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Biomedical subjects

C F Schaefer

Publications and source records attributed to C F Schaefer.

16 recordsLinked to original sources
PubMed1991

Rapid reduction of intestinal cytochrome a,a3 during lethal endotoxemia.

In vivo near-infrared spectrophotometry was used to determine whether lethal endotoxemia impairs small intestinal oxidative phosphorylation as reflected by the redox state of mitochondrial cytochrome a,a3 (AA3). Adult male Sprague-Dawley rats were anesthetized with 2.1% isoflurane in 30% O2:70% N2O, and the small intestine was partially exteriorized for spectrophotometric monitoring (OMNI-3). By 5 min after an iv bolus of Escherichia coli endotoxin (40 mg/kg, LD90, n = 7) a significant shift toward reduction in intestinal AA3 had occurred in association with hypotension and a marked fall in both superior mesenteric artery blood flow (SMAF) and cardiac output. In a separate group (n = 7) SMAF was kept at the baseline level by periodic infusions of donor rat plasma begun 1 min after endotoxin injection, and the reduction in AA3 was again found despite the fluid loading intervention which successfully maintained not only organ blood flow, but also cardiac output and mean arterial pressure in their normal ranges. Further experiments (n = 34) measuring SM vascular bed oxygen consumption indicated that intestinal VO2 remained unchanged during early endotoxemia. These findings suggest a rapid impairment of oxidative phosphorylation by endotoxin which seems to occur through direct (and/or indirect) toxic cellular effects rather than through impaired tissue perfusion.

Animals↗
PubMed1991

Dose-related reduction of intestinal cytochrome a,a3 induced by endotoxin in rats.

Dose-related, endotoxin-induced changes in oxidative metabolism were investigated in vivo using near-infrared spectrophotometry. Sixty fasted male Sprague-Dawley rats were randomly allocated to groups (N = 10 each) receiving saline, 0.08, 0.3, 1.25, 5, or 20 mg/kg Escherichia coli endotoxin by i.v. bolus (1 ml/kg volume). Isoflurane anesthesia with controlled ventilation was used for surgery and the subsequent collection of hemodynamic and metabolic data. Approximately half the length of the small intestine was exteriorized for continuous spectrophotometric monitoring of tissue oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), and mitochondrial cytochrome a,a3 (AA3) redox state. Hemodynamic parameters included arterial and central venous pressures, cardiac output, and superior mesenteric artery blood flow (SMAF). Intestinal AA3 exhibited a marked and sustained shift toward reduction in those groups (1.25, 5, and 20 mg/kg) which developed significant blood pressure and blood flow decreases. However, the AA3 reduction did not seem to reflect tissue hypoxia, since 1) the simultaneously measured tissue HbO2 levels remained essentially constant, 2) the AA3 redox shift did not reverse upon recovery of intestinal blood flow in the 1.25 mg/kg group, which exhibited only a transient decrease in SMAF, and 3) systemic oxygen consumption was unchanged in any group. Endotoxin-induced lethality was tested in six separate groups (N = 10 each) and was significant (60%) only in the 20 mg/kg group. These results suggest that endotoxin may induce a direct (or rapidly mediated indirect) impairment of cellular oxidative phosphorylation.

Animals↗
PubMed1990

Evaluation of thyrotropin releasing hormone as a therapeutic intervention for endotoxemia.

Thyrotropin releasing hormone (TRH) has been reported to reduce endotoxin-induced hypotension and mortality rate in conscious rats. Limited data are available to explain these effects. We evaluated hemodynamic parameters, metabolic function, tissue injury, and survival rate in three groups of instrumented conscious rats following intravenous endotoxin (20 mg/kg, LD/90-24 h) challenge. Pretreatment with TRH (2.0 mg/kg, i.v.) was administered 10 min before endotoxin (n = 10) and control (n = 10) animals were given an equivalent volume of saline. The post-treated group (n = 7) was given TRH at the nadir of the hypotensive response following endotoxin to duplicate published protocols. 5 min after endotoxin blood pressure and cardiac output were significantly higher in the post and pre-treatment groups, respectively, compared to the untreated group. There were no differences at other times. Systemic vascular resistance was not affected by either treatment mode at any time. TRH treatment following endotoxin resulted in transient increases in heart and respiration rates and decreased central venous pressure during the first 30 min. Metabolic function indicated by measurements of glucose, lactate, hematocrit, pH, PO2, and PCO2 at 60 and 240 min after endotoxin was not modified by TRH. The hemorrhagic small intestine characteristic of this model was not improved by either treatment mode. Mortality rates at 4 h after endotoxin were 20% for the untreated, 40% for the pre-treated, and 43% for the post-treated. These results suggest TRH exerts early transient effects on cardiovascular responses evoked by endotoxin in the conscious rat but no lasting beneficial effects were found to support the use of TRH as a mono-therapy for endotoxemia.

