Stress-induced renin and corticosterone secretion is mediated by catecholaminergic nerve terminals in the hypothalamic paraventricular nucleus

Cell bodies in the hypothalamic paraventricular nucleus (PVN) mediate stress-induced increases in renin and corticosterone secretion. Since the PVN has an extensive catecholaminergic innervation, we wanted to determine the role of catecholamines in the neuroendocrine response to stress. The stressor was a conditioned emotional (fear) response paradigm (CER). The catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA), was injected into the PVN 14 days before the rats were subjected to the CER procedure. Damage to noradrenergic nerve terminals was verified immunocytochemically, using an antibody against dopamine beta-hydroxylase. Injection of 6-OHDa into the PVN prevented the stress-induced increase in plasma renin activity (PRA), plasma renin concentration (PRC) and plasma corticosterone concentration, suggesting that intact catecholaminergic innervation of neurons in the PVN is necessary for the stress-induced increase in renin and corticosterone secretion. To determine if beta-adrenoceptors in the PVN mediate the effect of stress on renin and corticosterone secretion, the beta-adrenoceptor antagonist sotalol was injected into the PVN through chronically implanted bilateral cannulae. The injection was performed on the 4th day of the CER paradigm, just before the rats were placed into the CER chamber. Sotalol prevented the stress-induced increase in corticosterone concentration, but did not diminish the stress-induced increase in PRA and PRC. These results suggest that the stress-induced increase in corticosterone concentration is influenced by beta-adrenoceptors in the PVN. The stress-induced increase in PRA and PRC is mediated by different receptors whose ligands might be catecholamines acting at non-beta-receptors or other neuroactive substances colocalized in catecholaminergic nerve terminals.     

Amygdaloid lesions: differential effect on conditioned stress and immobilization-induced increases in corticosterone and renin secretion.

The purpose of this study was to examine the contribution of the central nucleus of the amygdala to the expression of stress-induced increase in corticosterone and renin secretion. Neurons in the central amygdaloid nucleus of male rats were destroyed by bilateral injections of ibotenic acid, a neurotoxin that destroys cells but leaves fibers of passage intact. Two weeks later, the rats were subjected to immobilization for 20 min or to a conditioned stress (conditioned emotional response) procedure. Central amygdala lesions inhibited the increases in plasma corticosterone after exposure to both conditioned stress and immobilization. Lesions in the lateral amygdala had no effect on the corticosterone response to either stressor. Lesions in the central amygdala attenuated the renin response to conditioned stress but not to immobilization. In contrast, lateral amygdala lesions potentiated the renin response to immobilization but did not affect the renin response to conditioned stress. The results confirm previous studies that demonstrate the importance of the central amygdaloid nucleus in the expression of corticosterone to immobilization stress. In addition, the results show that neurons within the central amygdaloid nucleus are necessary for the full expression of conditioned stress-induced increase in corticosterone and renin secretion. The results are discussed with respect to the potential pathways that mediate stress-induced increases in corticosterone and renin secretion.     

Brain regulation of renin secretion involves central histaminergic neurons

The possible involvement of histamine (HA) in the stress-induced increase in plasma renin activity (PRA) was investigated in male rats. Intracerebroventricular (ICV) infusion of histamine (HA; 3.8-60 micrograms) increased PRA dose-dependently, and the Kd (dissociation konstant) of HA was estimated to approximately 30 micrograms. ICV infusion of HA (30 micrograms) as well as 5 min of restraint stress increased plasma renin activity (PRA) 2- and 3-fold, respectively (p less than 0.01). These effects were abolished by prior ICV infusion of the H2-receptor antagonists cimetidine (100 micrograms) and ranitidine (125 micrograms) (p less than 0.01), which reduced the PRA to subbasal levels (p less than 0.05). When administered alone the H2-receptor antagonists had no effect on PRA. In contrast, the H1-receptor antagonist mepyramine (100 micrograms) increased the basal PRA level (p less than 0.01) and slightly augmented the HA- and stress-induced increase in PRA (p less than 0.05). HA as well as restraint stress increased the plasma levels of dopamine, norepinephrine and epinephrine almost 2-fold (p less than 0.01). The effect of the two stimuli was prevented by prior ICV infusion of mepyramine or cimetidine (p less than 0.01). Pretreatment with the beta-adrenergic receptor blocker propranolol (7 mg/kg i.p.) abolished the HA-induced and inhibited by 70% the stress-induced PRA increase. The results indicate that histaminergic neurons participate in the cerebral regulation of renin secretion. The H2-receptor-mediated PRA-increasing effect of HA involves activation of sympathetic nerves. In addition, HA seems to exert a minor inhibiting effect on PRA via H1-receptors.     

