Jørgen Warberg

Human circulatory and thermoregulatory adaptations with heat acclimation and exercise in a hot, dry environment.

1. Heat acclimation was induced in eight subjects by asking them to exercise until exhaustion at 60% of maximum oxygen consumption rate (VO2) for 9‐12 consecutive days at an ambient temperature of 40 degrees C, with 10% relative humidity (RH). Five control subjects exercised similarly in a cool environment, 20 degrees C, for 90 min for 9‐12 days; of these, three were exposed to exercise at 40 degrees C on the first and last day. 2. Acclimation had occurred as seen by the increased average endurance from 48 min to 80 min, the lower rate of rise in the heart rate (HR) and core temperature and the increased sweating. 3. Cardiac output increased significantly from the first to the final heat exposure from 19.6 to 21.4 l min‐1; this was possibly due to an increased plasma volume and stroke volume. 4. The mechanism for the increased plasma volume may be an isosmotic volume expansion caused by influx of protein to the vascular compartment, and a sodium retention induced by a significant increase in aldosterone. 5. The exhaustion coincided with, or was elicited when, core temperature reached 39.7 +/‐ 0.15 degrees C; with progressing acclimation processes it took progressively longer to reach this level. However, at this point we found no reduction in cardiac output, muscle (leg) blood flow, no changes in substrate utilization or availability, and no recognized accumulated ‘fatigue’ substances. 6. It is concluded that the high core temperature per se, and not circulatory failure, is the critical factor for the exhaustion during exercise in heat stress.

Acute and adaptive responses in humans to exercise in a warm, humid environment

Abstract Acute and repeated exposure for 8–13 consecutive days to exercise in humid heat was studied. Twelve fit subjects exercised at 150 W [45% of maximum O2 uptake (V.O2,max)] in ambient conditions of 35°C and 87% relative humidity which resulted in exhaustion after 45 min. Average core temperature reached 39.9 ± 0.1°C, mean skin temperature (T–sk) was 37.9 ± 0.1°C and heart rate (HR) 152 ± 6 beats min–1 at this stage. No effect of the increasing core temperature was seen on cardiac output and leg blood flow (LBF) during acute heat stress. LBF was 5.2 ± 0.3 l min–1 at 10 min and 5.3 ± 0.4 l min–1 at exhaustion (n = 6). After acclimation the subjects reached exhaustion after 52 min with a core temperature of 39.9 ± 0.1°C, T–sk 37.7 ± 0.2°C, HR 146 ± 4 beats min–1. Acclimation induced physiological adaptations, as shown by an increased resting plasma volume (3918 ± 168 to 4256 ± 270 ml), the lower exercise heart rate at exhaustion, a 26% increase in sweating rate, lower sweat sodium concentration and a 6% reduction in exercise V.O2. Neither in acute exposure nor after acclimation did the rise of core temperature to near 40°C affect metabolism and substrate utilization. The physiological adaptations were similar to those induced by dry heat acclimation. However, in humid heat the effect of acclimation on performance was small due to physical limitations for evaporative heat loss.

