Showing papers in "American Journal of Physiology-regulatory Integrative and Comparative Physiology in 1993"
TL;DR: After eccentric exercise ultrastructural damage to skeletal muscle is associated with neutrophil infiltration and muscle IL-1 beta accumulation and positively correlated to intracellular Z-band damage.
Abstract: Nine untrained men (22-29 yr) performed 45 min of downhill running (16% incline, 70% of maximum heart rate). Needle biopsies of the vastus lateralis were performed before, 45 min after, and 5 days after exercise. Immunohistochemical staining of muscle cross sections revealed a 135% increase in muscle interleukin-1 beta (IL-1 beta) immediately after and a 250% increase (P < 0.03) 5 days after exercise. Using a rating scale (0-3) for the presence of neutrophils, light microscopic examination showed a significant accumulation of neutrophils in muscle biopsies taken 45 min after and 5 days after exercise [before: 0.5 +/- 0.2, 45 min after: 1.5 +/- 0.3 (P < 0.01), and 5 days after: 1.2 +/- 0.2 (P < 0.04)]. In addition, electron microscopic analysis showed an increase in the percentage of damaged Z-bands relative to total Z-bands [before: 4.8 +/- 3.5%, 45 min after: 32.5 +/- 8.6% (P < 0.05), and 5 days after: 14.1 +/- 3.2%]. Neutrophil accumulation was positively correlated to intracellular Z-band damage (rho = 0.66, P < 0.001). Immunohistochemical staining for IL-1 beta was related to neutrophil accumulation in muscle (rho = 0.38, P < 0.06) and to plasma creatine kinase levels (rho = 0.416, P < 0.04). These data indicate that after eccentric exercise ultrastructural damage to skeletal muscle is associated with neutrophil infiltration and muscle IL-1 beta accumulation.
443 citations
TL;DR: Differences persisted during 24-h periods of enforced wakefulness in constant dim light, indicating that prior exposure to the two regimes induced abiding changes in the timing of internal processes, such as circadian pacemaker oscillations, that control the durations of nocturnal and diurnal periods of the rhythms.
Abstract: In animals, circadian pacemakers respond to seasonal changes in day length by making corresponding adjustments in the durations of diurnal and nocturnal periods of circadian rhythms; these adjustme...
296 citations
TL;DR: The alterations in fatty acid composition, vitamin E, and lipid conjugated dienes in muscle and in urinary lipid peroxides in controls after eccentric exercise are consistent with the concept that vitamin E provides protection against exercise-induced oxidative injury.
Abstract: The protective effect of vitamin E supplementation on exercise-induced oxidative damage was tested in 21 male volunteers. Nine young (22-29 yr) and 12 older (55-74 yr) sedentary male subjects parti...
253 citations
TL;DR: The results suggest that the life-threatening condition of prolonged sleep deprivation is a breakdown of host defense against indigenous and pathogenic microorganisms.
Abstract: Prolonged sleep deprivation in rats causes an unexplained hypercatabolic state, secondary malnutrition symptoms, and mortality. The nature of the vital impairment has long been a mystery. Its determination would help to elucidate the type of organic dysfunction that sleep prevents. There are no gross detectable disturbances in intermediary metabolism, clinical chemistry, or hematological indexes that provide substantial clues to the mediation of sleep-deprivation effects. Furthermore, postmortem examinations reveal no systematic morphological or histopathological findings. Taken together, the cachexia and the absence of evidence of structural damage or organ dysfunction pointed to involvement of a regulatory system that was diffuse, possibly the immune system. Blood cultures revealed invasion by opportunistic microbes to which there was no febrile response. These results suggest that the life-threatening condition of prolonged sleep deprivation is a breakdown of host defense against indigenous and pathogenic microorganisms.
250 citations
TL;DR: Carotid chemoreceptor activation in rats elicits STP and LTF similar to that in cats; the vermis may play a role in LTF.
Abstract: The objectives were to determine 1) respiratory responses to carotid chemoreceptor inputs in anesthetized rats and 2) whether the cerebellar vermis plays a role in these responses. A carotid sinus nerve was stimulated (20 Hz) with five 2-min trains, each separated by approximately 3 min. During stimulation, respiratory frequency (f), peak amplitude of integrated phrenic nerve activity (integral of Phr), and their product (f x integral of Phr) immediately increased. As stimulation continued, integral of Phr progressively increased to a plateau [short-term potentiation (STP)], but f and f x integral of Phr decreased [short-term depression (STD)] to a value still above control. Upon stimulus termination, integral of Phr progressively decreased but remained above control; f and f x integral of Phr transiently decreased below baseline. After the final stimulation, integral of Phr remained above control for at least 30 min [long-term facilitation (LTF)]. Repeated 5-min episodes of isocapnic hypoxia also elicited STP, STD, and LTF. Vermalectomy lowered the CO2-apneic threshold and eliminated LTF. In conclusion, carotid chemoreceptor activation in rats elicits STP and LTF similar to that in cats; the vermis may play a role in LTF. A new response, STD, was observed.
223 citations
TL;DR: Fifty percent of aborted-SIDS infants showed greater ApEn instability across quiet sleep than any normal infant exhibited, suggesting that autonomic regulation of heart rate occasionally becomes abnormal in a high-risk subject.
