Modulating effect of body temperature on the toxic response produced by the pesticide chlordimeform in rats.

Previous studies from this laboratory have demonstrated significant deficits in cardiovascular function in rats exposed to the pesticide chlordimeform (CDM) when body core temperature (TCO) was maintained at 37 degrees C. To investigate the role of TCO on CDM toxicity, similar experiments were conducted over a range of TCO values. Adult rats (n = 30) were anesthetized with sodium pentobarbital (35 mg/kg) and randomly assigned to one of six equal groups. Groups were paired and TCO was maintained in the rats in each of the respective group pairs at one of three levels (37, 35, or 33 degrees C). Rats in one group at each temperature level (groups T37, T35, and T33) were injected intraperitoneally with 60 mg/kg of CDM. Animals in the corresponding temperature-matched groups (groups C37, C35, and C33, respectively) received volume-matched injections of normal saline vehicle and served as time-paired controls. The electrocardiogram and heart rate (HR) were monitored throughout the experimental procedure. There was a significant decrease in HR in all CDM-treated groups when compared to the control group animals. The magnitude of the observed cardiac effect was attenuated in the T35 group when compared to that of the other treated groups. Similarly, lethality rates (number of deaths/total) for the T37, T35, and T33 groups were 2/5, 0/5, and 3/5, respectively; there were no deaths among the control-group animals. From these and previous data from this laboratory, we conclude there may be a beneficial effect of moderate hypothermia in rats exposed to toxic agents while more severe hypothermia appears to offer no advantage and may actually exacerbate the toxic effect.

Amidines↗
PubMed1988

Temperature regulation in laboratory mammals following acute toxic insult.

The purpose of this paper is to provide a concise review of the effects of acute chemical toxicity on thermoregulation in mammals, with particular emphasis on the effects of xenobiotic compounds in laboratory rodents. It has been shown that acute administration of compounds such as nickel, cadmium, lead, and some pesticides causes a reduction in the body temperature of mice when tested at normal room temperatures. When provided with the option of selecting their preferred ambient temperature, the toxic-treated animals generally select cool temperatures which augment the hypothermic effect of the toxic compounds. It would appear that many of the xenobiotic compounds have central as well as peripheral effects on the control of body temperature. That is, the hypothermic animals select cool temperatures, a condition indicative of a centrally mediated decrease in the set-point. This decrease in set-point, or regulated hypothermia, may be beneficial to survival since the lethality of most xenobiotic compounds increases with rising body temperature. The observation that acute doses of various compounds leads to behaviorally and autonomically mediated changes in body temperature may have significant implications for the measurement of other biological effects of these chemical agents (e.g., CNS dysfunction, bradycardia, immunosuppression).

Animals↗
PubMed1987

Effects of chlordimeform on heart rate and body temperature of unanesthetized, unrestrained rats.

Heart rate (HR) and body core temperature (Tco) were monitored in unanesthetized, unrestrained adult Sprague-Dawley rats following intraperitoneal administration of 0, 10, 30, or 60 mg/kg of the pesticide chlordimeform (CDM). Significant non-dose-related decreases were observed in both HR and Tco in all treated groups. Although similar in character, the HR response observed in the present study was of a lesser magnitude than that which was reported in previous studies from this laboratory using anesthetized animals in which Tco was maintained at control levels. It is proposed that the attenuation of the toxic response seen in the present study may be causally related to the concomitant decrease in Tco.

Amidines↗
PubMed1987

Cardiopulmonary effects in awake rats four and six months after exposure to methyl isocyanate.