Serotonin receptors involved in vasopressin and oxytocin secretion

Serotonin (5‐HT), 5‐HT agonists, the 5‐HT precursor 5‐hydroxytryptophan, 5‐HT‐releasers and ‐reuptake inhibitors stimulate the release of vasopressin and oxytocin. We investigated the involvement of 5‐HT receptors in the serotonergic regulation of vasopressin and oxytocin secretion. Vasopressin and oxytocin secretion was stimulated by 5‐HT, the 5‐HT1A+1B+5A+7 agonist 5‐carboxamidotryptamine (5‐CT), the 5‐HT2A+2C agonist DOI, the 5‐HT2C+2A agonist mCPP, the 5‐HT2C agonist MK‐212, the 5‐HT3 agonist SR 57277 and the 5‐HT4 agonist RS 67506. The 5‐HT1A agonist 8‐OH‐DPAT, which had no effect on vasopressin secretion, stimulated oxytocin secretion. The 5‐HT‐induced release of vasopressin and oxytocin was inhibited by central infusion of the 5‐HT antagonists WAY 100635 (5‐HT1A), LY 53857 (5‐HT2A+2C), ICS 205‐930 (5‐HT3+4) and RS 23597 (5‐HT4). The 5‐HT2+6+7 antagonist metergoline in combination with the 5‐HT1A+2+7 antagonist methysergide inhibited the stimulatory effect of 5‐CT on both hormones, whereas the 5‐HT1A+1B antagonist cyanopindolol only inhibited the oxytocin response. The 5‐HT2A antagonist 4‐(4‐flourobenzoyl)‐1‐(4‐phenylbutyl)‐piperidine oxalate had no effect on DOI‐induced hormone response. The 5‐HT2C antagonist Y 25130 partly inhibited the stimulating effect of MK‐212. ICS 205‐930 and RS 23597 inhibited vasopressin and oxytocin secretion induced by RS 67506. WAY 100635 inhibited 8‐OH‐DPAT‐induced oxytocin secretion. We conclude that 5‐HT‐induced vasopressin secretion primarily is mediated via 5‐HT2C, 5‐HT4 and 5‐HT7 receptors, whereas 5‐HT2A, 5‐HT3 and 5‐HT5A receptors seem to be of minor importance. 5‐HT‐induced oxytocin secretion involves 5‐HT1A, 5‐HT2C and 5‐HT4 receptors; in addition an involvement of 5‐HT1B, 5‐HT5A and 5‐HT7 receptors seems likely, whereas 5‐HT2A and 5‐HT3 receptors seem to be less important.

Erythropoietin treatment elevates haemoglobin concentration by increasing red cell volume and depressing plasma volume

Erythropoietin (Epo) has been suggested to affect plasma volume, and would thereby possess a mechanism apart from erythropoiesis to increase arterial oxygen content. This, and potential underlying mechanisms, were tested in eight healthy subjects receiving 5000 IU recombinant human Epo (rHuEpo) for 15 weeks at a dose frequency aimed to increase and maintain haematocrit at approximately 50%. Red blood cell volume was increased from 2933 ± 402 ml before rHuEpo treatment to 3210 ± 356 (P < 0.01), 3117 ± 554 (P < 0.05), and 3172 ± 561 ml (P < 0.01) after 5, 11 and 13 weeks, respectively. This was accompanied by a decrease in plasma volume from 3645 ± 538 ml before rHuEpo treatment to 3267 ± 333 (P < 0.01), 3119 ± 499 (P < 0.05), and 3323 ± 521 ml (P < 0.01) after 5, 11 and 13 weeks, respectively. Concomitantly, plasma renin activity and aldosterone concentration were reduced. This maintained blood volume relatively unchanged, with a slight transient decrease at week 11, such that blood volume was 6578 ± 839 ml before rHuEpo treatment, and 6477 ± 573 (NS), 6236 ± 908 (P < 0.05), and 6495 ± 935 ml (NS), after 5, 11 and 13 weeks of treatment. We conclude that Epo treatment in healthy humans induces an elevation in haemoglobin concentration by two mechanisms: (i) an increase in red cell volume; and (ii) a decrease in plasma volume, which is probably mediated by a downregulation of the rennin–angiotensin–aldosterone axis. Since the relative contribution of plasma volume changes to the increments in arterial oxygen content was between 37.9 and 53.9% during the study period, this mechanism seems as important for increasing arterial oxygen content as the well‐known erythropoietic effect of Epo.

Vagal slowing of the heart during haemorrhage: observations from 20 consecutive hypotensive patients.