Abstract: Approximate entropy (ApEn), a mathematical formula quantifying regularity in data, was applied to heart rate data from normal and aborted-sudden infant death syndrome (SIDS) infants. We distinguished quiet from rapid-eye-movement (REM) sleep via the following three criteria, refining the notion of REM as more "variable": 1) REM sleep has greater overall variability (0.0374 +/- 0.0138 vs. 0.0205 +/- 0.0090 s, P < 0.005); 2) REM sleep is less stationary (StatAv = 0.742 +/- 0.110) than quiet sleep (StatAv = 0.599 +/- 0.159, P < 0.03); 3) after normalization to overall variability, REM sleep is more regular (ApEnsub = 1.224 +/- 0.092) than quiet sleep (ApEnsub = 1.448 +/- 0.071, P < 0.0001). Fifty percent of aborted-SIDS infants showed greater ApEn instability across quiet sleep than any normal infant exhibited, suggesting that autonomic regulation of heart rate occasionally becomes abnormal in a high-risk subject. There was an association between low ApEn values and aborted-SIDS events; 5 of 14 aborted-SIDS infants had at least one quiet sleep epoch with an ApEn value below the minimum of 45 normal-infant ApEn values.
212 citations
TL;DR: It is demonstrated that heat pretreatments improved long-term survival fivefold in a mouse endotoxin model and this was correlated with the production of HSPs, suggesting a possible role for HSP72 in the protective effect.
Abstract: Recently, investigators have reported that heat shock proteins (HSPs) can protect isolated cells from cytotoxicity induced by two important mediators of sepsis: interleukin-1 and tumor necrosis factor. The present study was undertaken to examine the hypothesis that transient whole body hyperthermia could decrease mortality from subsequent challenge with gram-negative endotoxin. We demonstrate that heat pretreatments improved long-term survival fivefold in a mouse endotoxin model and this was correlated with the production of HSPs. There was a marked difference in individual organ expression of the inducible 72-kDa heat shock protein (HSP72). Heat treatments caused significant HSP72 formation in lung, liver, kidney, and small intestine, but much lesser formation in heart, brain, and abdominal wall muscle. Additional experiments demonstrated that the protective effect of hyperthermic treatments against an endotoxin challenge occurred early, i.e., 1 and 2 h after heating, was maximal at 12 h, and had significantly diminished by 48 h. The formation and decay of HSP72 demonstrated a time course that paralleled the survival curve from endotoxin challenge, thus suggesting a possible role for HSP72 in the protective effect. Surprisingly, and in contrast to studies reported in incubated cells, endotoxin alone did not cause significant formation of HSP72 in vivo.
203 citations
TL;DR: The lipid gain in EPI was due to fat cell hypertrophy alone, whereas RP showed bothhypertrophy and hyperplasia, and there was no difference in the LM or in lipid gains specifically caused by HF feeding of SC and MES between the HF groups.
Abstract: Because dietary n-3 polyunsaturated fatty acids (n-3 PUFA) from fish oils have profound effects on lipid metabolism, we examined whether they influence the growth of adipose tissue at different locations in growing rats. Rats were fed for 4 wk on high-fat (HF) diets (20% fat) containing very low (L), medium (M), and high (H) amounts of n-3 PUFA but similar amounts of saturated fatty acids and n-6 PUFA. A fourth group was fed a standard laboratory diet (control group) to estimate changes in adipose tissue mass related to growth. At the end of the dietary treatment, the lipid mass (LM) of the four major adipose depots (subcutaneous, SC; mesenteric, MES; retroperitoneal, RP; epididymal, EPI) and total adiposity were significantly higher in each of the three HF groups than in the control group. The lipid gain in EPI was due to fat cell hypertrophy alone, whereas RP showed both hypertrophy and hyperplasia. Energy intake, fatty acid excretion, and body mass were the same in the three groups fed HF diets. Similarly, there was no difference in the LM or in lipid gains specifically caused by HF feeding of SC and MES between the HF groups. In contrast, the LM of RP was significantly lower in the H than in the L and M groups (50 and 30%, respectively). The LM of EPI was also 30% lower in the H than in the L group.(ABSTRACT TRUNCATED AT 250 WORDS)
191 citations
TL;DR: Stimulation of carotid body chemoreceptors by saline saturated with 100% CO2 elicited an increase in mean arterial pressure, respiratory rate, tidal volume, and minute ventilation, and microinjections of L-glutamate increased VE.
Abstract: Stimulation of carotid body chemoreceptors by saline saturated with 100% CO2 elicited an increase in mean arterial pressure, respiratory rate, tidal volume, and minute ventilation (VE). Microinjections of L-glutamate into a midline area 0.5-0.75 mm caudal and 0.3-0.5 mm deep with respect to the calamus scriptorius increased VE. Histological examination showed that the site was located in the commissural nucleus of the nucleus tractus solitarii (NTS). The presence of excitatory amino acid receptors [N-methyl-D-aspartic acid (NMDA); kainate, quisqualate/alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and trans 1-amino-cyclopentane-trans-1,3-dicarboxylic acid (ACPD)] in this area was demonstrated by microinjections of appropriate agonists. Simultaneous blockade of NMDA and non-NMDA receptors by combined injections of DL-2-aminophosphonoheptanoate (AP-7; 1 nmol) and 6,7-dinitro-quinoxaline-2,3-dione (DNQX; 1 nmol) abolished the responses to stimulation of carotid body on either side. Combined injections of AP-7 and DNQX did not produce a nonspecific depression of neurons because the responses to another agonist, carbachol, remained unaltered. Inhibition of the neurons in the aforementioned area with microinjections of muscimol (which hyperpolarizes neuronal cell bodies but not fibers of passage) also abolished the responses to subsequent carotid body stimulation on either side.(ABSTRACT TRUNCATED AT 250 WORDS)
188 citations
TL;DR: The plasma membrane ion gradient is maintained during anoxia, and since the activity of the Na(+)-K( +)-ATPase decreases, the influx of ions must also decrease.
