Biomedical subjects

L K Malendowicz

Publications and source records attributed to L K Malendowicz.

At least 73 records · Page 4Linked to original sources

PubMed1998

Galanin stimulates glucocorticoid secretion in rats through a receptor-dependent activation of the adenylate cyclase/protein kinase A-dependent signaling pathway.

Galanin, a 29-amino acid peptide widely distributed in the central and peripheral nervous systems, was found to induce a concentration-dependent increase in corticosterone secretion and cyclic-AMP release by dispersed rat inner adrenocortical cells (maximal effective concentration, 10(-7) M). The effect of 10(-7) M galanin was blocked by 10(-6) M galantide, a specific antagonist of galanin receptors. Galanin (10(-7) M) also enhanced corticosterone and cyclic-AMP responses of dispersed cells to submaximal but not maximal (10(-9) M) effective concentrations of ACTH, and again this effect was reversed by galantide. The ACTH-receptor antagonist corticotropin-inhibiting peptide (10(-6) M) blocked corticosterone response of dispersed cells to 10(-9) M ACTH but not to 10(-7) M galanin; conversely, the specific protein kinase A inhibitor H-89 (10(-5) M) annulled the secretory response to both ACTH and galanin. In light of these findings, we conclude that galanin stimulates adrenal glucocorticoid secretion in rats, acting through specific receptors, coupled, like those of ACTH, with the adenylate cyclase/protein kinase A-dependent signaling pathway.

Adenylyl Cyclases↗

PubMed1998

Role of VIP, PACAP, and related peptides in the regulation of the hypothalamo-pituitary-adrenal axis.

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are members of a family of regulatory peptides that are widely distributed in the body and share numerous biologic actions. The two peptides display a remarkable amino acid-sequence homology, and bind to a class of G protein-coupled receptors, named PACAP/VIP receptors (PVRs), whose signaling mechanism mainly involves the activation of adenylate-cyclase and phospholipase-C cascades. A large body of evidence suggests that VIP and PACAP play a role in the control of the hypothalamo--pituitary-adrenal (HPA) axis, almost exclusively acting in a paracrine manner, since their blood concentration is very low. VIP and PACAP are contained in both nerve fibers and neurons of the hypothalamus, and VIP, but not PACAP, is also synthesized in the pituitary gland. Both peptides are expressed in the adrenal gland, and especially in medullary chromaffin cells. All the components of the HPA axis are provided with PVRs. VIP and PACAP enhance pituitary ACTH secretion, VIP by eliciting the hypothalamic release of CRH and potentiating its secretagogue action, and PACAP by directly stimulating pituitary corticotropes. Through this central mechanism, VIP and PACAP may increase mineralo- and glucocorticoid secretion of the adrenal cortex. VIP but not PACAP also exerts a weak direct secretagogue action on adrenocortical cells by activating both PVRs and probably a subtype of ACTH receptors. VIP and PACAP raise aldosterone production via a paracrine indirect mechanism involving the stimulation of medullary chromaffin cells to release catecholamines, which in turn enhance the secretion of zona glomerulosa cells via a beta-adrenoceptor-mediated mechanism. PACAP appears to be able to evoke a glucocorticoid response through the activation, at least in the rat, of the intramedullary CRH/ACTH system. The relevance of these effects of VIP and PACAP under basal conditions is questionable, although there are indications that endogenous VIP is involved in the maintenance of the normal growth and steroidogenic capacity of rat adrenal cortex. However, indirect evidence suggests that these peptides might play a relevant role under paraphysiological conditions (e.g., in the mediation of HPA axis responses to cold and inflammatory stresses) or may be somehow involved in the pathogenesis of Cushing disease or some case of hyperaldosteronism associated with secreting pheochromocytomas.

Adrenal Glands↗

PubMed1998

Arginine-vasopressin and corticotropin-releasing hormone are sequentially involved in the endothelin-1-induced acute stimulation of rat pituitary-adrenocortical axis.