Heart rate and arterial blood pressure were monitored in 20 consecutive patients during resuscitation from haemorrhagic shock. The mean blood loss (2.3 (SEM 0.3) 1) corresponded to 36(4)% of their estimated mean blood volume. During shock the mean blood pressure was 81/55 (3/2) mm Hg and heart rate 73 (3) beats/min. Administration of blood and crystalloids resulted in immediate increases to 111/72 (2/2) mm Hg and 102 (3) beats/min followed by steady state values of 131/79 (6/3) mm Hg and 82 (2) beats/min. In three otherwise healthy patients plasma concentrations of the vagally regulated hormone pancreatic polypeptide rose from resting values of 64-77 pmol/l (272-327 pg/ml) to 198-280 pmol/l (842-1190 pg/ml). These findings suggest that reversible hypotensive hypovolaemic shock is characterised by a decrease in heart rate conceivably reflecting an increase in vagal tone.

Involvement of 5-HT1, 5-HT2, and 5-HT3 Receptors in the Mediation of the Prolactin Response to Serotonin and 5-Hydroxytryptophan

Serotonin (5-HT) is involved in the neuroendocrine regulation of prolactin (PRL) secretion as a stimulator. Within the last decade several 5-HT receptor types have been identified, but their individual role in the mediation of the PRL response to 5-HT is only partly understood. We investigated in conscious male rats the effect of different 5-HT1, 5-HT2, and 5-HT3 receptor antagonists on the PRL response to 5-HT or to the 5-HT precursor 5-hydroxytrytophan (5-HTP) which was administered in combination with the 5-HT reuptake inhibitor fluoxetine. 5-HT (0.5-5.0 mg/kg BW i.v.) or 5-HTP (25-100 mg/kg i.p.) in combination with saline or fluoxetine (10 mg/kg i.p.) increased the plasma PRL concentration dose-dependently. Pretreatment with the 5-HT1+2 receptor antagonist methysergide (2.5 mg/kg i.p.) prevented the stimulatory effect of 5-HT or 5-HTP + fluoxetine. Pretreatment with the 5-HT2 receptor antagonists ketanserin or LY 53857 (2.5 mg/kg i.p.) inhibited the PRL response to 5-HT by approximately 80% and to 5-HTP + fluoxetine approximately 100%. A higher dose (10 mg/kg) of the 5-HT2 receptor antagonists possessed only 50% inhibitory effect. Pretreatment with the 5-HT3 receptor antagonists ICS 205-930 or GR 38032F (0.05-2.5 mg/kg i.p.) inhibited the PRL response induced by 5-HT or by 5-HTP + fluoxetine. The maximal inhibitory effect (approximately 80%) was obtained by a dose of 0.1 mg/kg of both compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Cocaine- and amphetamine-regulated transcript is present in hypothalamic neuroendocrine neurones and is released to the hypothalamic-pituitary portal circuit.

Cocaine‐ and amphetamine‐regulated transcript (CART) is present in a number of hypothalamic nuclei. Besides actions in circuits regulating feeding behaviour and stress responses, the hypothalamic functions of CART are largely unknown. We report that CART immunoreactivity is present in hypothalamic neuroendocrine neurones. Adult male rats received a systemic injection of the neuronal tracer Fluorogold (FG) 2 days before fixation, and subsequent double‐ and triple‐labelling immunoflourescence analysis demonstrated that neuroendocrine CART‐containing neurones were present in the anteroventral periventricular, supraoptic, paraventricular (PVN) and periventricular nuclei of the hypothalamus. In the PVN, CART‐positive neuroendocrine neurones were found in all of cytoarchitectonically identified nuclei. In the periventricular nucleus, approximately one‐third of somatostatin cells were also CART‐immunoreactive. In the medial parvicellular subnucleus of the PVN, CART and FG coexisted with thyrotrophin‐releasing hormone, whereas very few of the corticotrophin‐releasing hormone containing cells were CART‐immunoreactive. In the arcuate nucleus, CART was extensively colocalized with pro‐opiomelanocortin in the ventrolateral part, but completely absent from neuroendocrine neurones of the dorsomedial part. To assess the possible role of CART as a hypothalamic‐releasing factor, immunoreactive CART was measured in blood samples from the long portal vessels connecting the median eminence with the anterior pituitary gland. Adult male rats were anaesthetized and the infundibular stalk exposed via a transpharyngeal approach. The long portal vessels were transected and blood collected in 30‐min periods (one prestimulatory and three poststimulatory periods). Compared to systemic venous plasma samples, baseline concentrations of immunoreactive CART were elevated in portal plasma. Exposure to sodium nitroprusside hypotension triggered a two‐fold elevation of portal CART42‐89 immunoreactivity throughout the 90‐min stimulation period. In contrast, the concentration of portal plasma CART immunoreactivity dropped in the vehicle infused rats. The current study provides further evidence that CART is a neuroendocrine‐releasing factor with a possible impact on anterior pituitary function during states of haemodynamic stress.

