Brown adipose tissue thermogenesis heats brain and body as part of the brain-coordinated ultradian basic rest-activity cycle.

Brown adipose tissue (BAT), body and brain temperatures, as well as behavioral activity, arterial pressure and heart rate, increase episodically during the waking (dark) phase of the circadian cycle in rats. Phase-linking of combinations of these ultradian (<24 h) events has previously been noted, but no synthesis of their overall interrelationships has emerged. We hypothesized that they are coordinated by brain central command, and that BAT thermogenesis, itself controlled by the brain, contributes to increases in brain and body temperature. We used chronically implanted instruments to measure combinations of bat, brain and body temperatures, behavioral activity, tail artery blood flow, and arterial pressure and heart rate, in conscious freely moving Sprague-Dawley rats during the 12-h dark active period. Ambient temperature was kept constant for any particular 24-h day, varying between 22 and 27 degrees C on different days. Increases in BAT temperature (> or = 0.5 degrees C) occurred in an irregular episodic manner every 94+/-43 min (mean+/-SD). Varying the temperature over a wider range (18-30 degrees C) on different days did not change the periodicity, and neither body nor brain temperature fell before BAT temperature episodic increases. These increases are thus unlikely to reflect thermoregulatory homeostasis. Episodic BAT thermogenesis still occurred in food-deprived rats. Behavioral activity, arterial pressure (18+/-5 mmHg every 98+/-49 min) and heart rate (86+/-31 beats/min) increased approximately 3 min before each increase in BAT temperature. Increases in BAT temperature (1.1+/-0.4 degrees C) were larger than corresponding increases in brain (0.8+/-0.4 degrees C) and body (0.6+/-0.3 degrees C) temperature and the BAT episodes commenced 2-3 min before body and brain episodes, suggesting that BAT thermogenesis warms body and brain. Hippocampal 5-8 Hz theta rhythm, indicating active engagement with the environment, increased before the behavioral and autonomic events, suggesting coordination by brain central command as part of the 1-2 h ultradian basic rest-activity cycle (BRAC) proposed by Kleitman.

Dorsomedial hypothalamic sites where disinhibition evokes tachycardia correlate with location of raphe-projecting neurons.

Disinhibition of neurons in the region of the dorsomedial hypothalamus (DMH) elicits sympathetically mediated tachycardia in rats through activation of the brain stem raphe pallidus (RP), and this same mechanism appears to be largely responsible for the increases in heart rate (HR) seen in air jet stress in this species. Neurons projecting to the RP from the DMH are said to be concentrated in a specific subregion, the dorsal hypothalamic area (DA). Here, we examined the hypothesis that the location of RP-projecting neurons in the DA correspond to the sites at which microinjection of bicuculline methiodide (BMI) evokes the greatest increases in HR. To determine the distribution of RP-projecting neurons in the DA, cholera toxin B was injected in the RP in four rats. A consistent pattern of retrograde labeling was seen in every rat. In the hypothalamus, RP-projecting neurons were most heavily concentrated midway between the mammillothalamic tract and the dorsal tip of the third ventricle dorsal to the dorsomedial hypothalamic nucleus approximately 3.30 mm caudal to bregma. In a second series of experiments, the HR response to microinjections of BMI (2 pmol/5 nl; n = 76) was mapped at sites in the DA and surrounding areas in 22 urethane-anesthetized rats. All injection sites were located from 2.56 to 4.16 mm posterior to bregma, and the microinjections that evoked the largest increase in HR (i.e., >100 beats/min in some instances) were located in a region where RP-projecting neurons were most densely concentrated. Thus RP-projecting neurons in the DA may mediate DMH-induced tachycardia and thus play a role in stress-induced cardiac stimulation.

Tachycardia evoked by disinhibition of the dorsomedial hypothalamus in rats is mediated through medullary raphe.

Activation of neurons in the region of the dorsomedial hypothalamus (DMH) appears to generate the sympathetically mediated tachycardia seen in experimental stress in rats. The purpose of this study was to assess the role of neurons in the area of the medullary raphe pallidus (RP) in the tachycardia caused by stimulation of the DMH. The cardiovascular response to microinjection of the GABA(A) receptor antagonist bicuculline methiodide (BMI) 10 pmol (100 nl)(-1) into the DMH was assessed before, and after, injection of the GABA(A) receptor agonist muscimol 80 pmol (100 nl)(-1) or saline vehicle 100 nl into the RP in urethane-anaesthetized rats. Tachycardia evoked by microinjection of BMI into the DMH was mimicked by microinjection of BMI 30 pmol (75 nl)(-1) into the RP. This DMH-induced tachycardia was markedly suppressed after injection of muscimol into the RP, but the response was unaffected by injection of saline into the same region. Thus, DMH-induced tachycardia is mediated through activation of neurons in the area of the RP, suggesting that these neurons may play a previously unrecognized role in stress-induced cardiac stimulation.