Abstract: The maintenance of ion gradients across the plasma membrane by the Na(+)-K(+)-ATPase has been shown to utilize a large fraction of the total cellular energy demand. In view of the importance of ion...
181 citations
TL;DR: Data demonstrate that, in rats, signals produced by combined gastric load and exogenous CCK administration are integrated peripherally and interact synergistically, and suggest that signals arising from the vagus may provide sufficient information for the synergistic inhibition of food intake produced by combinations of gastric loads and exogeneous CCK.
Abstract: Both gastric preloads and exogenous cholecystokinin (CCK) administration inhibit food intake, and combinations of preloads and CCK suppress feeding to a greater degree than either stimulus delivered alone. A role for the vagus nerve in mediating CCK's inhibition of food intake has been proposed, and gastric vagal afferent fibers respond to both gastric loads and local CCK infusions. To examine whether combined load and CCK stimuli may synergistically augment gastric neural afferent activity at the level of the peripheral vagus, we have examined the gastric vagal afferent responses (n = 8) to a range of gastric saline loads (1, 2, and 3 ml) and exogenous close celiac arterial CCK (10 and 100 pmol) when administered alone or in combination. Gastric loads ineffective in eliciting a significant increase in vagal afferent activity when administered alone became effective when combined with doses of CCK that were subthreshold for the production of a vagal afferent response. Gastric loads that alone were effective in producing a significant vagal afferent response yielded an even greater response when administered in combination with both subthreshold and suprathreshold doses of CCK. These data demonstrate that, in rats, signals produced by combined gastric load and exogenous CCK administration are integrated peripherally and interact synergistically. These results suggest that signals arising from the vagus may provide sufficient information for the synergistic inhibition of food intake produced by combinations of gastric loads and exogenous CCK.
TL;DR: Rats and humans exhibit similar micturition dysfunctions after SCI (e.g., bladder-sphincter dyssynergia and impaired voiding), suggesting that the normal bursting EUS activity facilitates bladder emptying.
Abstract: Spinal cord injury (SCI) in humans results in inappropriate contractions of the external urethral sphincter muscle (EUS) during micturition (bladder-sphincter dyssynergia), leading to urinary retention. The major goal of this study was to determine whether SCI in rats has similar detrimental effects on micturition. After chronic SCI, urethan-anesthetized rats had a significantly (15-fold) increased bladder capacity and impaired voiding (31-fold increase in residual volume) compared with control rats. Bladder contractions in SCI rats were accompanied by abnormal tonic EUS electromyographic activity, whereas the EUS electromyograms of control rats exhibited a burst pattern (4-8 Hz) during voiding. Suppression of EUS activity with neuromuscular blockade did not improve the fraction of urine voided in SCI rats and reduced the fraction voided in control rats. Therefore, both tonic activity and complete quiescence of the rat's EUS appear to be detrimental to voiding, suggesting that the normal bursting EUS activity facilitates bladder emptying. In summary, rats and humans exhibit similar micturition dysfunctions after SCI (e.g., bladder-sphincter dyssynergia and impaired voiding).
TL;DR: The purpose of this study was to determine whether glucocorticoids exert inhibitory feedback on lipopolysaccharide (LPS)-induced fever, stress-induced fever (exposure to an open field), and plasma concentrations of interleukin-6 (IL-6)-like and tumor necrosis factor-alpha (TNF)-like activity in biotelemetered rats.
Abstract: The purpose of this study was to determine whether glucocorticoids exert inhibitory feedback on lipopolysaccharide (LPS)-induced fever, stress-induced fever (exposure to an open field), and plasma concentrations of interleukin-6 (IL-6)-like and tumor necrosis factor-alpha (TNF)-like activity in biotelemetered rats. Injections of LPS (50 micrograms/kg) or exposure to an open field (30 min) led to significantly higher fevers in adrenalectomized (ADX) rats than in sham-ADX rats. To test the hypothesis that higher fevers were specifically the result of an absence of glucocorticoids, the glucocorticoid antagonist RU 38486 (20 mg/kg) was administered orally to rats with intact adrenal glands. The RU 38486-treated rats had higher plasma concentrations of IL-6-like activity and developed significantly higher fevers than did vehicle-treated rats. Rats injected intracerebroventricularly with 10 ng RU 38486 also developed higher fevers. Other ADX animals were implanted subcutaneously with replacement corticosterone pellets before exposure to an open field or injection with LPS. In response to an open field or injection with LPS, ADX animals implanted with replacement pellets that mimic plasma concentrations of corticosterone observed in stressed animals (100-mg pellets) developed fevers that were significantly lower than those observed in ADX rats given placebo pellets, but that were not different from fevers in sham-ADX rats given placebo pellets. ADX animals implanted with replacement pellets that mimic plasma concentrations of corticosterone observed in unstressed animals (25-mg pellets) developed fevers that were significantly higher than those observed in sham-ADX rats given placebo pellets, but that were not different from fevers in ADX rats given placebo pellets.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: These experiments indicate that 1) the firing rate of most pontine noradrenergic cells is increased by peripheral chemoreceptor stimulation, and 2) pontines receive afferent information of a respiratory nature, possibly from their ventrolateral medullary inputs.
