Biomedical subjects

L K Malendowicz

Publications and source records attributed to L K Malendowicz.

At least 37 records · Page 2Linked to original sources

PubMed2001

Effects of orexins A and B on the secretory and proliferative activity of immature and regenerating rat adrenal glands.

Orexins A and B are two hypothalamic peptides, involved in the central regulation of feeding, which act through two receptor subtypes, named OX1R and OX2R. OX1R is selective for orexin-A, and OX2R binds both orexins. We have investigated the effects of three subcutaneous injections of 10 nmol/kg body weight of orexins on the secretion and proliferative activity of immature (20-day-old) and regenerating rat adrenal cortex. The presence of both OX1R and OX2R mRNAs has been detected by reverse transcription-polymerase chain reaction in adult, immature and regenerating adrenals. Orexin-A increased corticosterone plasma concentration in immature rats, but not in animals with regenerating adrenals. Both orexins raised metaphase index (%o of metaphase-arrested cells) in immature rat adrenals, orexin-B being more effective than orexin-A. In contrast, both orexins equipotently lowered adrenal metaphase index at day 5 (but not day 8) of adrenal regeneration. We conclude that orexins (1) stimulate secretion and proliferative activity of immature rat adrenals, acting through OX1R and OX2R, respectively; and (2) do not affect secretion, but inhibit proliferative activity of regenerating adrenals, mainly via the activation of OX2R.

Adrenal Cortex↗

PubMed2001

Cortisol-secreting adrenal adenomas express 11beta-hydroxysteroid dehydrogenase type-2 gene yet possess low 11beta-HSD2 activity.

BACKGROUND: 11beta-hydroxysteroid dehydrogenase Type-2 (11beta-HSD2) is an unidirectional enzyme that catalyzes the conversion of glucocorticoid hormones cortisol and corticosterone (B) into their corresponding inactive forms, cortisone, and 11-dehydrocorticosterone (DH-B). We have provided evidence that 11beta-HSD2 is expressed as messenger RNA (mRNA) and protein in human adrenocortical cells, where its activity is inhibited in vitro by the main glucocorticoid agonists, adrenocorticotropic hormone (ACTH) and angiotensin-II. It seemed worthwhile, therefore, to study the gene expression and activity of 11beta-HSD2 in cortisol-secreting adrenocortical adenomas. METHODS: Three adrenal adenomas that produced Cushing syndrome were recruited. Three normal adrenal glands were obtained from patients who underwent unilateral nephrectomy with ipsilateral adrenalectomy for renal cancer. 11beta-HSD2 gene expression was studied by reverse transcriptionpolymerase chain reaction (RT-PCR) in adenoma and normal adrenocortical tissue. Cortisol, B, cortisone, and DH-B production by adenoma and adrenal slices in vitro was assayed by quantitative high-performance liquid chromatography (HPLC), and the activity of 11beta-HSD2 was evaluated by measuring the conversion of [3H]-cortisol to [3H]-cortisone. RESULTS: RT-PCR allowed the detection of the 11beta-HSD2 mRNA in the three adrenal adenomas and normal adrenal cortices examined. Under basal conditions, adenoma slices secreted higher amounts of cortisol and B, but markedly lower amounts of cortisone and DH-B than adrenal slices. ACTH raised cortisol and B production from both specimens, and it lowered cortisone and DH-B yield. The level basal conversion of [3H]-cortisol to [3H]-cortisone was notably less in adenomas than in adrenals, and ACTH decreased it in both tissues. CONCLUSIONS: Collectively, our findings indicate that cortisol-secreting adrenal adenomas express the 11beta-HSD2 gene, but the activity of the enzyme is suppressed in adenomas when compared with the normal adrenal cortex. We advance the hypothesis that the elevated local concentration of steroid hormones that occur in adenomas down-regulates 11beta-HSD2 activity, thereby contributing to their abnormal steroidogenic function.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗

PubMed2001

Buffering action of endogenous nitric oxide on the adrenocortical secretagogue effect of endothelins in the rat.