Endothelin antagonism does not affect adrenal catecholamine secretion and system haemodynamics during acute stress in Wistar rats.

In the present work we evaluated the role of circulating endothelin-1 (ET-1) in haemodynamics and the adrenal medulla responses to stress using PD-142893, a mixed endothelin-A- and -B- (ET(A)/ET(B)) receptor antagonist. Male Wistar rats were chronically instrumented with arterial and venous catheters and a microdialysis probe placed into the adrenal medulla. Stress was induced by a 1 h period of immobilization. PD-142893 was infused (20 microg/kg/min) for 90 min starting 30 min before stress onset. Concentrations of norepinephrine and epinephrine in dialysate samples were measured by high-performance liquid chromatography (HPLC). At rest animals displayed a stable level of norepinephrine (85 +/- 34 pg/ml) and epinephrine (176 +/- 57 pg/ml) in adrenal perfusate and constant haemodynamic parameters. Stress increased adrenal secretion (norepinephrine 206 +/- 50%, epinephrine 202 +/- 45%) associated with hypertension (peak 141 +/- 3 mmHg) and tachycardia (peak 505 +/- 5 bpm). No significant changes in haemodynamics or of plasma catecholamine levels were observed during infusion of PD-142893. The antagonist did not significantly change the stress-induced increase in catecholamine secretion, tachycardia or hypertension. Thus, in Wistar rats, circulating ET-1 seems not to be essential for blood pressure control or adrenal catecholamine secretion during acute stress.

The effect of histamine receptor antagonists on stress-induced catecholamine secretion: an adrenomedullary microdialysis study in the rat.

The effects of pretreatment with selective histamine receptor antagonists on changes in sympathoadrenal activity and haemodynamics, induced by 60-min immobilization stress, were studied in conscious rats. Using adrenomedullary microdialysis, it was shown that ranitidine (5 mg/kg, i.v.), a histamine H2 receptor antagonist, selectively suppressed stress-stimulated noradrenaline secretion without affecting adrenaline response, whereas triprolidine (10 mg/kg, i.v.), a histamine H1 receptor antagonist, had little effect on stress-induced secretion of both catecholamines. Neither triprolidine nor ranitidine changed the pressor response to 60-min stress. The stress-induced increase in heart rate was not altered by triprolidine, whereas ranitidine reduced it after 30 min of stress. To test whether the anti-secretory effect of ranitidine could be of peripheral origin, in a separate experimental series, a local catecholamine secretion was stimulated by histamine (0.5 mM) perfused through the adrenomedullary dialysis probe. It appeared that triprolidine, but not ranitidine, reduced this effect of histamine. Thus, the present results suggest that during stress, the activity of the central histaminergic system, via histamine H2-receptors, may selectively modulate noradrenaline secretion by the adrenal gland.

Comparison of the effects of 2-deoxyglucose and immobilization on secretion and synthesis rate of catecholamines in the adrenal gland: a microdialysis study in conscious rats.

Using microdialysis, extracellular 3,4-dihydroxyphenylalanine (DOPA), noradrenaline (NA) and adrenaline (AD) concentrations in the adrenal gland were monitored in conscious rats during and after 60 min of immobilization (IMM) as well as after injection of 500 mg kg(-1) 2-deoxyglucose (2-DG). IMM produced a rapid and transient increase in secretion of AD (20-fold), NA (13-fold) and DOPA (3.6-fold). This was accompanied by an increase in blood pressure (+18 mmHG) and heart rate (+146 b.p.m.). Repeated exposure to IMM (daily 60 min, for 5 days) had no influence on either catecholamine secretion of haemodynamic profiles, indicating the lack of habituation to stressful conditions. Unlike IMM, the stress of 2-DG-induced central neuroglucopenia stimulated the release of AD without affecting NA secretion. AD levels peaked (5.1-fold increase) 40-60 min after 2-DG injection and then slowly declined. 2-DG induced no changes in blood pressure but reduced the heart rate (-48 b.p.m.). In separate experiments, steady-state dialysate DOPA levels, reached during continuous infusion of decarboxylase inhibitor NSD 1015 into adrenal gland tissue through the dialysis probe, served as an index of adrenomedullary tyrosine hydroxylase (TH) activity. IMM evoked a marked response in TH activity (DOPA formation increased 2.7-fold), which remained elevated 60 min after the cessation of stress when AD and NA secretion had already fallen to baseline. After 2-DG, despite significant hormonal response, adrenal TH activity was unchanged. These results give clear evidence that IMM and 2-DG-induced neuroglucopenia may be considered as two different types of stressful stimuli.