The acute effect of endothelin-1 (ET-1) on the hypothalamo-pituitary-adrenal (HPA) axis has been investigated in the rat. The plasma concentrations of arginine-vasopressin (AVP), ACTH, aldosterone and corticosterone have been measured by RIA 30 and 60 min after ET-1 administration. ET-1 (2.0 nmol kg(-1) raised AVP plasma concentration at both 30 and 60 min. ET-1 did not alter the ACTH plasma level at 30 min, but markedly increased it at 60 min. ACTH response was unaffected by the simultaneous administration of AVP-receptor antagonists (AVP-As) Des-Gly-[Phaa1,D-Tyr(Et)2,Lys6,Arg8]-vasopressin or [Deamino-Pen1,Tyr(Me)2,Arg8]-vasopressin (20 nmol kg(-1), but abolished by the corticotropin-releasing hormone (CRH)-receptor antagonist alpha-helical-CRH(9-41) (alpha-CRH, 10 nmol kg(-1). ET-1 evoked significant rises in the blood levels of aldosterone and corticosterone at both 30 and 60 min. AVP-As abrogated the response at 30 min, while alpha-CRH was ineffective. Both AVP-As and alpha-CRH partially reversed adrenocortical secretory response at 60 min. Collectively, these findings confirm that systemically administered ET-1 stimulates rat HPA axis, and provide evidence that the mechanism underlying this effect may involve the sequential activation of AVP and CRH release.

Adrenocorticotropic Hormone↗

PubMed1998

Corticotropin-inhibiting peptide enhances aldosterone secretion by dispersed rat zona glomerulosa cells.

Corticotropin-inhibiting peptide (CIP), the 7-38 fragment of human ACTH(1-39), is known to act as an antagonist of ACTH receptors. Accordingly, CIP has been found to inhibit ACTH-stimulated glucocorticoid secretion of dispersed rat adrenocortical cells, without per se affecting the basal production. We confirmed these findings, but unexpectedly observed that CIP concentration-dependently raised basal aldosterone secretion from fresh suspensions of rat zona glomerulosa (ZG) cells, maximal effective concentration being 10(-6) M. CIP (10(-6) M) partially reversed the ZG-cell response to ACTH, but not to the Ca2+-dependent agonists angiotensin-II (ANG-II) and K+. The aspecific ANG-II-receptor antagonist saralasin (10(-6) M) blocked the aldosterone response of ZG cells to 10(-6) M CIP, and in the presence of the Ca2+-channel blocker verapamil CIP was ineffective. Collectively, these findings suggest that CIP enhances aldosterone secretion of rat ZG through a mechanism involving the activation of ANG-II receptors and the consequent rise in the cytosolic Ca2+ concentration. They also stress that this side-effect of CIP must be taken into account in interpreting the results of investigations on the adrenal cortex, where CIP has been employed as an ACTH-receptor antagonist.

Adrenocorticotropic Hormone↗

PubMed1998

Acute effects of recombinant murine leptin on rat pituitary-adrenocortical function.

Leptin, the product of the ob gene, is an adipose-tissue secreted hormone, which regulates satiety, metabolic rate and thermogenesis. Many lines of evidence suggest the existence of mutual relationships between leptin and adrenal-cortex secretion, but in vivo studies gave rather conflicting results. Therefore, we have investigated the acute effect of the systemic bolus administration of leptin (5 or 10 nmol/kg) on the function of rat pituitary-adrenocortical function. The blood concentrations of ACTH, aldosterone and corticosterone were measured by specific RIA 60 or 120 min after the leptin injection. Leptin did not affect the blood concentrations of ACTH and aldosterone at 60 min, but at 120 min the lower dose of the peptide increased them. In contrast, the blood level of corticosterone was markedly enhanced by both doses of leptin at 60 and 120 min. Collectively, these findings indicate that leptin exerts a moderate acute activation of the pituitary-adrenocortical function in rats. They also suggest that the adrenocortical secretagogue action of leptin is not only mediated by the enhanced pituitary ACTH release, but is also consequent to a direct stimulatory effect of the peptide on adrenocortical cells.

Adrenal Cortex↗

PubMed1998

11beta-hydroxysteroid dehydrogenase expression and activity in the human adrenal cortex.

