Biomedical subjects

J T Stitt

Publications and source records attributed to J T Stitt.

At least 19 recordsLinked to original sources

PubMed1998

Production and absorption of nitric oxide gas in the nose.

Some nitric oxide gas (NO) produced in the sinuses and nasal cavity is absorbed before leaving the nose. To measure production and absorption, we introduced NO at different concentrations into one nostril while sampling the NO leaving the opposite nostril with the soft palate closed. The quantity of NO gas produced in six normal subjects (amount leaving plus the amount absorbed) averaged 352 nl/min and was the same at gas flows ranging from 8 to 347 ml/min and at 10 l/min. An absorption coefficient A was calculated by dividing the amount of NO absorbed by the concentration leaving the nose. A ranged from 17 ml/min at a nasal gas flow of 8 ml/min to an A of 24 ml/min at a nasal gas flow of 347 ml/min. The calculated rates of production and absorption did not change when gas flow rate was increased, suggesting diffusion equilibrium. The amount of uptake of NO in the nasal mucosa can be explained by its solubility coupled with tissue and blood reactivity.

Absorption↗

PubMed1997

Exhalation of gaseous nitric oxide by rats in response to endotoxin and its absorption by the lungs.

Rats injected with a lipopolysaccharide endotoxin produce detectable concentrations of nitric oxide gas (NO) in the expired air within 60 min. The concentration of NO reaches a plateau at 3 h. Production of the NO is dose dependent on lipopolysaccharide, and at a dose of 1 mg/kg i.v., lipopolysaccharide alveolar concentrations of > 260 parts per billion are observed. NO synthase inhibitors suppress this NO production in response to endotoxin. Experiments were conducted to ascertain the site of origin of this NO and to measure the capacity of the lungs to absorb NO from alveolar air. Results indicate that the endotoxin-induced NO originates from within the lungs themselves and that the lungs have the capacity to absorb > 60% of NO that is presented to them. Lung tissues absorb approximately 44-47% of the NO load, blood carries away between 15 and 19%, while the remainder is exhaled in the expired air. It is proposed that the exhalation of NO might prove useful as an early biomarker for acute lung injury.

Animals↗

PubMed1996

Accidental hypothermia. When thermoregulation is overwhelmed.

The diagnosis of hypothermia must be entertained when patients present with unexplained mental status changes or arrhythmias. Prompt recognition and aggressive treatment of complications should reduce cold-related fatalities. The choice of an appropriate rewarming method must be individualized and depends on the severity of hypothermia and the patient's degree of hemodynamic tolerance.

Body Temperature Regulation↗

PubMed1995

Heatstroke and other heat-related illnesses. The maladies of summer.

The spectrum of heat-related illnesses ranges from simple syncope to life-threatening heatstroke. Persons of all ages can be affected. Heat edema, heat cramps, heat syncope, and heat exhaustion respond readily to simple management techniques. Treatment of heatstroke must include aggressive cooling, adequate fluid and electrolyte repletion, maintenance of adequate cardiovascular performance, and prompt correction of any related or resulting complications.

Diagnosis, Differential↗

PubMed1995

Disorders of temperature regulation.

A remarkably effective and efficient thermoregulatory apparatus enables humans to maintain a normal body temperature despite widely varying and changing environmental and internal thermal conditions. Nevertheless, extreme ambient cold or heat and exhaustive exercise stress can overwhelm these defenses, leading to dangerous hypothermia or hyperthermia, respectively.

Body Temperature Regulation↗

PubMed1994

A study of the mechanism of action of the mild analgesic dipyrone.