Physical and inflammatory stressors elevate circadian clock gene mPer1 mRNA levels in the paraventricular nucleus of the mouse

Stress induces secretion of corticosterone through activation of the hypothalamic-pituitary-adrenal axis. This corticosterone secretion is thought to be controlled by a circadian clock in the suprachiasmatic nucleus (SCN). The hypothalamic paraventricular nucleus (PVN) receives convergent information from both stress and the circadian clock. Recent reports demonstrate that mammalian orthologs (Per1, Per2, and Per3) of the Drosophila clock gene Period are expressed in the SCN, PVN, and peripheral tissues. In this experiment, we examined the effect of physical and inflammatory stressors on mPer gene expression in the SCN, PVN, and liver. Forced swimming, immobilization, and lipopolysaccharide injection elevated mPer1 gene expression in the PVN but not in the SCN or liver. A stress-induced increase in mPer1 expression was observed in the corticotropin-releasing factor-positive cells of the PVN; however, the stressors used in this study did not affect mPer2 expression in the PVN, SCN, or liver. The present study suggests that a stress-induced disturbance of circadian corticosterone secretion may be associated with the stress-induced expression of mPer1 mRNA in the PVN.     

Differential effects of serotonin (5-HT1A and 5-HT2) agonists and antagonists on renin and corticosterone secretion

The present study was designed to investigate the effect of distinct serotonin (5-HT1A and 5-HT2) agonists and antagonists on renin and corticosterone secretion. Low doses of the selective 5-HT1A agonists 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) (5.0-500.0 micrograms/kg, i.p.) and ipsapirone (TVX Q 7821; 0.5-2.5 mg/kg, i.p.), and of the 5-hydroxytryptamine (5-HT) agonist MK-212 (2.0 mg/kg, i.p.), did not elevate plasma renin activity (PRA) and concentration (PRC) 30 min postinjection. Administration of a higher dose of MK-212 (10.0 mg/kg, i.p.) and of higher doses of ipsapirone (5.0-10.0 mg/kg, i.p.), as well as the 5-HT releaser, fenfluramine (5.0 mg/kg, i.p.), resulted in large increases in PRA and PRC. The effects of MK-212 and fenfluramine on PRA and PRC were blocked by pretreatment with the selective 5-HT2 antagonist, LY53857, in a dose-dependent (0.3-1.0 mg/kg, i.p.) manner. LY53857 (1.0 mg/kg, i.p.) by itself did not affect PRA or PRC. LY53857, furthermore, unmasked a renin-suppressive effect of MK-212, since injection of MK-212 (10.0 mg/kg, i.p.) following LY53857 administration led to a reduction in PRA and PRC. MK-212 (2.0 and 10.0 mg/kg), the high doses of 8-OH-DPAT (500.0 micrograms/kg), ipsapirone (1.0-10.0 mg/kg), and fenfluramine (5.0 mg/kg) all produced an increase in plasma corticosterone levels. The effects of MK-212 and fenfluramine on corticosterone were not inhibited by pretreatment with LY53857. These data suggest that 5-HT1A receptors do not play a role in the regulation of renin secretion, whereas stimulation of 5-HT2 receptors enhances renin release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulatory role of locus coeruleus and estradiol on the stress response of female rats