Although oxidation of cortisol or corticosterone by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) represents the physiological mechanism conferring specificity for aldosterone on the mineralocorticoid receptor in mineralocorticoid target tissues, little attention has been paid until now to the expression and activity of this enzyme in human adrenals. We have shown that human adrenal cortex expresses 11beta-HSD type 2 (11beta-HSD2) gene, and found a marked 11beta-HSD2 activity in microsomal preparations obtained from slices of decapsulated normal human adrenal cortices. Under basal conditions, adrenal slices secreted, in addition to cortisol and corticosterone (B), sizeable amounts of cortisone and 11-dehydrocorticosterone (DH-B), the inactive forms to which the former glucocorticoids are converted by 11beta-HSD. Addition of the 11beta-HSD inhibitor glycyrrhetinic acid elicited a moderate rise in the production of cortisol and B and suppressed that of cortisone and DH-B. ACTH and angiotensin II evoked a marked rise in the secretion of cortisol and B, but unexpectedly depressed the release of cortisone and DH-B. ACTH also lowered the capacity of adrenal slices to convert [3H]cortisol to [3H]cortisone. This last effect of ACTH was concentration-dependently abolished by both aminoglutethimide and cyanoketone, which blocks early steps of steroid synthesis, but not by metyrapone, an inhibitor of 11beta-hydroxylase. Collectively, these findings indicate that the human adrenal cortex possesses an active 11beta-HSD2 engaged in the inactivation of newly formed glucocorticoids. The activity of this enzyme is negatively modulated by the main agonists of glucocorticoid secretion through an indirect mechanism, probably involving the rise in the intra-adrenal concentration of non-11beta-hydroxylated steroid hormones.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1998

Role of endothelins in regulation of vascular tone in the in situ perfused rat adrenals.

This study examined the role of endothelins (ETs) and their receptor subtypes ETA and ETB in the regulation of vascular tone in the in situ perfused rat left adrenal gland. Endothelin-1 (ET-1), which binds both ETA and ETB receptors, decreased adrenal flow rate of the perfusion medium, and its effect was reversed by the ETA antagonist BQ-123 and enhanced by the ETB antagonist BQ-788. ET-3, which preferentially binds ETB, and the selective ETB agonist BQ-3020 increased adrenal flow rate of perfusate, and their effects were annulled by BQ-788. BQ-123 magnified the effect of ET-3 and did not affect that of BQ-3020. The ETA-mediated decrease and the ETB-mediated rise in the rate of collection of perfusate were abolished by Ro-31-8220, an inhibitor of protein kinase C (PKC), and by N(G)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase (NOS), respectively. Collectively, these findings suggest that ETs can regulate vascular tone in the in situ perfused rat adrenals via both PKC-coupled ETA and NOS-coupled ETB receptors, the activation of which evokes vasoconstriction and vasodilation, respectively.

Adrenal Glands↗

PubMed1998

Endothelin-1 enhances thymocyte proliferation in monolaterally adrenalectomized rats with contralateral adrenocortical regeneration.

Endothelins (ETs) are a family of vasoactive peptides widely distributed in the body systems, where they exert pleiotropic biological effects, acting through two main subtypes of receptors, named ETA and ETB. Evidence indicates that ET-1 plays a permissive role in the development of neural crest-derived structures, among which are the epithelial cells of the thymus. These cells are known to control proliferation and differentiation of thymocytes, a process requiring adequate levels of glucocorticoids. Therefore, we have investigated the effects of ET-1, that binds both ETA and ETB receptors, on thymocyte proliferation in monolaterally adrenalectomized rats with contralateral enucleated adrenal at day 4 and 8 of regeneration, when glucocorticoid production is very low and, respectively, rather normal. Metaphase index (percentage of metaphase arrested cells) of thymocytes is the lowest at day 4 of regeneration, and markedly rose at day 8, thereby confirming the need of sizable levels of circulating glucocorticoid for the maintenance of a normal rate of thymocyte proliferation. ET-1 markedly increased the mitotic index of thymocytes at both times of adrenal regeneration. At day 8 of regeneration, the ETA-receptor antagonist BQ-123 markedly lowered mitotic index of thymocytes, and annulled its ET-1-evoked raise. Conversely, the ETB-receptor antagonist BQ-788 was ineffective. Collectively, these findings clearly indicate that endogenous ETs, through the activation of ETA receptors, are involved in the maintenance and stimulation of thymocyte proliferation in the adult rat, thereby playing a possibly important role in the modulation of the immune-system functions.

Adrenal Cortex↗

PubMed1998

Distribution and functional significance of angiotensin-II AT1- and AT2-receptor subtypes in the rat adrenal gland.