The secretagogue effect of endothelins (ETs) on the rat adrenal cortex is mediated by the ETB receptor. ETB receptors are coupled with nitric oxide (NO) synthase (NOS), and NO is known to inhibit steroid-hormone secretion from adrenal cortex. We investigated whether ETB-mediated NO production interferes with the stimulatory action of ETs on rat adrenal cortex. The selective agonist of ETB receptor BQ-3020 concentration-dependently increased aldosterone secretion from dispersed zona glomerulosa (ZG) cells and corticosterone secretion from dispersed zona fasciculata-reticularis (ZF/R) cells, and the NOS inhibitor NG-nitro-L-arginine methylester (L-NAME) potentiated the effect of BQ-3020 in a concentration-dependent manner. The guanylate cyclase inhibitor Ly-83583, at a concentration suppressing guanylin- and L-arginine-induced cyclic-GMP release from dispersed adrenocortical cells, did not affect the secretory response of ZG and ZF/R cells to BQ-3020. ET-1, an agonist of both ETA and ETB receptors, stimulated the release of both aldosterone and corticosterone by in situ perfused rat adrenal gland. This effect was potentiated by L-NAME and unaffected by Ly-83583. Collectively, our findings allow us to suggest that endogenous NO exerts in vivo and in vitro a cyclic-GMP-independent buffering action on the ETB receptor-mediated adrenocortical secretagogue action of ETs.

Adrenal Cortex↗

PubMed2001

Signaling pathways involved in the A and B receptor-mediated cortisol secretagogue effect of endothelins in the human adrenal cortex.

Endothelins (ETs) are a family of 21-amino acid hypertensive peptides, which together with their receptors ETA and ETB are expressed in human adrenal cortex. Evidence has been provided that ETs exert a potent secretagogue effect on human adrenocortical cells, acting through both ETA and ETB receptors. Therefore, it seemed worthwhile to study the signaling cascades mediating the cortisol secretagogue effect of the two receptor subtypes. Normal adrenal glands were obtained from consenting patients undergoing unilateral nephrectomy with ipsilateral adrenalectomy for renal cancer. Dispersed zona fasciculata-reticularis (ZF/R) cells were obtained by collagenase digestion and mechanical disaggregation. The selective activation of ETA and ETB receptors was obtained by exposing dispersed cells to ET-1 plus the ETB receptor antagonist BQ-788 and to the selective ETB receptor agonist BQ-3020, respectively. ETA and ETB receptors about equally contributed to the cortisol response of dispersed ZF/R cells to ETs. The phospholipase (PL) C inhibitor U-73122 abolished ETA-mediated secretory response, but only partially prevented the ETB-mediated one. The phosphatidylinositol 3-kinase inhibitor wortmannin and the protein kinase (PK) C inhibitor calphostin-C significantly blunted the secretory responses ensuing from the activation of both receptor subtypes, while the Ca(2+)-channel blocker nifedipine was ineffective. The ETB receptor-, but not the ETA receptor-mediated cortisol response was partially reversed by the cyclooxygenase (COX) inhibitor indomethacin, which when added together with U-73122 abolished it. The inhibitors of adenylate cyclase, PKA, tyrosine kinase and lipoxygenase did not affect the secretory response to the activation of either receptor subtype. ETA-receptor activation raised inositol triphosphate (IP3) production from dispersed ZF/R cells, while ETB-receptor stimulation enhanced both IP3 and prostaglandin-E(2) production. Collectively, our findings indicate that ETs stimulate cortisol secretion from human ZF/R cells, acting through ETA receptors exclusively coupled with PLC/PKC-dependent pathway and ETB receptors coupled with both PLC/PKC- and COX-dependent cascades.

Adenine↗

PubMed2001

Prolonged orexin administration stimulates steroid-hormone secretion, acting directly on the rat adrenal gland.