Abstract: Sympathetic nerve discharge (SND), phrenic nerve discharge (PND), and unit activity of locus ceruleus (LC) and of putative A5 noradrenergic cells were recorded in vagotomized rats anesthetized with urethan. SND was activated by stimulation of carotid chemoreceptors with hypoxia (N2 inhalation, 5-15 s or 12% O2 inhalation, 2-5 min) and displayed a prominent central respiratory modulation during the hypoxic challenge (postinspiratory pattern). LC cells were also activated by peripheral chemoreceptor stimulation. The discharge of most LC units (28 of 31) exhibited central respiratory modulation. 15 LC units had a postinspiratory pattern and 11 had an inspiratory one. Putative A5 cells were also excited by hypoxia and also displayed a clear central respiratory modulation (mostly postinspiratory pattern). These experiments indicate that 1) the firing rate of most pontine noradrenergic cells is increased by peripheral chemoreceptor stimulation, and 2) pontine noradrenergic neurons receive afferent information of a respiratory nature, possibly from their ventrolateral medullary inputs.
TL;DR: The first to demonstrate aberrant SCN firing patterns and a decrease in amplitude in old rats imply that aging could either disrupt coupling between SCN pacemaker cells or their output, or cause deterioration of the pacemaking properties of SCN cells.
Abstract: The basis of the decline in circadian rhythms with aging was addressed by comparing the patterns of three behavioral rhythms in young and old rats with the in vitro rhythm of neuronal activity in the suprachiasmatic nuclei (SCN), the primary circadian pacemaker. In some old rats, rhythms of body temperature, drinking, and activity retained significant 24-h periodicities in entraining light-dark cycles; in others, one or two of the rhythms became aperiodic. When these rats were 23-27.5 mo old they were killed, and single-unit firing rates in SCN brain slices were recorded continuously for 30 h. There was significant damping of mean peak neuronal firing rates in old rats compared with young. SCN neuronal activities were analyzed with reference to previous entrained behavioral rhythm patterns of individual rats as well. Neuronal activity from rats with prior aperiodic behavioral rhythms was erratic, as expected. Neuronal activity from rats that were still maintaining significant 24-h behavioral rhythmicity at the time they were killed was erratic in most cases but normally rhythmic in others. Thus there was no more congruence between the behavioral rhythms and the brain slice rhythms than there was among the behavioral rhythms alone. These results, the first to demonstrate aberrant SCN firing patterns and a decrease in amplitude in old rats, imply that aging could either disrupt coupling between SCN pacemaker cells or their output, or cause deterioration of the pacemaking properties of SCN cells.
TL;DR: It is demonstrated that CNP circulates in low picomolar concentrations and is potently vasoactive in vivo, suggesting a potential role in the regulation of vascular tone.
Abstract: Studies were performed in three groups of anesthetized dogs to compare the structurally related peptides atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) Group 1 (n = 5) and group 2 (n = 4) received intravenous infusions of CNP or ANP respectively at doses of 10 ngkg-1min-1 and 100 ngkg-1min-1 Group 3 (n = 5) received CNP intrarenally at doses of 1 ngkg-1min-1 and 5 ngkg-1min-1 Intravenous infusion of CNP resulted in a greater decrease in blood pressure when compared with ANP This marked decrease in blood pressure observed with CNP was associated with a significantly smaller increase in guanosine 3',5'-cyclic monophosphate (cGMP) In contrast, neither intravenous nor intrarenal administration of CNP was associated with natriuresis as observed with ANP The current study also demonstrates the presence of CNP immunoreactivity in canine plasma at low picomolar concentrations Further characterization by gel permeation chromatography demonstrated that circulating CNP immunoreactivity corresponds to the 22-amino acid form of the peptide In conclusion, this study demonstrates that CNP circulates in low picomolar concentrations and is potently vasoactive in vivo, suggesting a potential role in the regulation of vascular tone
TL;DR: The results indicate that food deprivation can affect the ingestive behavior of rats in ways that are not revealed by measuring volumetric intake alone and support the view thatfood deprivation increases the palatability of the test solutions.
Abstract: The effects of 17 h food deprivation and stimulation by five concentrations (0.05-0.8 M) of sucrose solutions on the licking behavior of rats were investigated. Food deprivation increased the intake of the three lowest concentrations (0.05, 0.1, and 0.2 M) but had no effect on the volume ingested of the two highest concentrations (0.4 and 0.8 M). Food deprivation had no significant effect on the duration of the meals of any of the sucrose solutions; rather it affected the rate of ingestion. In those cases where food deprivation did affect volume intake, it did so by increasing the initial rate of ingestion. Although food deprivation had no effect on the volume ingested of the two strongest concentrations of sucrose, it nevertheless affected the ingestive behavior by increasing the duration of the sustained periods of bursts of licking and decreasing their number. Deprivation also significantly decreased the rate of licking within these sustained bouts of licking. The results indicate that food deprivation can affect the ingestive behavior of rats in ways that are not revealed by measuring volumetric intake alone. The data also support the view that food deprivation increases the palatability of the test solutions.
