The amount of free corticosterone is increased during lipopolysaccharide-induced fever.

The relation between lipopolysaccharide (LPS)-induced fever and bioavailability of corticosterone (B) was examined in male Wistar rats. Animals were injected with LPS (2.5 mg/kg i.p.) or saline and core temperature and heart rate were monitored continuously using a biotelemetry system. Blood samples were withdrawn from freely moving rats via jugular catheters for estimation of total and free plasma B. LPS induced a long-lasting increase (24-48 h) in core temperature and B secretion and a short-lasting increase (90 min) in heart rate. LPS-induced fever was accompanied by a significant increase in the free/total B ratio. In contrast, an acute injection of B, which resulted in circulating B levels similar to those found after LPS, did not affect the free/total B ratio. The important role of LPS-induced fever in the hormone secretion pattern and the equilibrium between free and total B was further demonstrated in an in vitro study showing that an increase in the temperature by 3 degrees C elevated the free B fraction and the free/total B ratio of plasma samples with concentrations of B in the physiological range (5-40 microg/dl). Taken together, these findings indicate that during LPS-induced fever there is an increase in the amount of biologically available B. Exposure of glucocorticoid-sensitive targets to elevated levels of free B could contribute to the restoration of homeostasis that is disturbed during inflammation.

Sudomotor function in human poikilothermia.

Hypohidrosis predisposes to hyperthermia and may indicate generalized thermoregulatory failure. To assess the sweating capacity in human poikilothermia, we performed a quantitative analysis of the central and peripheral sudomotor pathways in four women with acquired poikilothermia (aged 29 to 38 years) and nine controls. Heat challenge in a climatic chamber (ambient temperature 40 degrees C, 50% relative humidity) for 180 minutes revealed that both sweat secretion and evaporative weight loss were significantly lower in the patients than in the controls (p < 0.01). Temperature thresholds for thermal sweating were markedly elevated in at least two patients, whereas a third patient showed no sweating response. Stimulation of the eccrine sweat glands by intradermally injected acetylcholine during reduced core temperature (34.9 +/- 0.7 degrees C) revealed a significantly reduced sweating response in all patients (p < 0.01); the sudomotor response to pilocarpine iontophoresis was reduced or absent in three patients. We conclude that the generalized thermoregulatory sudomotor failure in these patients was attributable primarily to disorders of the central sudomotor drive; the impaired postganglionic sudomotor response is temperature related and possibly secondary to (long-standing) poikilothermia. Quantification of heat-dissipating capacity is pivotal for diagnosing severe thermolability and may help to prevent serious heat illness.

Corticosterone modulates interleukin-evoked fever in the rat.

The role of endogenous corticoids in fever responses caused by recombinant murine interleukin (IL)-1 beta and IL-6 was studied in adult male Wistar rats. Adrenalectomy diminished the development of fever after intracerebroventricular (icv) injection of these ILs and lowered body temperature. Intraperitoneal administration of the same doses of ILs did not produce fever in intact animals or hypothermia in adrenalectomized rats, thus suggesting a central site of action of IL-1 beta and IL-6 in these experiments. Chronic replacement with moderate doses of corticosterone restored the fever response in adrenalectomized animals in response to icv administration of IL-1 beta but only partially reversed the fever caused by IL-6. Adrenalectomized animals acutely treated with corticosterone and thereafter with either IL-1 beta or IL-6 developed fever more rapidly than did chronically corticosterone-treated animals. In intact animals corticosterone blocked the fever response to icv injected IL-1 beta. We propose that in the rat corticosterone acts in a bimodal manner on body temperature; it exerts a permissive central effect on the fever response and limits the production of inflammatory mediators in the brain. Conversely, higher corticosterone doses probably reduce the magnitude of the fever response.

Postmenopausal hot flushes and their management.

Hot flushes are frequently incapacitating to the patient and the severe vasomotor disturbances may seriously impair normal daily life. This review attempts to provide an understanding of the pathophysiology of the hot flush as a basis for rationale therapy for each individual patient. The physiological mechanisms controlling body temperature are discussed briefly, and the changes in the system which precipitate the menopausal hot flush are detailed. The neuroendocrine events leading to the onset of the flushing syndrome are then considered. Finally, the therapeutic strategies which may be used in the management of the affected patient are discussed.

Bepridil: a review of its pharmacology and clinical efficacy as an anti-anginal agent with anti-arrhythmic properties.

Bepridil is an anti-anginal agent with a novel chemical structure. Its main pharmacological effects are an increase in coronary blood flow, a reduction in myocardial oxygen demand, reduction in cardiac work, primarily by a decrease in after-load and a dose-dependent negative chronotropic effect, and anti-arrhythmic properties. These are mainly due to a calcium-antagonistic action. There is evidence that fast sodium channels in heart muscle are also inhibited. Trials have shown that bepridil is effective in the prophylactic treatment of various forms of angina pectoris and accompanying arrhythmias. Pharmacokinetic data justify once-daily administration. The evidence suggests that bepridil is generally well tolerated. This paper reviews already published studies and the results of recent investigations on the pharmacological and clinical efficacy of bepridil.

A primate model of human postmenopausal hot flushes.