The activity of the hypothalamic-pituitary-adrenal axis is modulated by the norepinephrinergic system and, in females, also by the ovarian hormones. We investigated the role of ovarian steroids and the locus coeruleus (LC) on stress-induced corticosterone secretion in female rats. Ovariectomized rats without hormonal replacement (OVX) or treated with estradiol (OVE) or estradiol plus progesterone (OVEP) were subjected to jugular cannulation. Immediately after that, each hormonal treatment group was subjected to LC lesion or sham surgery or no brain surgery. After 24 h, blood samples of all 9 groups were collected before and after ether inhalation. Other four groups (OVX control, sham and lesioned, and OVE) were perfused for glucocorticoid receptor (GR) immunocytochemistry in hippocampal CA1 neurons and paraventricular nucleus (PVN). Estradiol replacement decreased while LC lesions increased stress-induced corticosterone secretion. The effect of LC lesion was potentiated with the removal of ovarian steroids. Since GR expression of lesioned animals decreased in the hippocampus, but not in PVN, we suggest that the effect of LC lesion on corticosterone secretion could be due to a reduction in the efficiency of the negative feedback system in the CA1 neurons. However, this mechanism is not involved in the estradiol modulation on corticosteroid secretion, as no change in GR expression was observed in estradiol-treated animals.     

Influence of the paraventricular nucleus of the hypothalamus in the alteration of neuroendocrine functions induced by intermittent footshock or interleukin.

The documented ability of physical stress and cytokines to increase the secretion of corticotropin-releasing factor CRF by the paraventricular nucleus of the hypothalamus (PVN), coupled with our earlier demonstration that CRF acts within the brain to interfere with reproductive functions, led us to investigate the effect of lesions of the PVN on LH, testosterone, ACTH, and corticosterone (CORT) secretion. Bilateral lesions of the PVN were done electrolytically, and 2 weeks later a series of acute and chronic experiments were performed in intact or castrated male rats bearing indwelling jugular and/or intracerebroventricular cannulas. The first study involved a single 2-h exposure of intact male rats to footshocks (2 mA, 2-sec duration, 4 per min). Although PVN lesions did not measurably alter the ability of intermittent footshock to lower plasma testosterone levels, this treatment attenuated the rise in plasma ACTH and CORT. In a second study, which was done in castrated rats, shocks were delivered 2 h daily for 7 days, and circulating hormone levels were measured at the end of the last shock period. Plasma LH levels of stressed rats showed statistically comparable decreases in both sham- and PVN-lesioned animals. Chronic exposure to footshocks induced smaller increases of ACTH and CORT secretion in PVN-lesioned compared to sham-lesioned rats, but the lesions did not completely abolish stress-induced activation of the hypothalamic-pituitary adrenal (HPA) axis. The third experiment involved the central injection of the vehicle or 40 ng interleukin-1 beta (IL-1 beta) to castrated rats. As expected, IL-1 beta dramatically decreased plasma LH values and increased circulating ACTH and CORT levels measured 2 h later. Bilateral PVN lesion did not influence LH secretion after injection of the vehicle or IL-1 beta. In contrast, destruction of the PVN completely blocked the increase of HPA axis activity observed in sham-operated rats 2 h after the intracerebroventricular infusion of IL-1 beta. These results confirm our previous observation that exposure to either footshocks or interleukins alters the activity of the hypothalamic-pituitary gonadal and HPA axis. Additionally, the present studies suggest that the PVN, which represents the predominant hypothalamic nucleus controlling the response of the HPA axis to a number of stimuli, does not appear to be necessary for the antireproductive effects of intermittent footshock or immune activation.     