Orexins A and B are two hypothalamic peptides, that play a role in the central control of food intake. Orexins act via two subtypes of receptors: OX1R which is selective for orexin A, and OX2R which binds both orexins. Reverse transcription-polymerase chain reaction demonstrated the expression of both OX1R and OX2R gene in the adrenal cortex of adult female rats. The prolonged systemic administration of orexins A and B (20 ng/kg x day, for 7 days) affected neither adrenal weight and the morphology of adrenocortical zones (as evaluated by morphometric techniques) nor ACTH plasma concentration in rats. In contrast, the treatment with both orexins increased plasma concentration of both aldosterone and corticosterone. Taken together, these findings indicate that orexins exert a marked direct chronic secretagogue action on adrenocortical cells, acting through both OX1R and OX2R.

Adrenal Cortex↗

PubMed2001

Expression and function of adrenomedullin and its receptors in Conn's adenoma cells.

Adrenomedullin (ADM) is a hypotensive peptide, that derives from the proteolytic cleavage of pro(p)ADM and acts through two subtypes of receptors, called L1-receptor (L1-R) and calcitonin receptor-like receptor (CRLR). CRLR may function as a calcitonin gene-related peptide or a selective ADM receptor depending on the expression of the subtype 1 or the subtypes 2 and 3 of a family of proteins, named receptor-activity modifying proteins (RAMPs). Reverse transcription (RT)-polymerase chain reaction (PCR) allowed the detection of pADM mRNA in dispersed cells of eight Conn's adenomas (aldosteronomas). These cells also expressed peptidyl-glycine alpha-amidating monooxigenase, the enzyme converting immature ADM to the mature form, and contained sizeable amounts of ADM-immunoreactivity as measured by radioimmunoassay. RT-PCR also demonstrated the presence in aldosteronoma cells of the specific mRNAs of L1-R, CRLR and RAMPs 1-3. ADM (10(-8) M) inhibited angiotensin-II (10(-9) M)-simulated aldosterone secretion from cultured aldosteronoma cells, without affecting basal production. ADM (10(-8) M) also enhanced basal proliferation rate of cultured cells, as estimated by the 5-bromo-2'-deoxyuridine immunocytochemical technique. Both effects of ADM were annulled by the ADM-receptor selective antagonist ADM22-52 (10(-7) M). In conclusion, our study provides evidence that aldosteronoma cells express both ADM and ADM22-52-sensitive receptors. These findings, coupled with the demonstration that ADM exerts an aldosterone antisecretagogue action and a proliferogenic effect on cultured aldosteronoma cells, make it likely that endogenous ADM system plays a potentially important role in the paracrine or autocrine functional control of Conn's adenomas.

Adenoma↗

PubMed2001

Effect of pentagastrin on steroid secretion and proliferative activity of regenerating rat adrenal cortex.

The effects of three subcutaneous injections of 3 nmol/100 g body weight of the cholecystokinin type 2 (CCK2) receptor agonist pentagastrin on adrenocorticotrophic hormone (ACTH) and corticosterone secretion and proliferative activity of regenerating rat adrenal cortex were investigated. Pentagastrin did not alter either ACTH and corticosterone plasma concentrations or the adrenal mitotic index at day 5 of regeneration. In contrast, it increased (by about 50%) the adrenal mitotic index at day 8 of regeneration, and the effect was blocked by the simultaneous administration of equimolar doses of the CCK2-receptor antagonist PD-135,158. It is suggested that the activation of CCK2 receptors exerts a growth promoting action on the regenerating rat adrenal cortex.

Adrenal Cortex↗

PubMed2000

Endothelin-1[1-31], acting as an ETA-receptor selective agonist, stimulates proliferation of cultured rat zona glomerulosa cells.