The mechanism of action for the mild analgesics is controversial. While some have proposed that they inhibit prostaglandin synthesis in the central nervous system to interfere with nociceptive mediators in the brain, others have proposed that they act directly on nociceptive neural pathways to produce analgesia. This class of drugs also possesses antipyretic activity. We examined the antipyretic effect of one such drug, dipyrone, because this might elucidate the mechanism of its analgesic activity. In rats implanted with a femoral vein catheter and a cannula guide tube aimed towards the organum vasculosum laminae terminalis (OVLT) in the brain, an i.v. injection of 2 micrograms/kg interleukin-1 beta (IL-1 beta) produced a fever of 0.38 +/- 0.07 degrees C while an injection of 20 ng prostaglandin E1 (PGE) into the OVLT produced a fever of 1.18 +/- 0.18 degrees C. Dipyrone (25 mg/kg, i.v.) decreased the IL-1 beta fever but had no effect on the PGE fever. After pretreatment with the immunoadjuvant, zymosan, the IL-1 beta fevers were enhanced to equal those induced by PGE. Only 0.1 micrograms/kg, i.v. IL-1 beta raised body temperature by 1.20 +/- 0.10 degrees C. An increased dose of dipyrone (50 mg/kg, i.v.) was required to attenuate this IL-1 beta fever; however, the PGE fever remained unaffected by this treatment with dipyrone. Thus, dipyrone treatment blocks IL-1 beta fever where synthesis of prostaglandin is a crucial step in the febrile process, but it has no effect on PGE fever where synthesis is bypassed. This suggests that dipyrone, probably through its active metabolites, inhibits prostaglandin synthesis to induce antipyresis and, by analogy, analgesia as well.

Animals↗

PubMed1991

Differential sensitivity in the sites of fever production by prostaglandin E1 within the hypothalamus of the rat.

1. The febrile sensitivity of male Sprague-Dawley rats to microinjections of prostaglandin E1 (PGE) was investigated at three different locations in the rostromedial hypothalamic region. These were the preoptic anterior hypothalamic area (PO-AH), the organum vasculosum laminae terminalis (OVLT) and the rostral third ventricle (3V). 2. Stainless-steel cannula guide tubes were implanted in the OVLT region of one group of animals, within the PO-AH area of a second group and into the third ventricle of a third group of rats. After their recovery, the febrile response of each group was tested to a variety of doses of PGE, each administered in a volume of 1 microliter sterile 0.9% saline, via a sterile cannula inserted into the implanted guide tubes. Metabolic, vasomotor and rectal temperature changes were monitored continuously for the duration of the fevers. 3. Surprisingly, not only did the introduction of PGE into the OVLT region produce fevers, but the sensitivity of this region to PGE in the production of fever greatly exceeded that of the PO-AH area and the third ventricle. Fevers produced by microinjection of PGE into the PO-AH and 3V were identical. 4. Doses of PGE as low as 0.5 ng injected into the OVLT produced fevers of 0.5 degrees C. The fever dose threshold for the OVLT region was one-fifth those of the PO-AH area and the 3V, and the slope of the OVLT dose-response curve was twice those of the PO-AH and the 3V dose-response curves. 5. This study demonstrates that there is an anatomically distinct, regional sensitivity in the febrile responsiveness to PGE within the hypothalamus. These results are interpreted as evidence that the site of action of PGE in the production of fever is located within or immediately adjacent to the OVLT region, rather than within the medial PO-AH neuropil as has been believed previously.

Alprostadil↗

PubMed1991

Calcium channel blockers inhibit endogenous pyrogen fever in rats and rabbits.

We have previously shown that febrile responses in both rats and rabbits are elicited by the intravenous injection of a semipurified endogenous pyrogen (EP) prepared from human monocytes. We are now presenting evidence that these febrile responses are mediated via activation of Ca2+ channels by EP. The febrile responses of male New Zealand White rabbits and Sprague-Dawley rats to a standard dose of EP were determined at their respective thermoneutral ambient temperatures. The animals were then treated with Ca2+ channel blocker verapamil (7.5 mg/kg iv) 30-60 min before the EP challenge. In every case the febrile response to EP was markedly attenuated after verapamil pretreatment, while administration of verapamil by itself had no detectable effect on body temperature. Another Ca2+ channel blocker, nifedipine (5 mg/kg iv), was shown to possess antipyretic activity in rats also. To localize where in the fever pathway these Ca2+ channel blockers were acting, we investigated the effect of verapamil at the same dose on fevers that were produced by microinjection of prostaglandin E (PGE) directly into the brain. These PGE fevers were unaffected by verapamil pretreatment, indicating that the antipyretic action of Ca2+ channel blockers occurs before the formation of PGE in response to EP stimulation. The most likely locus of action is the activation of the enzyme phospholipase A2, which regulates the production of arachidonic acid from cellular phospholipids in the prostanoid cascade.

Alprostadil↗

PubMed1991

Site of action of calcium channel blockers in inhibiting endogenous pyrogen fever in rats.