Cyclical changes in plasma renin during the oestrous cycle in the rat: synchronized effect of oestrogen and progesterone

The aim of the present work was to study the relationship between sex hormones and plasma renin levels during the oestrous cycle in a Wistar-derived rat strain. Plasma renin activity (PRA) as well as a plasma renin concentration (PRC) were increased during the day of oestrus in rats with controlled 4-day oestrous cycles. This increase in PRA and PRC was not found when rats were ovariectomized on dioestrus day 2 and samples measured on the expected day of oestrus. The increase in PRA and PRC was not found when normal cyclic rats were treated with either tamoxifen or the progesterone receptor blocker RU 38486. Treatment with progesterone at pro-oestrus after ovariectomy on dioestrus day 2 partially increased the PRA and PRC when compared with the values found during the day of oestrus in control rats. The combined treatment of ovariectomized rats on dioestrus day 2 with oestrogen and progesterone restored the normal increase in PRA and PRC values on the expected day of oestrus. We therefore postulate that the sodium diuresis promoted by progesterone may be modulated by the previous peak of oestrogen. However, stimulation of extrarenal sources of renin cannot be excluded nor can an involvement of inactive precursors of renin in the fluctuations of active renin that occur during the oestrous cycle. No important change in plasma renin substrate (PRC) was observed during the oestrous cycle. PRA, PRC and PRS were determined every 4 h during the 4-day oestrous cycle. Our results clearly show a rhythmic variation in PRA and PRC which increases during the day of oestrus with a peak at 06.00 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrahypothalamic estradiol modulates hypothalamus-pituitary-adrenal-axis activity in female rats

Estrogen plays an important role in the regulation of the hypothalamus-pituitary-adrenal (HPA)-axis, but the neuroendocrine pathways and the role of estrogen receptor (ER) subtypes involved in specific aspects of this interaction remain unknown. In a first set of experiments, we administered estradiol (E2) intravenously, intracerebroventricularly, and by intrahypothalamic microdialysis to ovariectomized rats to measure plasma corticosterone (CORT) concentrations from carotid artery blood. Systemic infusion of E2 did not increase plasma CORT, but intracerebroventricular E2 induced a 3-fold CORT increase (P = 0.012). Local E2 infusions in the hypothalamic paraventricular nucleus (PVN) significantly increased plasma CORT (P < 0.001). A similar CORT increase was seen after PVN infusion of the ERα agonist propylpyrazoletriol, whereas the ERβ agonist diarylpropiolnitrile had no effect. In a second set of experiments, we investigated whether E2 modulates the HPA-axis response to acute stress by administering E2 agonists or its antagonist ICI 182,780 into the PVN during restraint stress exposure. After 30 min of stress exposure, plasma CORT had increased 5.0-fold (P < 0.001). E2 and propylpyrazoletriol administration in the PVN enhanced the stress-induced plasma CORT increase (8-fold vs. baseline), whereas ICI 182,780 and diarylpropiolnitrile reduced it, as compared with both E2 and vehicle administration in the PVN. In conclusion, central E2 modulates HPA-axis activity both in the basal state and during restraint stress. In the basal condition, the stimulation is mediated by ERα-sensitive neurons, whereas during stress, it is mediated by both ERα and ERβ.     

Renin-angiotensin system in hypothyroid rats: effects of potassium iodide and triiodo-L-thyronine

Kinetic studies of the renin-angiotensin system (RAS) were carried out by measuring plasma renin activity (PRA), plasma renin concentration (PRC) and plasma renin substrate (PRS). Changes in this system were studied during hypothyroidism, after administration of propylthiouracil (PTU), and in thyroidectomized rats. A significant decrease in PRA and PRC was observed in those animals previously treated with PTU. However, a significant increase in PRC, and a decrease in PRS, were found in T animals, but no changes in PRA were observed. In these animals, after daily administration of potassium iodide for 1 week (T + KI), no changes in RAS were observed in comparison with T rats. Nevertheless, administration of daily doses of triiodo-L-thyronine (T + T3) induced a significant increase in PRA, leaving PRC unaltered. In this case the changes in PRA were related to the increase in PRS after T3 treatment. These results suggest that two different mechanisms were involved in renin release, one activated in T rats and the other in pharmacological hypothyroidism.     

Measurement of plasma renin concentration using exogenous human renin substrate in normal subjects: correlation with plasma renin concentration and plasma aldosterone concentration.