Endothelin-1 (ET-1)[1-31] is a novel hypertensive peptide that mimics many of the vascular effects of the classic 21 amino acid peptide ET-1[1-21]. However, at variance with ET-1[1-21] that enhances aldosterone secretion from cultured rat zona glomerulosa (ZG) cells by acting via ETB receptors, ET-1[1-31] did not elicit such effect. Both ET-1[1-21] and ET-1[1-31] raised the proliferation rate of cultured ZG cells, the maximal effective concentration being 10(-8) M. This effect was blocked by the ETA-receptor antagonist BQ-123 and unaffected by the ETB-receptor antagonist BQ-788. Quantitative autoradiography showed that ET-1[1-21] displaced both [(125)I]PD-151242 binding to ETA receptors and [(125)I]BQ-3020 binding to ETB receptors in both rat ZG and adrenal medulla, while ET-1[1-31] displaced only [(125)I]BQ-3020 binding. The tyrosine kinase (TK) inhibitor tyrphostin-23 and the p42/p44 mitogen-activated protein kinase (MAPK) inhibitor PD-98059 abolished the proliferogenic effect of ET-1[1-31], while the protein kinase-C (PKC) inhibitor calphostin-C significantly reduced it. ET-1[1-31] (10(-8) M) stimulated TK and MAPK activity of dispersed ZG cells, an effect that was blocked by BQ-123. The stimulatory action of ET-1[1-31] on TK activity was annulled by tyrphostin-23, while that on MAPK activity was reduced by calphostin-C and abolished by either tyrphostin-23 and PD-98059. These data suggest that ET-1[1-31] is a selective agonist of the ETA-receptor subtype, and enhances proliferation of cultured rat ZG cells through the PKC- and TK-dependent activation of p42/p44 MAPK cascade.

Animals↗

PubMed2000

Acute orexin effects on insulin secretion in the rat: in vivo and in vitro studies.

Orexin-A and orexin-B are members of a family of newly described orexigenic hypothalamic neuropeptides. Scanty data are available suggesting the involvement of orexins in regulation of the secretion of pituitary hormones and in control of energy homeostasis. Present studies aimed to explain whether orexins affect blood insulin concentration and insulin secretion in the rat. To check this possibility, adult female rats were subcutaneously injected with different doses (1 or 2 nmol) of orexin-A or orexin-B. A bolus administration of orexin-A resulted in an increase in blood insulin (up to min 120) and glucose (60 min after injection) concentration. The higher dose of orexin-B, on the other hand, exerted effect on insulin secretion only at min 60 of experiment and neither doses changed blood glucose level. Only orexin-A stimulated insulin secretion in an in vitro perfusion system of the rat pancreas preparation, while orexin-B was less effective. The results demonstrate that orexins belong to a group of neuropeptides influencing insulin secretion and acting directly on the pancreas. Direct, at least partial, effect of orexin on insulin secretion may be connected with the regulation of metabolism by this peptide.

Animals↗

PubMed2000

Evidence for a paracrine role of adrenomedullin in the physiological resetting of aldosterone secretion by rat adrenal zona glomerulosa.