We have demonstrated that the Ca2+ channel blocker verapamil, administered intravenously, exerts an antipyretic effect on the febrile responses of rats to intravenously injected endogenous pyrogen (EP). We have also shown that the same intravenous dose of verapamil is ineffective in blocking fevers induced by the microinjection of exogenous prostaglandin E (PGE) into the organum vasculosum laminae terminalis (OVLT) of rats. Experiments were conducted to determine whether the site of this verapamil antipyresis was in the OVLT itself. The febrile responses of six male Sprague-Dawley rats to EP were determined at thermoneutrality. Verapamil (10 micrograms/rat) was microinjected directly into the OVLT, and the febrile responses to the EP dose were redetermined 15-30 min later. In every case the EP fevers were attenuated after verapamil pretreatment. Intra-OVLT injections of verapamil alone were without effect on body temperature. When the same dose of verapamil was injected into the OVLT 15 min before the injection of PGE into the same site, it had no effect on the ensuing PGE-induced fever. In view of the fact that less than 1/250th of the effective systemic dose of verapamil, when injected into the OVLT, was equally effective in blocking the EP fevers, we conclude that verapamil acts within the OVLT to block fever rather than peripherally. Furthermore, because verapamil administered into the OVLT does not block PGE fevers, it is unlikely that PGE produces fever by acting as a Ca2+ ionophore on hypothalamic neurons.

Animals↗

PubMed1990

Effects of cold and capsaicin desensitization on prostaglandin E hypothermia in rats.

Intraperitoneal injection of prostaglandin E1 (PGE) produces a transient hypothermia in rats that lasts 1-2 h. Rats exposed to an ambient temperature (Ta) of 26 degrees C displayed a decrease in rectal temperature (Tre) of 0.95 +/- 0.12 degrees C (SE) after injection with PGE (100 micrograms/kg ip). Hypothermia was produced mainly by heat losses, as indicated by increases in tail blood flow. At Ta of 4 degrees C, PGE produced a comparable fall in Tre of 1.00 +/- 0.14 degrees C. However, in the cold the hypothermia was caused solely by decreases in heat production. These results indicate that the PGE-induced hypothermia is not the result of a peripheral vasodilation induced by the direct action of PGE on the tail vascular smooth muscle but is a central nervous system-mediated response of the thermoregulatory system induced by PGE within the peritoneal cavity. Capsaicin injected subcutaneously induces a transient hypothermia in rats because of stimulation of the warm receptors. If administered peripherally in sufficient amounts, it is reputed to impair peripheral warm receptors so that they become desensitized to the hypothermic effects of capsaicin. We measured PGE-induced hypothermias in rats both before and after capsaicin desensitization at Ta of 26 degrees C. Before desensitization the hypothermia was -1.14 +/- 0.12 degrees C, whereas after capsaicin treatment the PGE-induced hypothermia was -0.34 +/- 0.17 degrees C. The biological effects of capsaicin are diverse; however, based on current thinking about the thermoregulatory effects of capsaicin desensitization, our results indicate that peripheral warm receptor pathways are in some manner implicated in the hypothermia induced by intraperitoneal PGE.

Animals↗

PubMed1989

Immunoadjuvants enhance the febrile responses of rats to endogenous pyrogen.

The febrile responses of male Sprague-Dawley rats to a semipurified endogenous pyrogen produced from human monocytes were characterized by establishing fever dose-response curves. The animals were then injected intravenously with a number of substances that possessed the common properties of stimulating the phagocytic activity of the cells of the reticuloendothelial system and of acting as immunoadjuvants. The substances used were zymosan, lipopolysaccharide endotoxin, and muramyl dipeptide. Three days after any of these immunoadjuvants were injected, the fever sensitivity of the rats was remeasured. In each case, the slope of the fever dose-response curve tripled, and in some instances the response threshold for fever response was reduced by factors of three to eight. Furthermore, the maximum increase in body temperature produced by the endogenous pyrogen was more than doubled after immunoadjuvant treatment. By contrast latex beads, which are also phagocytized by the cells of the reticuloendothelial system but do not subsequently increase their phagocytic index nor do they enhance immune responses, had no effect on the fever sensitivity of rats in response to endogenous pyrogen. In the light of these findings, it is suggested that the febrile responses of rats to endogenous pyrogen are mediated in some manner by cells that possess some of the properties of reticuloendothelial cells. The location of these putative cells must be close to the circulation, because the immunoadjuvants used in this study were, for the most part, large molecular weight molecules that could not cross the blood-brain barrier easily.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1989

Enhancement of the febrile responses of rats to endogenous pyrogen occurs within the OVLT region.