Measurement of plasma renin concentration (PRC) was done in normal subjects at rest and under acute stimulation of renin release under unrestricted sodium intake. Concurrent measurements of plasma renin activity (PRA) and plasma aldosterone concentration (PA) were carried out. The mean values of PRC at rest and after stimulation of renin release were 12.8 +/- 1.3 (SEM) and 21.7 +/- 4.4 (SEM) ng AT I/ml/h, respectively. These corresponded to renin contents of 3.4 +/- 0.34 (SEM) X 10(-5) Goldblatt units and 5.8 +/- 0.36 (SEM) respectively. The mean percent increase of PRC (82.1 +/- 19.3 (SEM)) %) was almost indentical to that of PA (81.5 +/- 16.4 (SEM) %), but differed from that of PRA (269 +/- 83.1 (SEM) %). A very high correlation between concurrent PRC and PA (r = 0.92, P less than 0.001) was found in normal subjects at rest and under acute stimulation of renin release. A good correlation between PRC and PRA (r = 0.85, P less than 0.001) was also observed. However, a higher correlation between percent increases of PRC and PA (r = 0.92, P less than 0.001) than that of PRA and PA (r = 0.80, 0.01 less than P less than 0.005) was found. Results show that PRA is a good index of the renin content in plasma in normal subjects at rest and PRC reflects actual renin concentration in plasma at rest as well as under stimulation of renin release.     

Gastric ulceration and expression of prolactin receptor in the brain in Hatano high- and low-avoidance rats

Recently, prolactin was shown to inhibit the development of stress-induced ulcers. However, the mechanism for suppression of gastric ulcers by prolactin has not been clarified. Hatano high-avoidance (HAA) and low-avoidance (LAA) strains of rats were originally selected and bred from Sprague-Dawley rats based on shuttle-boxtasks. The present study focused on the relationships among gastric ulceration and endocrine response with special reference to prolactin secretion and restraint stress in water of HAA and LAA rats. The restraint stress induced an elevation of plasma concentrations of ACTH, corticosterone, and prolactin. Peak levels of plasma ACTH during stressful condition were significantly higher in HAA rats than in LAA rats, while peak levels of prolactin were significantly lower in HAA rats than in LAA rats. The gastric erosion inde was significantly higher in HAA rats than in LAA rats 7 h after restraint stress in water. The numbers of prolactin-receptor-positive cells determined by immunohistochemistry in the paraventricular nucleus was significantly increased in LAA rats than in HAA rats 7 h after restraint stress in water. These results indicate that HAA rats were more sensitive than LAA rats to restraint stress in water. The strain differences in gastric ulceration under stress may be involved in peripheral prolactin secretion and central prolactin receptor expression. The expression of prolactin receptor in the paraventricular nucleus may be important in suppressing gastric ulceration.     

Mineralocorticoid secretion in essential hypertension with normal and low plasma renin activity.

In 19 control subjects, 33 patients with essential hypertension and normal plasma renin activity (PRA) and 11 patients with low PRA, secretory rates of 18-hydroxy-11-deoxy-corticosterone (18-OH DOC), 11-deoxycorticosterone (DOC) and corticosterone were measured. Patients with low PRA were significantly older and had higher arterial pressure and slightly lower plasma potassium levels than patients with normal PRA. Mean 18-OH DOC secretion rate was higher in patients with normal PRA (603 +/- 112 SEM mug/24 hr) than in control subjects (219 +/- 19) and considerably higher (P less than 0.001) in patients with low PRA (1800 +/- 472). DOC and corticosterone secretion rates were within normal limits in most hypertensive patients. Plasma aldosterone was significantly higher in the hypertensive population than in control subjects whereas no significant difference was observed between the low- and normal-renin groups. A significant (P less than 0.01) mutual positive correlation was found between the secretion rates of 18-OH DOC, DOC and corticosterone in patients with low plasma renin activity. In contrast, there was no correlation between the secretion rates of the three mineralocorticoids in control subjects and patients with normal plasma renin activity. These data suggest a biosynthetic variation of the mineralocorticoid pathways in essential hypertension.     