Animals↗
PubMed1990

An assessment of plasma histamine concentrations during documented endotoxic shock.

Recent reviews of the literature involving histamine release during sepsis and endotoxemia have reported that the majority of the studies are inconclusive due to inadequate assays or experimental protocols. In a controlled experimental setting we have employed a specific and sensitive radioenzymatic assay to determine plasma histamine concentrations temporally during documented endotoxin-induced shock in the conscious rat. Cardiovascular and metabolic measurements for the control group (n = 7) were normal during the study period. Endotoxin (n = 8, LD/90-24 hrs.) induced an early transient hypotensive episode and increase in systemic vascular resistance and a sustained decrease in cardiac index and central venous pressure and increase in heart and respiratory rates. Hypoglycemia and hyperlacticemia were present at the end of the four-hour study period. The small intestine was severely hemorrhaged in all animals given endotoxin. Histamine concentrations for the control group were unchanged throughout the study period. Contrary to previous reports, this model of endotoxemia revealed unchanging histamine concentrations during the first 30 minutes which were temporally coincident with the characteristic early hypotensive episode evoked by endotoxin. The histamine concentrations at 60 and 240 minutes following endotoxin were increased two and three-fold, respectively, compared to the control group. Three of the 8 rats given endotoxin died before four hours; histamine concentrations in plasma taken when death appeared certain were 42, 91, and 174, compared to the control value of approximately 8 ng/ml. There was no clear association of the increases in plasma histamine with any of the parameters measured in this study: however, established histamine effects may have been masked by the pre-existing effects of other mediators known to be active during endotoxemia. In separate groups of animals endotoxin (n = 5) elicited early increases in plasma concentrations of norepinephrine (5-fold) and epinephrine (8-fold) that remained elevated for the 4-hour study period while the control group (n = 4) remained stable. This study establishes that a) plasma histamine concentrations are increased during endotoxemia, b) plasma histamine is not elevated during the initial hypotension episode following endotoxin, c) plasma histamine increases during the progression of endotoxic shock, and d) plasma histamine concentrations are extremely high prior to death.

Animals↗
PubMed1989

Respiratory and cardiovascular effects of thyrotropin-releasing hormone as modified by isoflurane, enflurane, pentobarbital and ketamine.

Thyrotropin-releasing hormone (TRH) possesses significant arousing and cardio-respiratory stimulant actions. The effects of a 2 mg/kg i.v. bolus dose of TRH on respiration and systemic hemodynamics were compared in conscious, freely-moving rats and during anesthesia with 4 different anesthetics. Fifty-four male Sprague-Dawley rats weighing 285 +/- 4 g (mean +/- S.E.M.) were divided into 5 groups: conscious, enflurane (2%), isoflurane (1.4%), pentobarbital (8 mg/kg/h i.v.), and ketamine (60 mg/kg/h i.v.). Anesthetized rats were intubated and breathed oxygen or anesthetic/oxygen spontaneously. Aortic blood pressure, heart rate, cardiac output, respiratory rate, arterial blood pH, blood gases, lactate and glucose were measured, and data were collected over a 20 min baseline period and for 130 min post-TRH. TRH increased respiratory rate in all groups; concomitant changes in arterial PCO2 indicated increased minute ventilation in the inhalation agent groups but not in the i.v. anesthetic groups or in the awake group. Significant respiratory depression in the enflurane group was rapidly reversed by TRH. The respiratory stimulant and arousing effects of TRH were smallest with ketamine anesthesia. The hemodynamic responses to TRH were consistent with a pattern of sympathoadrenalmedullary activation and were relatively uniform across groups despite anesthetic-induced alterations in baseline values. TRH or its analogues may prove useful as an analeptic in clinical anesthesia.

Animals↗
PubMed1985

The effects of H1 and H2 histamine receptor antagonists on the development of endotoxemia in the conscious, unrestrained rat.