Adrenomedullin (ADM) has been recently found to directly inhibit agonist-stimulated aldosterone secretion by dispersed zona glomerulosa (ZG) cells and to stimulate basal catecholamine release by adrenomedullary fragments. In light of the fact that catecholamines enhance aldosterone secretion acting in a paracrine manner, we have investigated whether these two effects of ADM may interact when the integrity of the adrenal gland is preserved. ADM increased basal aldosterone output by adrenal slices containing a core of adrenal medulla, and the effect was blocked by the beta-adrenoceptor antagonist l-alprenolol. In contrast, ADM evoked a moderate inhibition of K(+)-stimulated aldosterone production, and the blockade was complete in the presence of l-alprenolol. The in vivo bolus injection of ADM did not affect plasma aldosterone concentration (PAC) in rats under basal conditions. Conversely, when rat ZG secretory function was enhanced (by sodium restriction or infusion with angiotensin-II [ANG-II]) or depressed (by sodium loading or infusion with the angiotensin-converting enzyme inhibitor captopril), ADM evoked a sizeable decrease or increase in PAC, respectively. The prolonged infusion with the ADM receptor antagonist ADM(22-52) caused a further enhancement of PAC in sodium-restricted or ANG-II-treated rats, and a further moderate decrease of it in sodium-loaded or captopril-administered animals. RIA showed that ADM plasma concentration did not exceed a concentration of 10(-11) M in any group of animals. Under basal conditions, ADM adrenal content was 1.2-2.0 pmol/g, which may give rise to local concentrations higher than 10(-8) M (i.e. well above the minimal effective ones in vitro). ADM adrenal concentration was markedly increased (from two-fold to three-fold) by both ZG stimulatory and suppressive treatments. Collectively, our findings suggest that in vivo 1) ADM, in addition to directly inhibit aldosterone secretion, may enhance it indirectly by eliciting catecholamine release, the two actions annulling each other under basal conditions; 2) under conditions leading to enhanced aldosterone secretion, the direct inhibitory effect of ADM prevails over the indirect stimulatory one, and the reverse occurs when aldosterone secretion is decreased; and 3) the modulatory action of ADM on the aldosterone secretion has a physiological relevance, endogenous ADM being locally synthesized in adrenals.

Adrenomedullin↗

PubMed2000

Effects of galanin on the secretion and proliferative activity of the immature and regenerating adrenal glands of rats.

The effects of galanin and the galanin-receptor antagonist (galanin-A) [D-Thr(6),D-Trp(8,9),15-ol]-galanin(1-15) on the immature and regenerating rat adrenal glands have been investigated in vivo. Adult female rats with adrenal regeneration and their offpring (20-day-old) were given three subcutaneous injections (28, 16, and 4 h before being killed) of 2 nmol/100 g galanin and/or galanin-A, and 0.1 mg/100 g vincristin 3 h before being killed. Plasma corticosterone concentration was measured by radioimmunoassay, and the mitotic index ( per thousand of metaphase-arrested cells) was evaluated. In immature rats, galanin increased plasma corticosterone concentration, without affecting mitotic index; the secretagogue effect was reversed by galanin-A, which alone was ineffective. In rats with regenerating adrenal, galanin-A increased both blood level of corticosterone and mitotic index; galanin was ineffective, but blocked the effects of galanin-A. These findings allowed us to draw the following conclusions: 1) galanin exerts a moderate glucocorticoid secretagogue action on immature rat adrenals, but endogenous galanin does not play a major physiological role in the functional control of the gland; and 2) endogenous galanin exerts a maximal tonic inhibitory control on both glucocorticoid secretion and proliferative activity of regenerating rat adrenals, whose physiological relevance remains to be investigated.

Adrenal Glands↗

PubMed2000

Secretin, glucagon, gastric inhibitory polypeptide, parathyroid hormone, and related peptides in the regulation of the hypothalamus- pituitary-adrenal axis.