TL;DR: Experiments were designed to examine the role of endothelin (ET) receptors, specifically ETA receptors, in mediating the renal vasoconstrictor effects of ET-1 in anesthetized Sprague-Dawley rats.
Abstract: Experiments were designed to examine the role of endothelin (ET) receptors, specifically ETA receptors, in mediating the renal vasoconstrictor effects of ET-1 in anesthetized Sprague-Dawley rats. Intravenous infusion of ET-1 at 25 pmol.kg-1 x min-1 for 60 min produced a significant increase in mean arterial pressure (20 +/- 7%) and decreases in renal plasma flow (-60 +/- 6%) and glomerular filtration rate (-47 +/- 6%). Renal vascular resistance was significantly increased from 17 +/- 1 mmHg.ml-1 x min.g kidney wt during control period to 54 +/- 11 mmHg.ml-1 x min.g kidney wt during the experimental period. A second group of rats was infused with both ET-1 and the specific ETA receptor antagonist BQ-123 (0.1 mg.kg-1 x min-1). ET-1-induced increases in mean arterial pressure were completely blocked by BQ-123 (the average change was -7 +/- 4%). However, the renal vasoconstrictor effects of ET-1 were not affected by the antagonist, since renal plasma flow and glomerular filtration rate were again significantly reduced (-54 +/- 4 and -56 +/- 6%, respectively). Once again, renal vascular resistance was significantly increased from 16 +/- 2 mmHg.ml-1 x min.g kidney wt during the control period to 33 +/- 5 mmHg.ml-1 x min.g kidney wt during the experimental period. In a third group, infusion of BQ-123 alone produced a significant decline in mean arterial pressure (-13 +/- 2%), with no significant changes in renal plasma flow or glomerular filtration rate, thus producing a significant decrease in renal vascular resistance (15 +/- 1 vs. 11 +/- 2 mmHg.ml-1 x min.g kidney wt).(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: It is demonstrated that impaired vasoconstriction in response to ET-1 in resistance arterioles of septic rats in vivo is reversed by NOS inhibition, suggesting an important role for nitric oxide as a mediator of refractory vasodilation in sepsis.
Abstract: Persistent vasodilation refractory to vasopressor agents is the hemodynamic abnormality characteristic of septic shock. Induction of nitric oxide synthase (NOS) by sepsis-induced cytokines has been hypothesized to play a pathogenetic role in this refractory vasodilation. To evaluate the mechanism of vasodilation in sepsis, we used in vivo videomicroscopy to measure responses of resistance arterioles (15-20 microm) to topical suffusion of the potent vasoconstrictor, endothelin-1 (ET-1), in rat cremaster muscle. Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. Responses to topically suffused ET-1 were assessed in septic and control rats before and after superfusion of the muscle with the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA). Sepsis produced a decrease in ET-1-induced vasoconstriction; the ET-1 concentration-response curve was shifted to the right in septic rats (P < 0.05). Contractions at ET-1 concentrations of 1, 10, and 100 nM were 20, 28, and 32%, respectively, of sham controls. Superfusion of the muscle with L-NMMA restored arteriolar responsiveness to ET-1 in the septic rats, significantly increasing arteriolar constriction at 1 and 10 nM. This effect was reversed with superfusion of excess L-arginine (1 mM). This study demonstrates that impaired vasoconstriction in response to ET-1 in resistance arterioles of septic rats in vivo is reversed by NOS inhibition. Taken together with previous studies showing sepsis-induced impairment of vasoconstriction with norepinephrine, a vasopressor with a mechanism of action different from ET-1, these findings suggest a generalized abnormality in the responsiveness of resistance arterioles in sepsis. Reversal of hyporesponsiveness to both of these vasopressor agents by NOS inhibition suggests an important role for nitric oxide as a mediator of refractory vasodilation in sepsis.
TL;DR: It is demonstrated that the AT2 receptors mediate a depressor response to ANG, which caused consistent decreases in pressure during AT1 receptor blockade and was inhibited during combined blockade of AT1 and AT1 receptors.
Abstract: Angiotensin (ANG) can produce a biphasic arterial pressure response, i.e., an increase followed by a decrease. Because ANG type 1 (AT1) receptors mediate the pressor response to ANG, we hypothesized that the opposing depressor action is mediated by the ANG type 2 (AT2) receptors. In thiobutabarbital (Inactin)-anesthetized rats bolus injections of angiotensin III (ANG III; 100, 300, and 1,000 ng/kg iv) produced peak increases in MAP at 20 s of 13.4 +/- 1.4, 20.1 +/- 2, and 27.5 +/- 2.8 mmHg and maximum decreases in pressure at 120 s of -6.3 +/- 1.5, -6.8 +/- 2.2, and -11.4 +/- 4.9 mmHg. During blockade of the AT1 receptors with DuP 753 (losartan, 10 mg/kg) the increases in MAP were eliminated (P < 0.01), whereas the depressor responses (-24.7 +/- 8, -32.8 +/- 9.3, and -42.0 +/- 10.0 mmHg) were significantly (P < 0.05) larger. In separate groups of rats, combined blockade of both AT1 and AT2 receptors eliminated all changes in MAP in response to ANG III, whereas blockade of AT2 receptors alone enhanced the pressor response to ANG III. During AT1 receptor blockade angiotensin II also caused consistent decreases in pressure, which were inhibited during combined blockade of AT1 and AT2 receptors. Therefore, we have demonstrated that the AT2 receptors mediate a depressor response to ANG.