This study was designed to use the H2 antagonist cimetidine and the H1 antagonist diphenhydramine alone and in combination to clarify the role of histamine in the development of endotoxin shock. The jugular vein and the carotid artery of male Sprague-Dawley rats were cannulated during enflurane anesthesia. After recovery, blood pressure, heart rate, and respiration rate were continuously monitored. Animals were pretreated with saline, a combination of the H1 and H2 receptor antagonists diphenhydramine (20 mg/kg) and cimetidine (80 mg/kg), or individual doses of diphenhydramine or cimetidine. After pretreatment an endotoxin bolus (40 mg/kg) was given. Arterial blood samples (0.35 ml) were taken before endotoxin and after endotoxin at 60 and 240 min for measurement of pH, PO2, PCO2, hematocrit, glucose, and lactate. Pathological examinations were made at 240 min. Four additional groups of animals (N = 10) were studied for the effect of each of the treatment modes on 24-hr survival rate. Treatment with cimetidine plus diphenhydramine prevented the endotoxin-induced blood pressure fall, increase in heart rate, and hypoglycemia; increased the 24-hr survival rate from 10 to 60%; and inhibited the small intestinal pathology found in control rats. Treatment with diphenhydramine alone produced similar results except that there was a gradual blood pressure decrease later in shock. The results obtained from the cimetidine-treated groups were much the same but there was a slight, transient decrease in blood pressure early after endotoxin and the survival rate was increased to 90%. These results demonstrate that in the conscious rat antagonism of the H1 and/or H2 receptors modifies hemodynamic and metabolic responses and the subsequent pathology, altering the course of endotoxin shock and survival. This study provides substantial evidence to implicate histamine as one of the key vasoactive mediators in the development of endotoxin shock.

Analysis of Variance↗
PubMed1977

Dose-related heart-rate, perceptual, and decisional changes in man following marihuana smoking.

Information processing was tested in 12 male subjects after smoking marihuana containing 0, 10, or 20 mg. of delta-9-tetrahydrocannabinol (THC) in three consecutive experimental sessions according to a Latin square protocol. Successful dose control was indicated both by the dose-related linear increase observed in heart rate and by preliminary assays of THC metabolites excreted in the urine. During tachistoscopic presentation of varying numbers of circles, statistically significant decrements in information processing occurred as a function of THC dosage. However, adding irrelevant information (triangles) to the display of circles eliminated effects of marihuana on accuracy of counting. Complex reaction times for oddity discrimination increased significantly only after the high dose. Nonetheless, both the social and high doses inappropriately inhibited the general tendency to respond to changing stimuli during oddity discrimination. Marihuana had no effect on field-dependence as measured by the Rod-and-frame test.

Adult↗
PubMedDate not supplied

Behavioral hyperreactivity in the spontaneously hypertensive rat compared to its normotensive progenitor.

The spontaneously hypertensive rat (SHR) is an excellent model of essential hypertensive disease. Hyperreactivity has been postulated as a contributing factor in the development of high blood pressure in the SHR and in man. In the maturing organism recurring hypertensive stesss responses may promote permanent vascular changes and result in a fixed hypertension. Simple behavioral activity and emotionality rating scales were used to compare a large number of SHR with equally large groups of closely-related and distantly-related normotensive rats. As predicted, the SHR were clearly more active and emotional than their ancestral Wistar Kyoto (WKY) strain. However, the distantly-related normotensive Wistars did not differ from the SHR in either activity or emotionality. These results indicate that behavior and hypertension are not necessarily related in the rat. Nonetheless, the behavioral differences between the SHR and their closest genetic match, the WKY, suggest that arousal and blood pressure levels may be causally linked in this case of naturally occurring hypertension.

Animals↗
PubMedDate not supplied

Lifelong hyperarousal in the spontaneously hypertensive rat indicated by operant behavior.

Instrumental conditioning techniques were used to obtain objective evidence of differences in behavioral arousal between the spontaneously hypertensive rat (SHR) and the normotensive ancestral Wistar Kyoto (WKY) strain. Subjective emotionality ratings previously indicated that the genetically hypertensive rats were more active and aggressive than their normotensive cousins. In a lengthy series of operant conditioning sessions using a small number of adult female SHR and WKY rats, hyperarousal in the SHR was confirmed by their significantly higher response outputs on either response contingent or time contingent schedules of reinforcement. Conditioned emotionality tests during this series of experiments also suggested hyperarousal and aggressiveness in the SHR, since the fear-conditioned stimulus suppressed bar-pressing in the SHR much less than in the WKY. Further experiments with young prehypertensive SHR rats provided the same evidence of hyperresponsivity in the SHR compared to the WKY strain. Furthermore, these young SHR failed to develop hypertension by the end of the study (14 weeks of age), while their nonconditioned SHR cousins had become clearly hypertensive by the same age. This suggests that factors related to the conditioning methods modified the development of high blood pressure in this animal model of essential hypertension.

Age Factors↗