Secretin, glucagon, gastric inhibitory polypeptide (GIP), and parathyroid hormone (PTH) belong, together with vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase (AC)-activating polypeptide, to a family of peptides (the VIP-secretin-glucagon family), which also includes growth hormone-releasing hormone and exendins. All the members of this peptide family possess a remarkable amino-acid sequence homology, and bind to G-protein-coupled receptors, whose signaling mechanism primarily involves AC/protein kinase A and phospholipase C/protein kinase C cascades. VIP and pituitary AC-activating polypeptide play a role in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and in this review we survey findings that also other members of the VIP-secretin-glucagon family may have the same function. Secretin and secretin receptors are expressed in the hypothalamus and pituitary gland, and secretin inhibits adrenocorticotropic hormone (ACTH) release. No evidence is available for the presence of secretin receptors in adrenal glands, but secretin selectively depresses the glucocorticoid response to ACTH of dispersed zona fasciculata-reticularis (ZF/R) cells. Glucagon and glucagon-like peptide-1 are contained in the hypothalamus, and all the components of the HPA axis are provided with glucagon and glucagons-like-1 receptors. These peptides exert a short-term inhibitory effect on stress-induced pituitary ACTH release and depress the ZF/R cell response to ACTH by inhibiting the AC/protein kinase A cascade; they also stimulate hypothalamic arginine-vasopressin release. GIP receptors are present in the ZF/R of the normal adrenals, and are particularly abundant in some types of adrenocortical adenomas and hyperplasias. GIP, through the activation of the AC/protein kinase A cascade, evokes a sizeable glucocorticoid secretagogue effect, leading to the identification of a food/GIP-dependent Cushing's syndrome. PTH and PTH-related protein are expressed in the hypothalamus and pituitary gland, and PTH and PTH-related protein receptors in all the components of the HPA axis. Both peptides enhance ACTH and arginine-vasopressin release, as well as stimulate aldosterone and glucocorticoid secretion of dispersed zona glomerulosa and ZF/R cells, respectively. The involvement of growth hormone-releasing hormone and exendins in the functional regulation of the HPA axis has not yet been extensively investigated.

Amino Acid Sequence↗

PubMed2000

Cerebellin stimulates the secretory activity of the rat adrenal gland: in vitro and in vivo studies.

Cerebellin is a 16-aminoacid peptide widely distributed in the central nervous system, where it exerts neuromodulatory functions. Cerebellin is contained in human adrenal medulla, and it has been recently demonstrated that cerebellin elicits catecholamine release by human adrenal in vitro. Aim of the present study was to ascertain whether cerebellin affects adrenal function in the rat. Cerebellin concentration-dependently (from 10(-9)to 10(-7)M) increased norepinephrine (but not epinephrine) and cyclic-AMP production by adrenomedullary tissue in vitro. The norepinephrine response to 10(-7)M cerebellin was blocked by the protein kinase (PK) A inhibitor H-89, but not by the phospholipase C inhibitor U-73122 or the PKC inhibitor calphostin-C. Cerebellin did not affect aldosterone and corticosterone secretion of dispersed zona glomerulosa and zona fasciculata-reticularis adrenocortical cells. Cerebellin concentration-dependently (from 10(-8)to 10(-7)M) enhanced norepinephrine release by in situ perfused rat adrenals. Cerebellin (10(-7)M) also elicited a significant rise in aldosterone and corticosterone output, and this effect was annulled by either the beta1-adrenoceptor antagonist l -alprenolol or H-89. Collectively, the present findings allow us to conclude that cerebellin 1) directly stimulates norepinephrine release via the adenylate cyclase/PKA-dependent signaling pathway; and 2) indirectly enhances adrenocortical secretion in vivo, through a paracrine mechanism involving medullary catecholamine release.

Adrenal Cortex↗

PubMed2000

Decrease of TSH levels and epithelium/colloid ratio in rat thyroid glands following administration of proadrenomedullin N-terminal peptide (12-20).

Adrenomedullin (AM) exerts a potent and long-lasting hypotensive effect and is considered to be an important hormone in blood pressure control. AM is a 52-amino-acid peptide synthesized as part of a 185-amino-acid preprohormone that also contains 20-amino-acid residues in the N-terminus, which has similar biological activity. This sequence is named a proadrenomedullin N-terminal 20 peptide (PAMP). Also, proadrenomedullin N-terminal peptide (PAMP)(12-20) exerts vasodepressor response, however this response is 3-fold less potent than the effect evoked by full-sequence peptide. Both AM and PAMP controls secretory activity of the pituitary gland and adrenal cortex, however, their action on the other endocrine glands is not recognized. Therefore, the aim of the study was to examine whether PAMP(12-20) is able to affect the structure and function of the rat thyroid gland. In adult female rats, subcutaneous PAMP(12-20) administration (1 or 4 nmol/rat/day for 6 days, autopsy 60 min after the last injection) had no effect on the weight of the thyroid gland. Peptide administration however, resulted in a dose-dependent increase in the volume of thyroid colloid, and lowered epithelium/colloid ratio in the gland (3.76 +/- 0.49, 2.66 +/- 0.27, 2.38 +/- 0.26, means +/- SE, n = 6, control, 1 and 4nmol PAMP/rat, respectively). PAMP administration changed neither the length of thyroid capillaries per unit area of surface nor their diameter. Lower dose of PAMP(12-20) significantly lowered blood TSH concentration (p < 0.01) while total and free T3 and T4 concentrations remained unchanged. Collectively, these findings suggest that PAMP(12-20) exerts a mild inhibitory effect on secretory activity of the rat thyroid gland.