Cardiopulmonary function was assessed four and six months after Fischer 344 rats were exposed to 2 hr to 0, 3, or 10 ppm methyl isocyanate (MIC). During assessment, the rats were challenged with 4 and 8% carbon dioxide (CO2) to stimulate ventilatory drive. Minute ventilation (VE) during CO2 challenge was increased in MIC-treated rats compared to controls when examined 4 months after exposure to 10 ppm MIC, suggesting a ventilation/perfusion inequality. An increase in maximum expiratory flow and a decrease in expiratory time indicated increased lung recoil in these rats. Evidence of pulmonary hypertension was observed in electrocardiograms (ECGs) and supported by postmortem analysis that showed a positive association between increased ECG abnormalities and increased right ventricular weights in the rats treated with 10 ppm MIC. At 6 months, forced expiratory flow-volume curves indicated persistent airway obstruction; however, no changes in inspiratory or expiratory resistance were evident. Decreased dynamic compliance and changes in two new measures of lung function (volume and time at zero expiratory intrapleural pressure) suggest that MIC-induced lung dysfunction also exhibited elements of a restrictive disease.

Airway Obstruction↗
PubMed1986

Effects of chlordimeform on cardiovascular functional parameters: Part 2. Acute and delayed effects following intravenous administration in the postweanling rat.

The effects of intravenous (iv) administration of chlordimeform (CDM) were investigated in 22- to 30-d-old pentobarbital-anesthetized Sprague-Dawley rats. Animals (n = 25) were given sequential iv injections of 5, 10, 30, 60, and 120 mg CDM/kg, or normal saline vehicle followed by a single injection of 60 mg CDM/kg. Heart rate (HR), arterial blood pressure (BP), and electrocardiogram (ECG) were monitored for all animals, while body temperature was maintained at control levels (37 degrees C). CDM produced profound acute effects on all cardiovascular parameters monitored and persistent delayed effects on HR and BP. These effects were similar to but less severe than those observed in a previous study using geriatric animals. Younger animals also appeared to be more resistant to the lethal actions of CDM.

Amidines↗
PubMed1986

Effects of chlordimeform on cardiovascular functional parameters: Part 3. Comparison of different routes of administration in the postweanling rat.

The effects of intraperitoneal (ip) administration of chlordimeform (CDM) were investigated in 22- to 24-d-old pentobarbital-anesthetized Sprague-Dawley rats. Animals (n = 32) received a single ip injection of CDM at either 10, 30, or 60 mg/kg, or of normal saline vehicle. Heart rate (HR) and electrocardiogram (ECG) were monitored for all animals, while body temperature was maintained at control levels (37 degrees C). HR decreased 21-29% in the treated animals, and there were no differences observed across dose groups or over time. ECG effects were confined to rate-related changes only. The decrease in HR produced by CDM in these animals was comparable to the delayed HR effect seen in previous studies from this laboratory, despite major differences in dosing regimens and routes of administration.

Amidines↗
PubMed1986

Improved technique for monitoring electrocardiograms during exposure to radio-frequency radiation.

Studies were conducted utilizing improved methodology that examined the effects of radio-frequency (RF) radiation on heart rate (HR), deep body temperature (Tco), and electrocardiographic (ECG) waveform parameters in anesthetized rats. One group of animals was exposed to two power levels of continuous-wave RF radiation averaging 1.0 and 7.4 W/kg at a frequency of 600 MHz. A second group of animals, treated identically but not exposed to RF radiation, served as a control. The electrodes used for monitoring the ECG during RF exposure were fabricated from carbon-loaded Teflon wire, a semiconductor material that does not perturb the RF field. Analyses of the ECG were conducted by use of a recently developed computer-assisted procedure that quantitates HR and waveform intervals over 25-40 individual ECG complexes. There were no artifacts or arrhythmias in the ECGs of the animals exposed to RF radiation. There was a significant linear correlation between HR and Tco in the RF-exposed group that was not present in the control group.

Animals↗
PubMed1985

A computer-assisted electrocardiographic analysis system: methodology and potential application to cardiovascular toxicology.