The febrile responses of male Sprague-Dawley rats to a semi-purified endogenous pyrogen (EP) derived from human monocytes are markedly enhanced 3 days after the animals are intravenously injected with a variety of immunoadjuvants. The present study was designed to investigate the site within the body at which these substances act to produce this febrile-enhancing phenomenon. Stainless steel microinjection cannula guide tubes were implanted within the region of the organum vasculosum lamina terminalis (OVLT) of the rats and control febrile dose-response curves to EP were established. Minute quantities of the immunoadjuvants zymosan, lipopolysaccharide endotoxin, and the synthetic adjuvant peptide, muramyl dipeptide, were microinjected into the OVLT region and 3 days later, the febrile responses of the animals were retested. In each case the febrile response elicited by a standard dose of EP was more than doubled, the slope of the fever dose-response curve was tripled, and the dose threshold was lowered by a factor of four to five. These responses are identical with those produced when much larger amounts of these immunoadjuvants are injected intravenously, and, thus, we conclude that the site of action of these substances in enhancing fever in response to EP resides in or near the OVLT region. It is proposed that EP stimulates a type of reticuloendothelial cell residing within the OVLT to release prostaglandin E, which in turn crosses the blood-brain barrier to effect the changes in the thermoregulatory neurons of the preoptic anterior hypothalamic area that result in fever.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1987

A comparison of the febrile responses of the Brattleboro and Sprague-Dawley strains of rats to endotoxin and endogenous pyrogens.

The febrile responses of homozygous (di/di) Brattleboro rats, to both intravenous endogenous pyrogen and to a lipopolysaccharide endotoxin, were compared with those of normal Sprague-Dawley rats. There were no detectable differences between the fever curves of the two strains in response to endogenous pyrogen. Brattleboro rats, which are deficient in the neuropeptide arginine vasopressin (AVP), displayed fevers that were both qualitatively and quantitatively indistinguishable from those of normal Sprague-Dawley rats that do not suffer from congenital diabetes insipidus. It is concluded that the absence of AVP-containing cells in Brattleboro rats is not an important factor in determining the nature of their febrile responses to endogenous pyrogen. More remarkable, however, were the divergent febrile responses of the two strains to intravenously injected endotoxin. Normal rats displayed hypothermic responses, whereas the Brattleboro rats became febrile. By 2 h after the injection of endotoxin, body temperatures in both strains had returned to normal. Three hours after the rats had been exposed to endotoxin, both strains were found to be totally refractory to endogenous pyrogen. However, when both strains of rats were tested to endogenous pyrogen 3 days later, their febrile responses were more than double the magnitude of their initial control responses. These alterations in the febrile responsiveness of rats occurring at different times after the injection of endotoxin appear to be related to the effects that endotoxin has on the cells of the reticuloendothelial system, over the same time course.

Animals↗

PubMed1985

Hypothalamic thermosensitivity in capsaicin-desensitized rats.

In rats, we tested the hypothesis that capsaicin desensitization reduces hypothalamic warm thermosensitivity. We locally heated and cooled the hypothalamus using water-perfused thermodes while observing thermoregulatory variables. In untreated rats, a small dose of capsaicin had profound effects on thermoregulation. However, desensitizing rats to capsaicin had no effect on hypothalamic thermosensitivity for metabolic rate or changes in body temperature due to displacements of hypothalamic temperature. Contrary to current opinion, we conclude that capsaicin desensitization does not alter hypothalamic thermosensitivity to warm or cold.

Animals↗

PubMed1985

Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats.

Control febrile responses to intravenous injections of endogenous pyrogen were determined in groups of rabbits and rats, exposed to their respective thermoneutral ambient temperatures. Discrete electrolytic lesions were placed within the confines of the organum vasculosum laminae terminalis (o.v.l.t.) of each species. The fever responses of the animals were remeasured 3 days later, and in every case there was a marked enhancement of the fevers produced, using the same doses of endogenous pyrogen that were used earlier. Similar lesions that were placed unilaterally within the preoptic anterior hypothalamic area in groups of control animals, were not effective in enhancing the febrile responses of these animals. The course of this lesion-induced fever enhancement in rabbits was studied during the succeeding 3 week period, when it was found to return gradually towards the control levels. It is postulated that the o.v.l.t. is involved in some manner in the process whereby circulating pyrogen is translated into a febrile stimulus. Lesions posited within this region are thought to either increase the amount of pyrogen entering the o.v.l.t., or to increase the sensitivity of pyrogen receptor sites within the o.v.l.t.