Adrenomedullin↗

PubMed2000

Effects of recombinant murine leptin[1-147] and leptin fragment 116-130 on steroid secretion and proliferative activity of the regenerating rat adrenal cortex.

Leptin, the product of the ob gene, is a hormone mainly secreted by the adipose tissue, which acts through specific receptors (Ob-R) widely distributed in the body tissues. Ob-Rs are present in the mammalian hypothalamo-pituitary-adrenal axis, and evidence indicates that leptin regulates adrenocortical secretion. Moreover, leptin is known to act as a growth promoting factor in some tissues, including the endocrine ovary. We have investigated the effects of three subcutaneous injections of 2 nmol/100 g of native murine leptin[1-147] and of its biologically active fragment 116-130 on the secretory and proliferative activity of the regenerating rat adrenal cortex. Leptin[1-147] increased plasma aldosterone concentration at day 8 and plasma corticosterone concentration (PBC) at day 5 of regeneration, without affecting mitotic index. In contrast, leptin[116-130] lowered PBC and mitotic index at both times of adrenal regeneration. In light of the fact that adrenal regeneration is at least in part dependent on the pituitary ACTH, we conclude that: (i) native leptin moderately stimulates steroid secretion, acting directly on the adrenal cortex, through signaling mechanisms other than those involved in the ACTH action; (ii) native leptin is unable to enhance the proliferative activity of regenerating adrenals, which conceivably is maximally stimulated by ACTH; (iii)leptin[1-147] and leptin[116-130] differently interact with Ob-Rs or interact with different receptors; and (iv) leptin[116-130] inhibits the signaling pathways mediating both the secretagogue effect of native leptin and the proliferogenic effect of ACTH.

Adrenal Cortex↗

PubMed2000

Role of adrenal renin-angiotensin system in the control of aldosterone secretion in sodium-restricted rats.

This study examined the effect of the pharmacological manipulation of adrenal renin-angiotensin system (RAS) on aldosterone secretion from in situ perfused adrenals of rats kept on a normal diet and sodium restricted for 14 days. Neither the angiotensin-converting enzyme inhibitor captopril nor the nonselective angiotensin II receptor antagonist saralasin and the AT(1) receptor-selective antagonist losartan affected basal aldosterone output in normally fed rats. In contrast, they concentration dependently decreased aldosterone secretion in sodium-restricted animals, with maximal effective concentration ranging from 10(-7) to 10(-6) M. Captopril (10(-6) M), saralasin (10(-6) M), and losartan (10(-7) M) counteracted aldosterone response to 10 mM K(+) in sodium-restricted rats but not in normally fed animals. Collectively, these findings provide evidence that adrenal RAS plays a role in the regulation of aldosterone secretion, but only under conditions of prolonged stimulation of zona glomerulosa probably leading to overexpression of adrenal RAS.

Adrenal Glands↗

PubMed2000

Adrenomedullin enhances cell proliferation and deoxyribonucleic acid synthesis in rat adrenal zona glomerulosa: receptor subtype involved and signaling mechanism.