TL;DR: The results reflect the cell's ability to suppress protein synthesis under anoxia in a manner that is coordinated with the reduction in total metabolic rate, and suggest that this change occurs through increasing concentrations of ADP and GDP, with concentrations of ATP and GTP and total purines remaining constant.
Abstract: Hepatocytes from the western painted turtle (Chrysemys picta bellii) display a profound metabolic suppression under anoxia. Fractional rates of protein synthesis fell by 92% during 12 h anoxia at 25 degrees C and were indistinguishable from the rate obtained with cycloheximide. Normoxic recovery saw protein synthesis increase to 160% of control values and return to normal after 2 h. The GTP-to-GDP ratio, implicated in the control of translation, fell threefold during anoxia. Purine nucleotide phosphate profiles suggest that this change occurs through increasing concentrations of ADP and GDP, with concentrations of ATP and GTP and total purines remaining constant. The normoxic cost for protein synthesis was calculated at 47.6 +/- 6.8 mmol ATP/g protein. Normoxic protein synthesis accounted for 36% of overall ATP turnover rates, close to the extent of O2 consumption inhibitable by cycloheximide (28%). Under anoxia, the proportion of ATP turnover utilized by protein synthesis did not change significantly. ATP turnover rates for urea synthesis reflected a similar pattern, falling 72% under anoxia. These results reflect the cell's ability to suppress protein synthesis under anoxia in a manner that is coordinated with the reduction in total metabolic rate.
TL;DR: In vivo microdialysis of the gigantocellular tegmental field (FTG) was performed in 10 adult male cats while respiration was being measured and results demonstrate a simultaneous time course of enhanced ACh release in the FTG and respiratory rate depression.
Abstract: The present study examined the hypothesis that cholinergic neurons in the pedunculopontine tegmental nucleus (PPT) can cause the release of acetylcholine (ACh) in the pontine reticular formation and contribute to respiratory depression. In vivo microdialysis of the gigantocellular tegmental field (FTG) was performed in 10 adult male cats while respiration was being measured. In four intact, unanesthetized cats these measurements were obtained during states of quiet wakefulness and during the rapid eye movement (REM) sleeplike state caused by FTG microinjections of carbachol. The results demonstrate a simultaneous time course of enhanced ACh release in the FTG and respiratory rate depression. In six barbiturate-anesthetized cats similar measurements were obtained while PPT regions containing NADPH-positive neurons were electrically stimulated. PPT stimulation caused increased ACh release in the FTG and caused respiratory rate depression. Together, these findings are consistent with the hypothesis of a causal relationship between ACh release in the FTG and respiratory depression.
TL;DR: Results suggest that changes in resistance in the postglomerular circulation of deep nephrons are responsible for the poor autoregulation of medullary blood flow in volume expansion despite well Autoregulated cortical blood flow.
Abstract: The present study examined the autoregulation of blood flow in different regions of the renal cortex and medulla in volume-expanded or hydropenic anesthetized rats. Blood flow was measured in the whole kidney by electromagnetic flowmetry, in the superficial cortex with implanted fibers and external probes for laser-Doppler flowmetry, and in the deep cortex and inner and outer medulla with implanted fibers for laser-Doppler flowmetry. At renal perfusion pressure > 100 mmHg, renal blood flow, superficial cortical blood flow, and deep cortical blood flow were all very well autoregulated in both volume-expanded and hydropenic rats. Inner and outer medullary blood flow were also well autoregulated in hydropenia, but blood flow in these regions was very poorly autoregulated in volume-expanded animals. As renal perfusion pressure was decreased below 100 mmHg in volume-expanded and hydropenic animals, renal blood flow, superficial and deep cortical blood flow, and inner and outer medullary blood flow all decreased. The results of these experiments demonstrate that blood flow in both the inner and outer portions of the renal medulla of the kidney is poorly autoregulated in volume-expanded rats but well autoregulated in hydropenic animals. In contrast, blood flow in all regions of the renal cortex is well autoregulated in both volume-expanded and hydropenic animals. These results suggest that changes in resistance in the postglomerular circulation of deep nephrons are responsible for the poor autoregulation of medullary blood flow in volume expansion despite well autoregulated cortical blood flow.
TL;DR: In this study, electrophysiological single unit recordings are utilized to evaluate the effects of nonpeptidergic angiotensin II (ANG II) antagonists on neural responses of hypothalamic paraventricular nucleus (PVN) neurons to either electrical stimulation in subfornical organ (SFO) or direct application of ANG II.