Relation of the ventromedial nuclei of the hypothalamus to the regulation of renin secretion

During an investigation of the role of the mediobasal hypothalamus in the regulation of renin secretion from the kidneys, we found that lesions of the ventromedial nuclei prevented the increase in plasma renin activity produced by p-chloroamphetamine. In the present study, we tested the effects of bilateral electrolytic lesions of the ventromedial nuclei on the increase in plasma renin activity produced in sham-operated rats by immobilization, head-up tilt under inactin anesthesia, and a low-sodium diet. Ventromedial lesions reduced or abolished the plasma renin activity increase to all three stimuli without any change in plasma angiotensinogen. The plasma renin concentration responses to immobilization and a low-sodium diet were also reduced. All these stimuli probably exert their effect by way of the sympathetic nervous system. The data support the hypothesis that the ventromedial nuclei or neural fibers passing through them are important in the renin response to diverse stimuli that act by way of sympathetic discharge.     

Serotonergic stimulation of prolactin and corticosterone secretion is mediated by different pathways from the mediobasal hypothalamus

In previous studies we obtained evidence that serotonin release by p-chloroamphetamine (PCA) causes an increase in corticosterone secretion but that this effect is not mediated via the raphe nuclei in the midbrain. In contrast, PCA-induced prolactin secretion was abolished by dorsal raphe lesions. In the present study, posterolateral cuts which interrupted caudal inputs to the hypothalamus attenuated the effect of PCA on plasma prolactin but did not block the PCA-induced increase in plasma corticosterone levels. Large lesions of the mediobasal hypothalamus produced a significant reduction of plasma corticosterone concentration but did not completely prevent the effect of PCA on corticosterone secretion. Hypophysectomy performed 24 h before sacrifice caused a marked decrease in plasma corticosterone levels but did not completely abolish the effect of PCA. These results suggest that PCA also stimulates corticosterone secretion via a direct action on the adrenal gland. The lesions in the mediobasal hypothalamus caused an increase in plasma prolactin concentration, and in these rats, PCA suppressed rather than stimulated prolactin secretion. This suggests that the known weak dopamine agonist activity of PCA is exposed when the effects of serotonin release in the brain are eliminated.     

The amygdala regulates the pituitary-adrenocortical response and release of hypothalamic serotonin following electrical stimulation of the dorsal raphe nucleus in the rat

The amygdala is known to modulate the function of the hypothalamo-pituitary-adrenocortical (HPA) axis, but the mechanism of this effect is still not clear. In the present study we examined the specific role of the serotonin (5-HT) system in mediating the effect of the amygdala on the activity of the HPA axis. Bilateral lesions of the amygdala in rats reduced the adrenocorticotropin (ACTH) and corticosterone responses to electrical stimulation of the dorsal raphe nucleus, where the cell bodies of serotonergic neurons are located. Amygdala lesions had no effect on the ACTH and corticosterone responses to administration of a 5-HT(1A) receptor agonist directly into the paraventricular nucleus (PVN) of the hypothalamus, indicating that there was no impairment in the activity of postsynaptic 5-HT(1A) receptors in the hypothalamus. In vivo microdialysis showed that amygdala lesions markedly attenuated the effect of electrical stimulation of the dorsal raphe to increase extracellular secretion of 5-HT in the PVN. This is the first demonstration that the amygdala has a facilitatory effect on the function of dorsal raphe 5-HT neurons which project to the PVN, and suggests a mechanism by which the amygdala may modulate the function of the HPA axis.     

Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis

A recently discovered satiety molecule, nesfatin-1, is localized in neurons of the hypothalamus and brain stem and colocalized with stress-related substances, corticotropin-releasing hormone (CRH), oxytocin, proopiomelanocortin, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Intracerebroventricular (icv) administration of nesfatin-1 produces fear-related behaviors and potentiates stressor-induced increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in rats. These findings suggest a link between nesfatin-1 and stress. In the present study, we aimed to further clarify the neuronal network by which nesfatin-1 could induce stress responses in rats. Restraint stress induced c-Fos expressions in nesfatin-1-immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the nucleus of solitary tract (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DR) in the brain stem, without altering plasma nesfatin-1 levels. Icv nesfatin-1 induced c-Fos expressions in the PVN, SON, NTS, LC, DR and median raphe nucleus, including PVN-CRH, NTS-NA, LC-NA and DR-5-HT neurons. Nesfatin-1 increased cytosolic Ca2+ concentration in the CRH-immunoreactive neurons isolated from PVN. Icv nesfatin-1 increased plasma ACTH and corticosterone levels. These results indicate that the central nesfatin-1 system is stimulated by stress and activates CRH, NA and 5-HT neurons and hypothalamic-pituitary-adrenal axis, evoking both central and peripheral stress responses.     

Regulation of corticotropin-releasing factor and its types 1 and 2 receptors by leptin in rats subjected to treadmill running-induced stress

The present study was conducted to investigate the long-term effects of subchronic elevation of central leptin levels on the expression of corticotropin-releasing factor (CRF) and its types 1 and 2 receptors in the brain of rats subjected to treadmill running-induced stress. PBS or recombinant murine leptin was infused continuously for a period of 5 days into the third ventricle of rats with the aid of osmotic minipumps at a delivery rate of 2 mug/day. On the fifth day of infusion, rats were killed under resting conditions or after a session of treadmill running, which is known to induce a stress response in rats. Leptin treatment significantly decreased food intake, body weight, white adipose tissue weight, glucose and insulin plasma contents, and blunted the treadmill running-induced elevation in plasma levels of corticosterone. Leptin infusion prevented stress-induced de novo synthesis of CRF in the paraventricular hypothalamic nucleus (PVN), which was measured using the intronic probe for CRF heteronuclear RNA. The induction of the type 1 CRF receptor (CRF(1)R) in the PVN and supraoptic nucleus in running rats was also significantly blunted by leptin. In contrast, leptin treatment strongly increased the expression of type 2 CRF receptor (CRF(2)R) in the ventromedial hypothalamic nucleus (VMH). The present results suggest that subchronic elevation of central levels of leptin blunts treadmill running-induced activation of the hypothalamic-pituitary-adrenal axis through the inhibition of activation of the CRFergic PVN neurons, and potentially enhances the anorectic CRF effects via the stimulation of expression of CRF(2)R in the VMH.     

FACTORS IN THE CONTROL OF PLASMA RENIN ACTIVITY AND CONCENTRATION IN TYPE 1 (INSULIN-DEPENDENT) DIABETES

Possible factors involved in the control of plasma renin activity (PRA) and concentration (PRC) have been analysed in 49 patients with long-standing Type 1 diabetes and in 40 healthy controls matched for age and sex. Eighteen of the diabetic subjects were clinically free of all microvascular and macrovascular complications of their disease (Group A); 31 had proliferative retinopathy (Group B). Both lying and standing PRA and PRC were similar in Group A and healthy controls. Mean PRA was 50-115% higher in Group B diabetics than in controls (P less than 0.001 supine and erect) and 50-70% higher than in Group A diabetics (P less than 0.05 supine and erect); PRC also was 60% higher in Group B than in Group A (P less than 0.05 supine and erect). Control subjects showed significant falls in both PRA and PRC with increasing age, while Groups A and B showed significant falls in PRA or PRC with age. Group A showed a significant inverse correlation between systolic blood pressure and supine PRC (r = -0.57), but this was not significant in the controls and was completely absent in Group B. With correction for the effect of age there were significant relationships of PRA and PRC with sodium excretion in the controls and in Group A, but not in Group B. PRA and PRC are thus normal in uncomplicated long-standing Type 1 diabetes, but regulation of renin secretion appears to be impaired in patients with microvascular disease. Renin secretion inappropriate to their blood pressure and sodium status may contribute to maintenance of their relative hypertension.