The effect of adrenomedullin (ADM) on the proliferative activity of the rat adrenal cortex has been investigated in vivo, using an in situ perfusion technique of the intact left gland. ADM and other chemicals were dissolved in the perfusion medium, and the perfusion was continued for 180 min. ADM infusion concentration dependently increased the mitotic index and [3H]thymidine incorporation into DNA in the zona glomerulosa (ZG; the maximal effective concentration was 10(-8) M), but not in inner adrenocortical layers, where basal proliferative activity was negligible. The effect of 10(-8) M ADM was equipotently counteracted by both the calcitonin gene-related peptide (CGRP) type 1 receptor antagonist CGRP-(8-37) and ADM-(22-52). The adenylate cyclase inhibitor SQ-22536 (10(-4) M), the cAMP blocker Rp-cAMP-S (10(-3) M), and the protein kinase A inhibitor H-89 (10(-5) M), although counteracting the ZG proliferogenic action of 10(-9) M ACTH, did not affect the 10(-8) M ADM-elicited increase in ZG DNA synthesis. Similar results were obtained using the phospholipase C inhibitor U-73122 (10(-5) M), the inositol-1,4,5-trisphosphate antagonist D,L-myo-inositol-1,4,5-trisphosphothiate (10(-4) M), and the protein kinase C inhibitor calphostin C (10(-5) M), which, however, significantly inhibited the ZG proliferogenic effect of 10(-9) M angiotensin II. The growth-promoting action of 10(-8) M ADM was not affected by the phospholipase A2 inhibitor AACOCF3 (10(-5) M), the cyclooxygenase (COX) inhibitor indomethacin (10(-5) M), or the mixed COX/lipoxygenase inhibitor phenidone (10(-5) M). In contrast, the ZG proliferogenic effect of 10(-8) M ADM was abolished by either the tyrosine kinase (TK) inhibitor tyrphostin-23 (10(-5) M) or the mitogen-activated protein kinase (MAPK) antagonists PD-98059 and U0216 (10(-4) M). ADM (10(-8) M) stimulated TK and p42/p44 MAPK activity in dispersed ZG, but not ZF, cells, and the effect was reversed by either 10(-6) M CGRP-(8-37) and ADM-(22-52) or preincubation with 10(-5) M tyrphostin-23. Collectively, our findings indicate that 1) ADM stimulates cell proliferation in the rat ZG, through CGRP-(8-37)- and ADM-(22-52)-sensitive receptors, probably of the CGRP1 subtype; and 2) the mitogenic effect of ADM is mediated by activation of the TK-MAPK cascade, without any involvement of the adenylate cyclase/protein kinase A-, phospholipase C/protein kinase C-, and COX- or lipoxygenase-dependent signaling pathways.

Adenylyl Cyclase Inhibitors↗

PubMed2000

Prolonged kallikrein inhibition does not affect the basal growth and secretory capacity of rat adrenal cortex, but enhances mineralo- and glucocorticoid response to ACTH and handling stress.

The effects on the pituitary-adrenocortical functions of the prolonged (7-day) blockade of endogenous bradykinin (BK) synthesis, obtained by the administration of the kallikrein inhibitor (K-I) cyclohexylacetyl-Phe-Arg-Ser-Val-Gln amide, were investigated in the rat. K-I treatment did not cause significant changes in the (i) body and adrenal weights; (ii) basal plasma levels of ACTH, aldosterone and corticosterone; and (iii) average volume of adrenocortical cells and their basal secretory capacity. Conversely, K-I administration induced a significant magnification of the in vivo mineralo- and glucocorticoid responses to the intraperitoneal (i.p.) bolus injection of ACTH. Moreover, K-I-treated rats, but not control ones, displayed a moderate and short-term adrenal secretory response to the mild stress evoked by the placebo i.p. injection. Collectively, these findings rule out the possibility that endogenous BK plays a relevant role in the control of adrenocortical function under basal conditions. However, they suggest that endogenous BK may be involved in quenching exceedingly high adrenocortical responses to ACTH and stresses.

Adrenal Cortex↗