Abstract: In this study, we have utilized electrophysiological single unit recordings to evaluate the effects of nonpeptidergic angiotensin II (ANG II) antagonists on neural responses of hypothalamic paraventricular nucleus (PVN) neurons to either electrical stimulation in subfornical organ (SFO) or direct application of ANG II. Electrical stimulation (200-400 microA; 0.1 ms) in the SFO resulted in excitatory responses in 36 of 50 PVN neurons tested. Peristimulus histogram analysis of such excitatory effects demonstrated latencies of < 30 ms and variability of response times of approximately 50 ms in 14 of these 36 neurons. In view of previous anatomic and electrophysiological studies such inputs were therefore considered to be monosynaptically mediated by direct neural inputs from the SFO. The remaining 22 cells excited by such SFO stimulation showed responses of longer latency and duration suggestive of a different underlying synaptic mechanism. Local pressure ejection of ANG II into the PVN resulted in increased neural activity in 50% (9 of 18) of the neurons tested. After systemic (3 mg/kg iv) or local (2 x 10(-2) M; 1-25 s; 2-40 psi) microinjection of the nonpeptidergic angiotensin II1 (AT1) receptor antagonist losartan, SFO excitations were attenuated in 63.9% (23 of 36) of the PVN neurons tested, such pharmacologically blocked excitatory responses being reduced by 68.3 +/- 5.2% from control stimulation effects (P < 0.001). Similar losartan-induced attenuations of both short latency (presumed monosynaptic) (50.0%) and longer latency (72.7%) responses were observed. In addition, losartan also abolished the excitatory effects of local administration of ANG II on 77.8% (7 of 9) of ANG II-sensitive neurons in PVN tested.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: In this article, the effects of pioglitazone, an agent that increases insulin sensitivity, on the development of hypertension in the Dahl salt-sensitive (Dahl-S) rat and in the one-kidney, one-clip Sprague-Dawley rat were evaluated.
Abstract: Hypertension is frequently associated with insulin resistance. We evaluated the effects of pioglitazone, an agent that increases insulin sensitivity, on the development of hypertension in the Dahl salt-sensitive (Dahl-S) rat and in the one-kidney, one-clip Sprague-Dawley rat. We also evaluated the effects of pioglitazone on growth of cultured preglomerular renal arteriolar smooth muscle cells. In Dahl-S rats fed a 3% NaCl diet, tail systolic blood pressures and direct arterial pressures were lower (P < 0.05) in pioglitazone-treated (20 mg/kg daily by gavage for 3 wk) than in control rats (n = 10 rats/group). In one-kidney, one-clip Sprague-Dawley rats, systolic blood pressures were also lower in pioglitazone-treated animals (P < 0.0001). In vitro, proliferation of arteriolar smooth muscle cells was stimulated (P < 0.01) by insulin, epidermal growth factor (EGF), and fetal calf serum (FCS); pioglitazone (5 microM) reversibly inhibited (P < 0.01) insulin-, EGF-, and FCS-induced proliferation. Pioglitazone (0.01-100 microM) also inhibited insulin- (1 mU/ml), EGF- (100 ng/ml), and 5% FCS-induced [3H]thymidine incorporation in a concentration-dependent manner (P < 0.01). Thus pioglitazone attenuated the development of hypertension in the Dahl-S rat and the one-kidney, one-clip rat. The ability of pioglitazone to inhibit growth of vascular smooth muscle may contribute to its hypotensive effect.
TL;DR: Antioxidant defenses appear to be part of the adaptive machinery for reptilian tolerance of freezing and anoxia, and H2O2- and O2(-)-detoxification systems may be activated in preparation for possible oxygen free radical overgeneration during thawing or reoxygenation.
Abstract: The garter snake Thamnophis sirtalis parietalis can readily tolerate several hours of freezing or anoxia exposure Both stresses halt oxygen availability to tissues and to endure these stresses snakes must cope with potential oxidative stress arising as a result of the ischemic/anoxic condition followed by reperfusion of aerated blood during recovery To determine whether antioxidant defenses are important for freezing and anoxia survival, we monitored the activities of antioxidant enzymes and the levels of glutathione (GSH and GSSG) during freezing (5 h at -25 degrees C) and anoxia (10 h under N2 gas at 5 degrees C) exposures in three organs (muscle, liver, and lung) of snakes Freezing resulted in a significant rise in the activity of muscle and lung catalase (by 183 and 63%) and in muscle glutathione peroxidase (52%) Anoxia enhanced muscle and liver superoxide dismutase activities (by 59 and 118%) and also caused a 57% increase in muscle GSH levels The increase in muscle GSH concentration in anoxia (from 045 to 071 mM) could also stimulate muscle glutathione peroxidase activity in vivo by 15-fold because of its low affinity for GSH (Km = 11 mM) The ratio of GSSG/GSH was not affected by experimental state in any tissue, suggesting that oxidative stress did not occur during the freezing or anoxic exposure Rather, H2O2- and O2(-)-detoxification systems may be activated in preparation for possible oxygen free radical overgeneration during thawing or reoxygenation Antioxidant defenses appear to be part of the adaptive machinery for reptilian tolerance of freezing and anoxia
TL;DR: Both functional and radioligand binding studies suggest that the receptor is different from the classical mammalian AT1 and AT2 receptors.
