This paper provides a key element for the calculation of the damage costs of air pollution, namely the valuation of mortality, important because premature mortality makes by far the largest contribution. Whereas several studies have tried to quantify the cost of air pollution mortality by multiplying a number of deaths by the ‘value of prevented fatality’ (also known as ‘value of statistical life’), we explain why such an approach is not correct and why one needs to evaluate the change in life expectancy due to air pollution. Therefore, an estimate for the monetary value of a life year (VOLY) is needed. The most appropriate method for determining VOLY is contingent valuation (CV). To determine VOLY for the EU, we have conducted a CV survey in 9 European countries: France, Spain, UK, Denmark, Germany, Switzerland, Czech Republic, Hungary, and Poland with a total sample size of 1463 persons. Based on the results from this 9-country CV survey we recommend a VOLY estimate of 40,000 € for cost–benefit analysis of air pollution policies for the European Union. As for confidence intervals, we argue that VOLY is at least 25,000 € and at the most 100,000 €.

The biological actions of leptin on target tissues are mediated via several isoforms of receptors (Ob-Rs), which may differently interact with native leptin and its fragments. Based on the presence in the rat adrenals of at least two Ob-R isoforms and the conflicting findings on the effect of leptin on adrenocortical secretion, we investigated the effects of the native leptin and several leptin fragments (10(-8) and 10(-6)M) on aldosterone and corticosterone secretion from freshly dispersed rat zona glomerulosa (ZG) and zona fasciculata-reticularis (ZF/R) cells. Reverse transcription (RT)-polymerase chain reaction (PCR) showed the expression of Ob-Ra and Ob-Rb mRNAs in both ZG and ZF/R cells. Native murine leptin (1-147) enhanced aldosterone and corticosterone secretion from dispersed ZG and ZF/R cells, and similar effects were elicited by murine leptin fragment 116-130, and human leptin fragments 138-167, 150-167 and [Tyr] 26-39. Human leptin fragment 93-105 was ineffective, while fragment 22-56 decreased corticosterone output without affecting aldosterone secretion. Taken together, our findings indicate that in rat adrenocortical cells leptin and leptin fragments may differently interact with Ob-Rs or interact with different Ob-R isoforms. Moreover, they suggest that (1) the direct adrenocortical secretagogue effect of leptin mainly depends on the C-terminal sequence 116-166; and (2) the N-terminal sequence is not needed for leptin to activate Ob-Rs positively coupled to steroidogenesis, but is possibly responsible for a direct inhibitory effect on glucocorticoid secretion.

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.

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.

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.

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.

We have investigated the effects of cerebellin on the pituitary adrenal axis and the proliferative activity of immature and regenerating adrenal cortex in the rat. The acute bolus administration of cerebellin did not alter ACTH plasma concentration, but at its higher dose (15 nmol/kg) the peptide enhanced the blood levels of both aldosterone and corticosterone. Three injections of cerebellin (10 nmol/kg) markedly increased the mitotic index (parts per thousand of metaphase-arrested cells) in the zona glomerulosa of immature rat adrenals. This treatment did not alter either aldosterone or corticosterone plasma concentrations in rats bearing regenerating adrenals, but did it decrease the proliferative activity at day 8 of adrenal regeneration. We conclude that cerebellin exerts its adrenocortical secretagogue and proliferogenic actions acting directly on the adrenal gland of adult and immature rats, independently of any effect on the pituitary ACTH release. The lack of secretagogue effects and the clearcut antiproliferogenic action observed in rats with regenerating adrenals may be ascribed to the effects of cerebellin on the various mechanism involved in this process.

The effects of galanin and the galanin-receptor antagonist (galanin-A) [d-Thr6,d-Trp8,9,15-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 (‰ 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.