An automated analysis of electrocardiographic (ECG) waveforms, based on a precise one-dimensional analysis of features within a generalized computer-enhanced ECG waveform, has been developed in our laboratory. ECG signals are monitored, amplified, and recorded using standard techniques. The recorder output signal is distributed to a microcomputer system. Software developed for the microcomputer slows the signal playback rate and permits operator review of the slowed signal for arrhythmia analysis. The analysis program identifies and superimposes 10-40 individual ECG complexes, depending on the heart rate, and generates an "ensembled" waveform. Operator interaction permits delineation of specific points on the displayed waveform and calculation of heart rate and duration of components within the ECG complex. The primary advantages of this system include (1) extensive automation--computer support decreases analytical time, increases precision, and permits rapid screening of large numbers of animals; (2) enhanced sensitivity--the use of functional parameters should provide a more sensitive index of toxicity than morphological parameters; (3) broad utility--this system provides the capability to utilize a variety of animals, both anesthetized and unanesthetized, ranging in age from fetuses to geriatrics, and permits studies of block as well as longitudinal design; and (4) ease of replication--standardization of equipment and techniques facilitates replication by other laboratories.

Animals↗
PubMed1985

Effects of chlordimeform on cardiovascular functional parameters: Part 1. Lethality and arrhythmogenicity in the geriatric rat.

Chlordimeform (CDM), a formamidine pesticide, had a profound effect on the cardiovascular function of geriatric rats. Two-year-old pentobarbital-anesthetized Sprague-Dawley rats (n = 8) received sequential intravenous CDM injections of 5, 10, 30, and 60 mg/kg. A control group of rats (n = 8) received multiple injections of normal saline vehicle over a similar time period, followed by a single CDM injection of 60 mg/kg. Heart rate (HR), arterial blood pressure (BP), and electrocardiogram (ECG) were monitored for all animals. CDM produced abrupt decreases in HR and BP at all doses. In addition, striking changes in ECG waveforms and intervals and various conduction-related arrhythmias were observed. These acute effects triggered a reflex-mediated overshoot in HR and BP above preinjection levels, followed by a delayed, persistent depression of these parameters. Three animals from the CDM-treated group died after injection of the 30-mg/kg dose, while 60 mg/kg was lethal in the remaining animals. In the majority of cases, death appeared to be due to cardiac arrest.

Aging↗
PubMed1983

Electrocardiographic responses of rat fetuses with clamped or intact umbilical cords to acute maternal uterine ischemia.

Uterine ischemia results in severe cardiac disturbances in the fetus. It has been postulated that these effects are due to interaction between the fetus and the ischemic uterus or placenta, and not to hypoxia or buildup of metabolites in the fetus. Rat fetal cardiac responses to uterine clamping and umbilical cord clamping were compared by electrocardiography. On day 21 of gestation, fetuses in a total of 14 pregnant rats were exposed to umbilical clamping, uterine clamping, or no clamping. Electrocardiograms were recorded for each fetus immediately after clamping and at 10, 20, and 30 minutes after clamping. Immediately after clamping, the uterine clamping group alone showed severe sinus bradycardia. At all other observation times, fetuses exposed to uterine or umbilical clamping showed bradycardia and other electrocardiographic changes typically associated with hypoxia. Therefore, umbilical clamping protected the fetuses from the adverse effects of uterine clamping for only a very short time.

Animals↗
PubMed1983

Effect of phenytoin on maternal heart rate in A/J mice: possible role in teratogenesis.

Phenytoin (diphenylhydantoin, Dilantin, PHT), an anticonvulsant and antiarrhythmic drug, is teratogenic to A/J mice, producing an increased incidence of cleft lip with or without cleft palate [CL(P)] and cardiac defects. Although its mechanism of teratogenic action remains unclear, one possibility may involve uterine ischemia resulting from an exaggerated depressant effect on maternal cardiovascular function. To test this hypothesis, the heart rate response of susceptible A/J and resistant C57Bl/6J mice was monitored following intraperitoneal injection of doses of PHT of known teratogenic potential. Heart rate (HR) was obtained electrocardiographically from unanesthetized, pregnant mice on day 10 of gestation via previously implanted subcutaneous electrodes. The HR of A/J mice was significantly depressed relative to vehicle-injected controls following doses of 40, 60, and 75 mg/kg, with the greatest effect occurring in the high-dose group. In C57Bl/6J mice, the HR response of the group treated with 75 mg/kg was not different from that of the vehicle-treated controls. At the same dose level, the depression of HR of A/J mice was significantly greater in magnitude and duration than that of C57Bl/6J mice. A proposed maternally mediated mechanism of CL(P) in A/J mice involving low placental/embryonic oxygen delivery is discussed. The results of the present study indicate the potential significance that changes in maternal physiology may have on embryonic development.