Animals↗

PubMed1985

Differences in endogenous pyrogen fevers induced by iv and icv routes in rabbits.

We have compared the characteristics of fevers produced by endogenous pyrogen administered by the intravenous (iv) and by the intracerebroventricular (icv) routes in conscious rabbits. Fevers induced by the intracerebroventricular route have a longer latency to onset, a less steep rise in body temperature, and a longer time to peak elevation in body temperature than do fevers induced by the intravenous route. Furthermore, a dose of indomethacin (2 mg/kg) administered intravenously, which is effective in markedly attenuating fevers produced by the intravenous route, was completely without effect on fevers induced by the intracerebroventricular route. On the other hand, when indomethacin (500 micrograms) was infused intracerebroventricularly, it markedly reduced fevers induced by the subsequent injection of endogenous pyrogen into the contralateral cerebral ventricle, but such pretreatment had little effect on fevers elicited by intravenous injections of endogenous pyrogen. It is concluded that the sites of action of endogenous pyrogen in response to intravenous injections of pyrogen are different from those responding to intracerebroventricular injections of pyrogen and that this is manifest in several distinct differences in the characteristics of the two fevers. These results indicate that the intracerebroventricular model of fever production is not appropriate for the study of the normal pathogenesis of fever.

Animals↗

PubMed1985

A study of the variability in the febrile responses of rabbits to endogenous pyrogen.

The range of body temperature increases elicited by a standard dose of endogenous pyrogen (0.5 ml/kg iv) was examined in a population of 26 male New Zealand White rabbits. Although the mean maximum increase in rectal temperature was 0.88 +/- 0.06 degree C (SE), individual responses varied from 0.4 degree to 1.5 degree C. Three representative animals that responded to the standard dose of pyrogen with small, intermediate, and large febrile responses were selected and challenged with the same dose of pyrogen on eight separate occasions, and the variability of these responses was examined. There was little variability within the characteristic responses of any particular animal to the repeated challenges. The variability of the febrile responses elicited by both intravenous and intracerebroventricular administration of the same pyrogen was examined and compared using another group of 11 rabbits. The variability in response to the intravenous route was similar to that found in the larger population, whereas the variation in response to the intracerebroventricular route was smaller, and all 11 animals had fevers that were greater than 1 degrees C. It is concluded that the variability of the febrile responses of rabbits to intravenous pyrogen was due to differences between individual sensitivities of animals to the intravenously administered pyrogen. This difference in sensitivity may be due to a difference in the amount of pyrogen that reaches the putative receptor sites, or to a difference in the density or effectiveness of receptor sites in translating the pyrogenic stimulus into a fever response.

Animals↗

PubMed1985

Comparison of febrile responsiveness of rats and rabbits to endogenous pyrogen.

The fever responses of rats and rabbits were compared in detail using a single common source of semipurified endogenous pyrogen prepared from human monocytes. The characteristics and dynamics of the fever-response curves for each species were examined and their dose-response curves were determined and compared. The fevers displayed by rats were qualitatively similar to those of rabbits, but, typically, they developed and terminated more rapidly than those of rabbits. Rabbits were much more sensitive to the endogenous pyrogen than rats. The threshold dose of pyrogen required to elicit a fever was 5 times lower in the rabbit, and the slope of the rabbit's dose-response curve was 1.5 times steeper than that of the rat. The maximum fevers attainable in rabbits were approximately twice those attainable in rats. It was also shown that the more rapid febrile responses of the rat were not due to the 10-fold smaller mass of the rat; instead, we proposed that this difference was more likely due to a closer diffusional proximity of the pyrogen receptor sites to the circulation in rats. The lower sensitivity of the rat to endogenous pyrogen was attributed to a relative insensitivity of the pyrogen receptor sites in rats in the translation of the endogenous pyrogen stimulus into fever.

Animals↗