The distribution and the functional significance of angiotensin-II (ANG-II) receptor subtypes, AT1 and AT2, in the rat adrenal gland has been investigated in vitro. Autoradiographic assessment of the selective displacement of [125I]ANG-II binding by selective ligands of the two receptor subtypes indicated that zona glomerulosa (ZG) was provided with both AT1 and AT2, and adrenal medulla (AM) almost exclusively with AT2 receptors. ANG-II (10(-9) M) evoked a marked rise in the secretion of aldosterone by dispersed ZG cells and catecholamines by AM fragments. The selective AT1-receptor antagonist DuP753 blocked aldosterone response to ANG-II, while the selective AT2-receptor antagonist PD123319 was ineffective. Catecholamine response to ANG-II was inhibited by PD123319 and only moderately affected by high concentrations of DuP753. The selective AT2-receptor agonist CGP42112 did not change basal aldosterone release of ZG cells, but concentration-dependently enhanced basal catecholamine release by AM fragments. In light of these findings the conclusion is drawn that in the rat the aldosterone secretagogue effect of ANG-II is exclusively mediated by the AT1 receptors present in the ZG, while the catecholamine secretagogue action preminently involves the activation of AT2 receptor located on medullary chromaffin cells.

Adrenal Glands↗

PubMed1998

The AT2 receptor-mediated stimulation of adrenal catecholamine release may potentiate the AT1 receptor-mediated aldosterone secretagogue action of angiotensin-II in rats.

The role played by AT1 and AT2 receptors in the mediation of angiotensin-II (ANG-II) aldosterone secretagogue action has been investigated in vitro using different types of rat adrenal preparations. ANG-II enhanced aldosterone secretion of dispersed zona glomerulosa (ZG) cells in a concentration-dependent manner (EC50, 3 x 10(-10) M), and its effect was annulled by the AT1-receptor antagonist DuP753 and unaffected by the AT2-receptor antagonist PD123319. ANG-II was significantly more effective in stimulating aldosterone secretion when capsule-ZG and adrenal slices containing medullary chromaffin cells were used (EC50, 1 x 10(-11) M and 7 x 10(-12) M, respectively); moreover, both DuP753 and PD123319 caused partial reversals (intense and moderate, respectively) of the responses to ANG-II, and when added together annulled them. The beta-adrenoceptor antagonist l-alprenolol did not affect aldosterone response to ANG-II of dispersed ZG cells, but exerted a PD123319-like effect on the responses of capsule-ZG and adrenal slices. In light of these findings we conclude that, when the integrity of adrenal tissue is preserved, ANG-II stimulates aldosterone secretion by activating both AT1 and AT2 receptors, the major role being played by AT1 receptors located on ZG cells. The activation of AT2 receptors probably elicits the local release of catecholamines, which in turn enhance aldosterone secretion in a paracrine manner acting through the beta-adrenoceptors with which ZG cells are provided.

Adrenal Glands↗

PubMed1997

Distribution and functional significance of the endothelin receptor subtypes in the rat adrenal gland.

Endothelins (ET) are a family of vasoactive peptides that act via two subtypes of receptors, named ETA and ETB. ET-1 binds to both ETA and ETB, whereas the isopeptide ET-3 preferentially binds to ETB. The localization of ETA and ETB receptors in the rat adrenal gland and their involvement in the adrenal secretagogue effect of ETs has been studied in vitro. Autoradiographic assessment of the selective displacement of [125I]ET-1, [125I]ET-3 and [125I]BQ-3020 (an ETB agonist) by BQ-123 or BQ-788 (specific antagonists of ETA and ETB, respectively) indicates that the zona glomerulosa and adrenal medulla possess both ETA and ETB, whereas the zona fasciculata/reticularis is exclusively provided with ETB. ET-1, ET-3 and BQ-3020 enhance aldosterone and corticosterone secretion by dispersed cells of the zona glomerulosa and zona fasciculata/reticularis, respectively. BQ-123 does not affect the secretagogue action of these three agonists, whereas BQ-788 completely annuls it. ET-1 induces a marked rise in catecholamine release by fragments of the adrenal medulla, and both BQ-123 and BQ-788 partially reverse this effect. ET-3 and BQ-3020 elicit a catecholamine release that is less intense than that produced by ET-1; this response is unaffected by BQ-123 and abolished by BQ-788. Thus, in the rat, the corticosteroid secretagogue effect of ETs seems to be exclusively mediated by the ETB receptor subtype, and the catecholamine secretagogue action by both ETA and ETB. The functional relevance of ETA receptors present in the zona glomerulosa remains to be investigated.

Adrenal Glands↗

PubMed1997

Effect of 5-bromo-2'-deoxyuridine on the proliferative activity of thymus and regenerating adrenal cortex.

