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J T Stitt

Publications and source records attributed to J T Stitt.

14 recordsLinked to original sources
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↗
PubMed1979

Fever versus hyperthermia.

A variety of conditions that result in the elevation of body temperature are described and discussed. These hyperthermias are divided into four categories; fever, exercise hyperthermia, hyperthermias due to inadequate means of heat dissipation, and hyperthermias resulting from pathological or pharmacological impairments of thermoregulatory mechanisms. A comparison of the physical and physiological characteristics of these hyperthermias is presented and distinctions are drawn on the basis of these characteristics. Fever is shown to differ markedly from all other forms of hyperthermias. Specifically, the elevation in body temperature encountered during fever is a regulated rise that is defended by fully functional thermoregulatory mechanisms; the thermopreferendum is also elevated in fever, particularly at the onset or "chill phase"; and aspirin-like drugs can intervene in febrile hyperthermia and will return body temperature to its normal level. No other forms of hyperthermia possess these characteristics and thus only fever can be attributed to an upward displacement of the "set point" for body temperature regulation. Furthermore, in attempting to control rises in body temperature, it is apparent that aspirin is effective only in fever, while whole-body cooling is all but ineffective. In all other forms of hyperthermia, whole-body cooling is the only effective treatment.

Animals↗
PubMed1976

The regulation of respiratory evaporative heat loss in the rabbit.

1. Respiratory evaporative heat loss in the rabbit has a minimum value of 0-2-0-3 W/kg and a maximum value of about 1-1 W/kg in non-evaporatively limited environments. 2. Both skin temperature and hypothalamic temperature influence respiratory evaporative heat loss, and they do so in a multiplicative fashion. Thus, at low skin temperature the hypothalamic temperature threshold for the onset of panting is above normal hypothalamic temperature and hypothalamic thermosensitivity is high. On the other hand, at high skin temperatures, the hypothalamic temperature threshold for the onset of panting is well below normal hypothalamic temperature, but hypothalamic thermosensitivity is greatly reduced. 3. The influence of mean skin temperature (Tsk) and hypothalamic temperature on respiratory evaporative heat loss (Eres) in the rabbit can be described by the equation: Eres=1-1-0-08 (Tsk-39-7) (Thy-42-9) greater than or equal to 0-3 W/kg. 4. Thus, the ability of a lowered mean skin temperature to increase the thermosensitivity of the hypothalamus in response to local temperature changes applies to heat loss mechanisms as well as heat production mechanisms. It is suggested that the characteristics of this peripheral input into the C.N.S. are fulfilled by tonic cold fibre input originating from the peripheral cold receptors on the body surface.

Animals↗
PubMed1975

Behavioural and autonomic induction of prostaglandin E-1 fever in squirrel monkeys.

1. Prostaglandins E1 (PGE1) was injected into the preoptic/anterior hypothalamic (PO/AH) area of the squirrel monkey. 2. Increases in rectal temperature (Tre) produced by PGE1 injections of 20 ng to 500 ng were dose-dependent. 3. When ambient temperature (Ta) was below the thermoneutral zone, increases in Tre were produced entirely by increases in metabolic rate. With Ta at the upper end of the thermoneutral zone, increases in Tre were produced by vasoconstriction in addition to lesser increases in metabolic rate. 4. During sessions of behavioural temperature regulation, PGE1 injections were followed by the selection of a higher Ta, increased skin temperature and subsequent increases in Tre. 5. PGE1 injections produce dose-dependent increases in Tre which are similar regardless of ambient temperature or whether behavioural or autonomic means are utilized to raise the heat content of the body.

Animals↗
PubMed1975

Microelectrophoresis of PGE1 onto single units in the rabbit hypothalamus.

Prostaglandin E1 (PGE1) when micro-injected into the preoptic anterior hypothalamus (PO/AH) of conscious rabbits is a potent pyrogenic agent. We have investigated the action of PGE1 on the activity of single units of the PO/AH area using the microelectrophoretic technique. One hundred and thirty-eight PO/AH units were tested both for their response to changes in local PO/AH temperature and for their response to PGE1 application. Less than 9.0% of the total population of units tested showed any response to PGE1 application. When present, the response was invariably one of mild facilitation. No specific unit type (thermally sensitive or insensitive) appeared to be selectively affected by PGE1. Thus, the proportion of units affected by PGE1 was constant at 8-10% for warm-sensitive, cold-sensitive, or thermally insensitive units. There was no evidence to support an antagonistic role for PGE1 on the effects on norepinephrine on PO/AH units. On the basis of these results, we cannot predicate any simple neuronal basis for the action of PGE1 in producing fever in conscious rabbits. However, it is suggested that the action of PGE1 might be the modulation of presynaptic release of neurotransmitter onto the units of the PO/AH area.

Animals↗
PubMedDate not supplied

Passage of immunomodulators across the blood-brain barrier.

The question is considered of how and where cytokines, such as interleukin 1 (IL-1), that are released into the circulation during the host defense response, reach and interact with the central nervous system to produce fever or act as neuroimmunomodulators. Evidence is presented suggesting a role for a brain circumventricular organ (CVO) in this respect. Several interactions between a specific CVO, the organum vasculosum laminae terminalis (OVLT) and endogenous pyrogen (EP) in the production of fever are reviewed. A more general hypothesis is developed on a role for the brain CVOs in monitoring the blood concentrations of several proteins and complex polypeptides such as the circulating endocrines that are regulated via the autonomic nervous system. A proposed connection between the release of prostaglandin E (PGE) at the blood-brain interface in response to infection and the ability of the brain to maintain an immunoprivileged status in the face of exposure of its CVOs to foreign antigens is discussed.

Acute-Phase Reaction↗