Serotonergic involvement in stress-induced ACTH release

We investigated the involvement of serotonin (5-HT) and 5-HT receptors in mediation of stress-induced ACTH secretion in adult male rats, which were pretreated by 5-HT antagonists before restraint-, ether-, cold swim-stress or endotoxin. All stressors potently increased plasma ACTH. Lesion of 5-HT neurons with 5, 7-dihydroxytryptamine injected intracerebroventricularly, into the paraventricular nucleus or into the raphe nuclei, inhibited the restraint stress-induced ACTH response by 50%. Restraint increased the content of 5-HT and its metabolite 5-hydroxyindole acetic acid, in the raphe nuclei, whereas the other stressors had no such effect. Pretreatment with the 5-HT1A receptor antagonist WAY 100635 inhibited the restraint stress- and endotoxin-induced ACTH secretion by 50%. The 5-HT1+2 antagonist methysergide or the 5-HT2 antagonist ketanserin inhibited the restraint- or ether stress-induced ACTH response, and eliminated the endotoxin-induced ACTH response. The 5-HT2 receptor antagonist LY 53857 blocked only the endotoxin-induced ACTH response. Pretreatment with the 5-HT3 receptor antagonist ondansetrone had no effect on stress-stimulated ACTH secretion. The 5-HT3+4 receptor antagonist tropisetrone inhibited the restraint- and ether stress-induced response. The ACTH response to swim stress was not affected by any of the antagonists used. It is concluded that the 5-HT1A, the 5-HT2A and the 5-HT2C receptor, but not the 5-HT3 receptor are involved in the stress-induced ACTH secretion. An involvement of the 5-HT4 receptor is possible. Furthermore, that serotonergic neurons in the raphe nuclei are activated during restraint stress, and that these neurons and neurons in PVN of the hypothalamus, are important for the mediation of the restraint stress-induced ACTH response.

Histamine- and Stress-Induced Secretion of ACTH and β-Endorphin: Involvement of Corticotropin-Releasing Hormone and Vasopressin