5-Bromo-2'-deoxyuridine (BrdU) has been recently found to enhance adrenal glucocorticoid secretion in rats. Since BrdU-labeling is today the most employed technique for assessing cell proliferation, we have investigated whether this side-effect of BrdU may influence mitotic activity (as evaluated by metaphase-arrested cell counting) in the thymus cortex and regenerating adrenal cortex. BrdU (1 mg/100 g body weight) evoked a 6-fold rise in the blood level of corticosterone in intact rats, but not in animals bearing regenerating adrenals, in which glucocorticoid secretion was very low. Mitotic index in the thymus of intact rats was not changed by BrdU, but it was strongly depressed in regenerating adrenals. These findings rule out the possibility that the glucocorticoid secretagogue action of BrdU exerts a sizable effect on the proliferative activity of both thymus and adrenal cortex. The marked lowering in the mitotic rate in the regenerating adrenal cortices could be ascribed to the well-know differentiation promoting action of BrdU, a finding which, if confirmed, would make highly unreliable the use of BrdU-labeling technique in cultures of adrenocortical cells.

Adrenal Cortex↗

PubMed1997

Neurotensin stimulates CRH and ACTH release by rat adrenal medulla in vitro.

Neurotensin (NT) is a 13-amino acid peptide, widely distributed in the central and peripheral nervous system, which is able to stimulate the activity of the hypothalamo-pituitary CRH-ACTH system. We investigated by RIA the effect of NT on the release of CRH and ACTH immunoreactivities (ir) by rat adrenal medulla in vitro. NT enhanced the release of both CRH-ir and ACTH-ir, the maximal effective concentration being 10(-8) M. [D-Trp11]-NT, a specific NT receptor antagonist, abrogated the effects of NT. The stimulatory effect of 10(-8) M NT on ACTH-ir release was blocked by alpha-helical-CRH (an antagonist of CRH receptors), thereby suggesting that the enhancement in ACTH secretion is consequent to the stimulation of CRH release. These findings suggest that NT is a stimulator not only of the central (hypothalamo-pituitary), but also of the peripheral (intramedullary), branch of the CRH-ACTH system.

Adrenal Medulla↗

PubMed1997

Arginine-vasopressin stimulates CRH and ACTH release by rat adrenal medulla, acting via the V1 receptor subtype and a protein kinase C-dependent pathway.

Arginine-vasopressin (AVP) is a hypothalamic hormone that, like CRH, stimulates the pituitary release of ACTH, thereby activating adrenal glucocorticoid secretion. Evidence indicates that rat adrenal medulla contains a CRH-ACTH system duplicating that existing at the hypothalamo-pituitary level and involved in the paracrine stimulation of the cortex secretion. Therefore, we investigated by RIA the effect of AVP on the release of CRH and ACTH immunoreactivities (IR) by rat adrenal medulla in vitro. AVP concentration-dependently enhanced the release of both CRH-IR and ACTH-IR, and the effect was blocked by a selective antagonist of the V1 subtype of AVP receptors. The CRH receptor antagonist alpha-helical-CRH partially reversed AVP-evoked rise in ACTH-IR release, without altering either CRH response or basal secretions of CRH and ACTH. The specific inhibitors of protein kinase C Ro31-8220 and calphostin C abolished both CRH and ACTH responses to AVP. In conclusion, our present findings suggest that AVP stimulates intramedullary the CRH-ACTH system, acting via V1 receptors and activating protein kinase C.

Adrenal Medulla↗

PubMed1997

Neuropeptide K and neurokinin A stimulate CRH and ACTH release by rat adrenal medulla in vitro.

Tachykinins are a family of peptides that are able to modulate the activity of the hypothalamo-pituitary CRH-ACTH system. Mammalian tachykinins include neurokinin A (NKA), neurokinin B (NKB), neuropeptide K (NPK), and substance P (SP). We investigated by RIA the effects of tachykinins on the release of CRH and ACTH by rat adrenal medulla in vitro. NKA and NPK concentration-dependently enhanced the release of both CRH and ACTH, NPK being more active than NKA. NKB exerted only a minor stimulatory action exclusively on CRH release, and SP was ineffective. The stimulatory effect of both NKA and NPK on ACTH release was blocked by the CRH receptor antagonist alpha-helical-CRH, thereby suggesting that the increase in ACTH secretion is consequent to the stimulation of CRH release. These findings indicate that NKA and NPK are stimulators not only of the central (hypothalamo-pituitary), but also of the peripheral (intramedullary) branch of the CRH-ACTH system.