Abnormalities, Drug-Induced↗
PubMed1983

Electrocardiographic studies of developing rodents exposed in utero to trypan blue.

Techniques, based on computer-assisted analyses of ensembled ECG waveforms, have been developed in this laboratory to serve as a screening procedure for potentially cardiotoxic substances. This procedure was tested on fetal and neonatal rats exposed in utero to two levels of trypan blue, a known cardiovascular teratogen. The offspring of the treated animals exhibited decreased viability, as well as significant levels of both cardiac and noncardiac malformations. Qualitative assessment of ECG irregularities demonstrated an increased number of abnormalities in the treated groups. Correlations were also obtained between observed morphological defects and ECG irregularities in the trypan blue treated groups.

Abnormalities, Drug-Induced↗
PubMed1980

Effect of adenosine on transmural myocardial blood flow distribution in the awake dog.

Studies were conducted to determine the effects of adenosine on transmural myocardial blood flow distribution. Both maximal and submaximal vasodilatory doses of adenosine were infused into awake resting dogs chronically instrumented with coronary flow probes and aortic and left atrial pressure catheters. Radioactive microspheres (8-10 micron) were used to determine regional coronary blood flow. Four experimental protocols were evaluated: 1) the effects of maximal (1.00 mg . kg-1 . min-1) as well as submaximal (0.45 mg . kg-1 . min-1) vasodilatory levels of adenosine, 2) the dose-response characteristics of adenosine, 3) the dose-response characteristics of dipyridamole, and 4) the effects of adenosine in the presence of an increased arterial PO2. The data indicate that maximal vasodilatory doses of adenosine have little effect on the endocardial-to-epicardial blood flow ratio, whereas submaximal doses result in a marked preferential endocardial perfusion. This relative increase in endocardial perfusion was not altered by hyperoxia. Dipyridamole, in submaximal doses, produced a similar preferential flow to the endocardial layer. These data demonstrate that the vasodilator reactivity to adenosine infusion is greater in the endocardial layer,

Adenosine↗
PubMedDate not supplied

Behavioral and autonomic thermoregulation in the rat following chlordimeform administration.

This study was designed to assess the effects of a single acute injection of chlordimeform (CDM) on some behavioral and autonomic effectors of the thermoregulatory system of the Sprague-Dawley rat. In one experiment rats injected intraperitoneally with 60 mg/kg CDM were placed in an environmental chamber set at an ambient temperature (Ta) of 5, 10, 15, 20, 25 or 30 degrees C for 60 min. Exposure to CDM resulted in hypothermia at Ta's of 5 to 25 degrees C and had no effect on body temperature at a Ta of 30 degrees C. In a second experiment, rats injected with 60 mg/kg CDM were placed in a temperature gradient which permitted the continuous recording of preferred Ta (i.e., behavioral thermoregulation), oxygen consumption (i.e., metabolic rate), and total activity. CDM-treated rats preferred Ta's of 20 degrees C after 60 min in the temperature gradient in spite of a hypothermic body temperature (35.3 degrees C). That is, the animals could have moved to the warm end of the gradient and thereby prevented a fall in body temperature. CDM also led to a significant reduction in oxygen consumption. In a third experiment, foot and tail skin temperature, and heart rate were recorded in anesthetized rats maintained under normothermia while treated with CDM. Tail and foot skin temperature rapidly increased following CDM administration which was indicative of peripheral vasodilation and increased heat loss. The changes in temperature were concomitant with an abrupt drop in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Amidines↗