The hot flush is the only symptom specifically attributable to the menopause. Hot flushes appear to represent an episodic derangement of thermoregulation as a result of estrogen deficiency but the underlying physiological mechanisms are unknown. We have developed an animal model for the study of hot flushes. Two female monkeys (Macaca arctoides) were trained to accept monitoring of scalp cutaneous temperatures. After baseline temperature recordings were obtained both monkeys were ovariectomized. A few days after operation the previously stable scalp temperature changed to an undulating pattern with cycles lasting approximately 40-50 min. Ethinyl estradiol (20 micrograms orally or im) and (7 alpha,17 alpha)-17-hydroxy-7-methyl-19-nor-pregn-5(10)-en-20-yn-3-one (2.5 mg orally), a steroid with weak estrogenic, progestogenic, and androgenic properties, suppressed the characteristic undulating temperature pattern; this returned after withdrawal of replacement therapy. Clonidine (0.15 mg twice a day) suppressed the cyclic changes for 2 to 3 h. Domperidone and naloxone had no significant effect. This animal model may be useful for the investigation of alternative therapy for the management of menopausal flushes.

An automated superfusion technique for measuring circular muscle contraction. Effects of serotonin on intra- and extracranial arteries.

A new in vitro technique is described and its advantages are demonstrated: "true" circular contraction is measured; arteries are in cascade, permitting comparison of intra- and extracranial arteries from the same animal; the mechanical influences on contractility are reduced; long-lasting experiments of up to 50 h can be performed; the procedure is fully automated. The maximal effect of an agonist was not only markedly modified during the first 2--4 h after fixing the arteries in the apparatus but also slightly during the next 3--4 h. After the initial stabilization period, the arterial response to an agonist remained highly reproducible for 24--48 h (standard deviation not exceeding 7%). This was demonstrated in all the types of arteries tested. With serotonin as agonist, there was a significant difference in --log ED50 values for intracranial arteries (basilar 8.70, middle cerebral 8.72) vs. extracranial (lateral nasal 8.15; facial 8.14) and peripheral (branch of saphenous 8.14) arteries.

Some effects of ORG GC 94, a potential anti-migraine drug, on human platelets.

Some effects of Org GC 94 (1,3,4,14b-tetrahydro-2,7-dimethyl-2H-dibenzo[b,f]pyrazino[1,2-d][1,4]oxazepine maleate) on human platelets have been investigated. Without pretreatment with ADP, 5-HT-induced aggregation of humam platets was completely inhibited by 2.5 x 10(-8) M of Org GC 94. Aggregation triggered by noradrenaline (2.5 x 10(-5) M) and uptake of 5-HT by human platelets were inhibited only at the high concentrations of 10(-5) and 10(-4) M of Org GC 94 respectively. Up to millimolar concentrations, Org GC 94 did not liberate lactate dehydrogenase from human platelets. Org GC 94 did not block the oxidative deamination of benzylamine by human platelet rich plasma up to 2.5 x 10(-4) M.

Effects of various drugs supposed to interact with serotonin on PGO frequency changes induced by reserpine and 5-hydroxytryptophan.

Reserpine induced ponto-geniculo-occipital (PGO) spikes in the lateral geniculate nucleus. This was used as a model to evaluate the possible anti-reserpine effects of Org GB 94-1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino [1,2-alpha]azepine monohydrochloride-methiothepin, imipramine and atropine. In cats, under local anaesthesia, 3.2 mg/kg of methiothepin (a serotonin antagonist and neuroleptic) increased PGO density while 5-hydroxytryptophan (5-HTP) effects were blocked. A dose of 0.32 mg/kg of imipramine or atropine greatly reduced PGO density while potentiating 5-HTP effects. Org GB 94 had no effect in doses up to 10 mg/kg, where a slight decrease of PGO density was found, while 5-HTP effects were unchanged. At 32 mg/kg, EEG was pronouncedly changed by Org GB 94 but only a short-lasting decrease in PGO density was noted. On the basis of these results it seems improbable that the behavioural effects of Org GB 94 are to be explained by the same mechanism (i.e. serotonin uptake inhibition) as that of imipramine.

Clinical and animal pharmacology of migraine: new perspectives.

Animal and clinical pharmacological studies show in certain vascular beds a biphasic action [potentiation and inhibition of serotonin (5-HT) responses] of some anti-migraine drugs, such as ergotamine, methysergide and more recently Org GC 94. Potentiation occurs at therapeutic drug concentrations. The present investigations seem to support the 5-HT theory of migraine and other essential headaches. In this theory, anti-migraine drugs, such as ergotamine, methysergide, pizotifen, and Org GC 94 could reduce the occurrence of pain in migraine and other esscutial headaches by acting as partial agonists tending to correct a deficiency of central 5-HT concentrations or turnover.

Heterophile antibodies and tissue injury. 3. A role for platelets in the development of lethal vascular injury during Forssman shock in guinea pigs.

Platelets appear to be pathogenetic determinants in the development of lethal Forssman shock, which was provoked in guinea pigs by an intravenous injection of rabbit antiserum to sheep erythrocyte stromata. Within moments, circulating platelets (prelabeled with (14)C-serotonin) were removed from the blood stream and impacted in the lungs, where they liberated (14)C into the tissues. When animals were depleted of platelets prior to the production of shock, they survived for prolonged periods of time or were protected against death. Pretreatment with antiinflammatory compounds capable of inhibiting platelet aggregation and release phenomena had a similar protective influence. It would appear, therefore, that Forssman shock is a convenient and accessible model for investigating the mechanisms whereby platelets mediate immune vascular damage.