Histamine (HA) stimulates the release of the pro-opiomelanocortin (POMC)-derived peptides ACTH, beta-endorphin (beta-END), beta-lipotropin and alpha-melanocyte-stimulating hormone, and HA is involved in the mediation of the stress-induced release of these peptides. The effect of HA is indirect and may involve the hypothalamic regulating factors, corticotropin-releasing hormone (CRH) and/or arginine-vasopressin (AVP). We studied the effect of immunoneutralization with specific antisera against CRH or AVP on the response of ACTH and beta-END to HA, restraint stress, CRH, AVP or a posterior pituitary extract in male rats. Intracerebroventricular infusion of HA (34-540 nmol) increased the plasma levels of ACTH and beta-END immunoreactivity (beta-ENDir) in a dose-dependent manner. Pretreatment with antiserum to CRH or AVP prevented the ACTH response to 270 nmol HA and inhibited the beta-ENDir response by 30-60%. One to five minutes of restraint stress caused an increase in the plasma levels of ACTH and beta-ENDir. The increase was dependent on the duration of stress exposure. Pretreatment with CRH antiserum abolished the ACTH response to 5 min of restraint stress and inhibited the beta-ENDir response by 60%. Immunoneutralization with AVP antiserum had only half the inhibitory effect of that seen with CRH antiserum. CRH (100 pmol i.v.) increased the plasma levels of ACTH and beta-ENDir. This effect was abolished by pretreatment with CRH antiserum, whereas pretreatment with AVP antiserum prevented the CRH-induced ACTH release and inhibited the beta-ENDir response by 50%. AVP (24-800 pmol i.v.) stimulated ACTH and beta-ENDir in a dose-dependent manner. CRH and AVP antisera each prevented the effect of AVP (800 pmol) on ACTH secretion, whereas the beta-ENDir response to AVP was only inhibited by about 60% by the antisera. An extract of the posterior pituitary gland administered in a dose corresponding to 0.15 or 0.5 pituitary equivalents had no effect on ACTH secretion, while 1.0 pituitary equivalent increased the ACTH concentration in plasma. This effect was abolished by AVP antiserum. The posterior pituitary extract caused a dose-dependent rise in plasma beta-ENDir which might be due to an unavoidable contamination of the posterior pituitary extract by a small amount of beta-END from the intermediate lobe. Consistent with this view, AVP antiserum had no effect on the rise in the plasma concentration of beta-ENDir following administration of the posterior pituitary extract.(ABSTRACT TRUNCATED AT 400 WORDS)

Serotonin Stimulates Hypothalamic mRNA Expression and Local Release of Neurohypophysial Peptides

The neurotransmitter serotonin (5‐HT) stimulates the secretion of vasopressin and oxytocin, and 5‐HT is involved in the mediation of the vasopressin and oxytocin response to stress. In male Wistar rats, we investigated the 5‐HT receptors involved in the 5‐HT‐induced increase of mRNA expression of vasopressin and oxytocin in the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). The 5‐HT precursor, 5‐hydroxytryptophan, injected in combination with the 5‐HT reuptake inhibitor, fluoxetine, increased oxytocin mRNA expression in the PVN, and the concentration of vasopressin and oxytocin in plasma, whereas mRNA in the SON was not affected. Intracerebroventricular infusion of 5‐HT agonists selective for the 5‐HT1A, 5‐HT1B, 5‐HT2A and 5‐HT2C receptor increased oxytocin mRNA in the SON and PVN. Infusion of agonists selective for the 5‐HT2A + 2C receptor increased vasopressin mRNA in the PVN, whereas none of the 5‐HT agonists affected vasopressin mRNA in the SON. All the 5‐HT agonists infused increased peripheral oxytocin concentration and vasopressin was increased by stimulation of the 5‐HT2A, 5‐HT2C and 5‐HT3 receptor. Intracerebroventricular infusion of 100 nmol 5‐HT increased the extracellular hypothalamic concentration of vasopressin as measured by microdialysis in the PVN. To evaluate the involvement of hypothalamic‐pituitary system in the 5‐hydroxytryptophan and fluoxetine‐induced vasopressin secretion, rats were immunoneutralized with a specific anti‐corticotropin‐releasing hormone antiserum. This treatment reduced plasma vasopressin and oxytocin responses. We conclude that stimulation with 5‐hydroxytryptophan or 5‐HT agonists increases mRNA expression of oxytocin in the PVN and the SON via stimulation of at least 5‐HT1A, 5‐HT1B, 5‐HT2A and 5‐HT2C receptors. Vasopressin mRNA in the PVN was increased only via the 5‐HT2 receptor, whereas vasopressin mRNA in the SON does not seem to be affected by 5‐HT stimulation. Corticotropin‐releasing hormone appears to be partly involved in the mediation of 5‐HT induced vasopressin and oxytocin secretion.