Adrenal Medulla↗

PubMed1997

Different mechanisms mediate the in vivo aldosterone and corticosterone responses to 5-bromo-2'-deoxyuridine in rats.

The subcutaneous injection of 5'-bromo-2' deoxyuridine (BrdU) was found to raise the plasma concentrations of ACTH, aldosterone and corticosterone in rats. The aldosterone response was observed at a lower dose of BrdU and lasted for a longer period than those of ACTH and corticosterone (1.25 versus 2.50 mg/100 g body weight; 48 versus 24 h). Corticosterone response to BrdU was partially reversed by the ACTH-receptor antagonist corticotropin-inhibiting peptide (CIP), and aldosterone response by the arginine vasopressin (AVP) V1-receptor antagonist [amino-Pen1, Val4,D-Arg8]-vasopressin (AVP-A). The angiotensin-II (ANG-II)-receptor antagonist [Sar1, Val5, Ala8]-ANG-II (SAR) was ineffective. CIP, AVP-A and SAR, when administered alone, did not alter basal levels of ACTH, aldosterone and corticosterone. In light of these findings the following conclusions can be drawn: (i) BrdU stimulates the hypothalamo-pituitary-adrenal axis in rats, and this effect may influence the results of cell-kinetics studies carried out with the BrdU-labelling technique, especially in those tissue that are highly responsive to glucocorticoids (e.g. pituitary, adrenal and lymphatic tissues); and (ii) different mechanisms underlie the aldosterone and corticosterone secretagogue effects of BrdU, the former being at least in part dependent on the stimulation of AVP release and the latter on the rise in ACTH secretion.

Aldosterone↗

PubMed1997

17 alpha-Hydroxylase and chromogranin A in 6th week human fetal adrenals.

The development of the human fetal adrenals starts in the 6th week gestational age and adrenal C19 steroid production becomes of major importance for the maintenance of the pregnancy. Therefore, in the present study, human fetal adrenals at 6 weeks of gestational age were immunostained for 17 alpha-hydroxylase, the key enzyme for the production of C19-steroids. In parallel, chromaffin cells were characterized by immunohistochemical staining for chromogranin A, the major soluble protein in adrenal chromaffin granules. Large 17 alpha-hydroxylase-immunoreactive cells were found in the center of the adrenal anlagen during the 6th week of gestation. At the same developmental stage, chromaffin cells with a neuronal-like appearance occurred in the paraortic area and started to invade the adrenal primordium. Our results show that, even at week 6 gestational age, when chromaffin cells start to enter the adrenal anlagen, human adrenals already contain differentiated, 17 alpha-hydroxylase immunoreactive cortical cells which were located to the center of the primordium.

Adrenal Glands↗

PubMed1997

Effects of endothelin-1 on the rat pituitary-adrenocortical axis under basal and stressful conditions.

Endothelins (ETs) and their receptor subtypes A and B (ETA and ETB) are expressed in the various components of the mammalian hypothalamo-pituitary-adrenal (HPA) axis, but their involvement in the functional regulation of HPA is controversial. To gain insight into this topic, we have investigated the effects of ET-1 and/or the specific antagonists of ETA and ETB receptors (BQ-123 and BQ-788, respectively) on the plasma concentrations of ACTH, corticosterone and aldosterone of non-stressed (control) and ether- or cold-stressed rats. The study of the effects of the administration of the two ET-receptor antagonists alone could provide informations about the possible action of endogenous ETs on the HPA axis. Exogenous ET-1 increased ACTH, corticosterone and aldosterone blood levels in control rats, as well as evoked a sizable enhancement of the HPA axis response to ether stress and a marked depression of the response to cold stress. BQ-123 and BQ-788 did not prevent the stimulatory effect of exogenous ET-1 in control rats, but when administered alone, raised the plasma concentrations of ACTH, corticosterone and aldosterone. Both ET-receptor antagonists magnified the HPA axis response to ether and cold stresses, but their effect was not counteracted by exogenous ET-1. Although very difficult to interpret, our present findings allow us to conclude that endogenous ETs play a role in the maintenance of the basal activity of rat HPA axis acting through ETA and ETB receptor subtypes, which are partially insensitive to BQ-123 and BQ-788. Conversely, the involvement of ETs in the modulation of the HPA axis responses to various stresses is very doubtful.

Adrenocorticotropic Hormone↗