Abstract: Angiotensin II acts as a growth factor in the cardiovascular system and has been implicated in angiogenesis. The existence of at least two types of angiotensin II receptors, the AT1 and the AT2 receptors, has been suggested by ligand binding studies. We used three different AT receptor antagonists to study the receptor mediating angiotensin II-induced angiogenesis in the chorioallantoic membrane (CAM) of the chick embryo. Angiotensin II caused pronounced angiogenesis of pre- and postcapillary vessels of 30-40%. This response could only be blocked by adding the peptidergic AT2 antagonist CGP-42112A. The nonpeptidergic AT2 antagonist PD123319 and AT1 antagonist losartan (DuP 753) were not effective. In addition, we used radioligand binding studies with a range of ligands to define the nature of the receptor. Our results show a high density of specific single class AT receptor with a total number of binding sites of 1,190 fmol/mg protein and an affinity constant for angiotensin II of 2.7 nM. The inhibitory concentrations (IC50) for CGP-42112A, PD 123319 and losartan were 724, > 100,000, and 59,000 nM, respectively. Our studies suggest that these binding sites act as receptors for angiotensin II-induced angiogenesis. Both functional and radioligand binding studies suggest that the receptor is different from the classical mammalian AT1 and AT2 receptors.
TL;DR: Despite their lack of brown adipose tissue, 6-wk-old cold-acclimated muscovy ducklings exhibit nonshivering thermogenesis (NST) in the cold, which is estimated by measuring leg muscle blood flow and arteriovenous difference in oxygen content across the leg, enabling an estimation of muscle O2 consumption.
Abstract: Despite their lack of brown adipose tissue, 6-wk-old cold-acclimated muscovy ducklings (4 degrees C; CA) exhibit nonshivering thermogenesis (NST) in the cold. To determine the site of this NST, the regional distribution of blood flow was measured by the microsphere method in the thermoneutral zone (25 degrees C) and during acute exposure to cold (8 degrees C). Ducklings reared at thermal neutrality (TN), which use shivering to produce extra heat in the cold, were compared with CA ducklings, which substitute NST for shivering. Further, the contribution of skeletal muscle thermogenesis to the increased heat production in the cold was estimated by measuring leg muscle blood flow and arteriovenous difference in oxygen content [(a-v)O2] across the leg, enabling an estimation of muscle O2 consumption. During cold exposure, a similar increase in total leg muscle blood flow occurred in TN and CA ducklings (+127 and +130% respectively), while hepatic arterial blood flow increased less (+56 to +37%, respectively). This rise in blood flow was accounted for by an increase in cardiac output, which was smaller in CA than in TN ducklings, and in both groups by a redistribution of blood flow to the most thermogenic organs (skeletal muscles and liver). The (a-v)O2 across the leg was not changed by cold exposure, indicating that the increase in leg muscle O2 consumption resulted mainly from the increase in blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Syrian hamsters fitted with guide cannulas stereotaxically aimed at the suprachiasmatic nuclei were housed in constant darkness in cages equipped with running wheels and received 300-nl injections of either vehicle, CNQX, or MK-801 into the region of the SCN 5 min before a brief light exposure.
Abstract: Syrian hamsters were fitted with guide cannulas stereotaxically aimed at the suprachiasmatic nuclei (SCN) and housed in constant darkness in cages equipped with running wheels. Animals received 300-nl injections of either vehicle, CNQX, or MK-801 into the region of the SCN 5 min before a brief (10 min at 20 lx) light exposure. Local administration of either 1 mM CNQX or 1 mM MK-801 at circadian time (CT) 18 significantly inhibited light-induced phase advances (vehicle = 52 +/- 9 min; CNQX = 12 +/- 7 min; MK-801 = 12 +/- 5 min; P < 0.05 relative to vehicle+light group). The effects of both drugs were reversible and dose related. Injection of 1 mM MK-801 at CT13.5 resulted in a 71% inhibition of light-induced phase delays (vehicle = -51 +/- 6 min; MK-801 = -15 +/- 5 min; P < 0.05), while CNQX failed to significantly inhibit light-induced phase delays (-39 +/- 10 min). Local administration of either 1 mM CNQX or MK-801 into the SCN region reduced the number of Fos-immunoreactive cells relative to vehicle-injected controls by approximately 32 and 44%, respectively (vehicle = 951 +/- 79; CNQX = 643 +/- 135, P < 0.05; MK-801 = 533 +/- 143, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: In this article, the suprachiasmatic nucleus (SCN) was found to serve as an inhibitory system for corticosteroid secretion during the day in rats.
Abstract: The diurnal rhythm of corticosteroid secretion is controlled by the suprachiasmatic nucleus (SCN). In rats, plasma corticosteroid levels rise just before the onset of the activity period during the dark phase. Our previous results indicated that vasopressin as a neurotransmitter from the SCN inhibited corticosteroid secretion in the area of the paraventricular/dorsomedial nucleus of the hypothalamus. We hypothesized that during the day the SCN may serve as an inhibitory system for corticosteroid secretion. To investigate this possibility, intact and SCN-lesioned animals were exposed to mild stress in the morning and evening and their plasma corticosteroid levels were monitored. The results indicate that SCN-lesioned animals have higher morning corticosteroid levels and respond both in the morning and evening with higher corticosteroid levels after stress than do intact control animals. We conclude, therefore, that these results indicate an inhibitory role of the SCN on corticosteroid secretion. The apparent discrepancy with the reported stimulatory role of the SCN on adrenocorticotropic hormone secretion is discussed.