Gastric inhibitory polypeptide (GIP), a gastrointestinal hormone released after feeding, has been recently found to evoke a moderate glucocorticoid secretory effect in the rat. We have investigated whether a prolonged (from 1 to 3 weeks) infusion with ACTH changes the responsiveness of rat adrenal zonae fasciculata (ZF) and reticularis (ZR) to GIP. As expected, ACTH treatment caused hypertrophy of adrenals, rise in the plasma corticosterone concentration, and increase in the basal production of both corticosterone and cyclic-AMP by dispersed ZF/R cells. GIP evoked a net increase in corticosterone plasma concentration, and corticosterone and cyclic-AMP release by dispersed ZF/R cells in ACTH-untreated rats. ACTH infusion enhanced in vivo and in vitro adrenal responses to GIP in relation to the duration of treatment. The protein kinase A (PKA) antagonist H-89 abolished corticosterone response to GIP of ZF/R cells from either untreated and ACTH-treated rats. Autoradiography evidenced [I-125]GIP binding sites in the ZF/R, and computer-assisted densitometry showed that their number significantly increased as a function of the duration of ACTH infusion. [I-125]GIP binding was displaced by an excess of cold GIP, and unaffected by ACTH. Taken together, these findings suggest that prolonged ACTH treatment induces ZF/ R cell glucocorticoid hyper-responsive,ness to GIP in rats, probably through the up-regulation of adenylate cyclase/PKA-coupled GIP receptors.

Neurotensin (NT) and bombesin (BM)-like peptides are known to be involved in the regulation of the rat hypothalamo-pituitary-adrenal axis. By using selective NT- and BM-receptor antagonists (NT-A and BM-A, respectively) we investigated whether endogenous NT and BM-like peptides play a role in the control of rat adrenal secretion and growth during enucleation-induced regeneration. At day 5 of regeneration, NT-A did not affect the plasma concentrations of aldosteronc (PAC) and corticosterone (PBC), but at day 8, it raised both PAC and PBC over the respective baseline value; the simultaneous administration of NT abolished this effect of NT-A. BM-A did not alter PAC and PBC at day 5 of regeneration, while at day 8 it enhanced PBC, an effect reversed by BM. NT-A did not alter mitotic index, and BM-A lowered it at both day 5 and day 8 of regeneration, an effect suppressed by the simultaneous administration of BM. Collectively, these findings allow us to draw the following conclusions: 1) endogenous NT and BM-like peptides influence adrenocortical regeneration in rats; 2) NT exerts a tonic inhibitory action on both aldosterone and corticosterone secretion, without affecting cell-proliferation rate; and 3) BM-like peptides exert a tonic suppressive effect on corticosterone production, coupled with a clear-cut stimulating effect on cell proliferation.

Cholecystokinin (CCK) is a multifunctional regulatory peptide, which acts through two main subtypes of receptors, named CCK-A and CCK-B. Evidence indicates that CCK modulates cell proliferation in various tissues in a paracrine manner, and proofs are available of the presence of CCK in both adrenal glands and thymus. Hence, we have investigated the possible mitogenic action of this peptide on these two tissues, by evaluating the /1000 of metaphase-arrested cells after vincristin injection (mitotic index). The systemic administration of CCK (three subcutaneous injections of 20 nmol/kg, 28, 16 and 4 h before the sacrifice) increased the mitotic index in both the outer adrenal and thymus cortexes of immature (20-day-old) rats and the enucleated adrenal gland of adult (2-month-old) animals at day 5 and 8 of regeneration. The simultaneous administration of equimolar doses of a selective CCK-A receptor antagonist blocked the effect of CCK, while a CCK-B antagonist was ineffective. These findings indicate that CCK exerts a marked CCK-A-mediated proliferogenic effect on both adrenal cortex and thymus in the rat, the physiological relevance of which, however, remains to be demonstrated. In fact, the administration of the CCK-A antagonist alone was ineffective, thereby casting doubts on the role played by endogenous CCK in the maintenance and stimulation of adrenal and thymus growth.

W patogenezie raka błony śluzowej trzonu macicy w około 5% wymienia się czynnik genetyczny. Badania epidemiologiczne analizujące przyczyny zgonów krewnych pierwszego stopnia umożliwiają oszacowanie wpływu predyspozycji dziedzicznych na zachorowalność na nowotwory złośliwe w poszczególnych lokalizacjach narządowych. Celem pracy jest wyodrębnienie rodzin z predyspozycją do swoistego miejscowego gruczolakoraka błony śluzowej trzonu macicy.

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.

Pneumadin (PNM) is a biologically active decapeptide, which has previously been found to enhanced rat adrenal growth; the mechanism is indirect and probably involves the stimulation of both arginine-vasopressin (AVP) and ACTH release. The effects of 2- and 6-day PNM administration on the atrophic adrenal cortices of rats treated for 8 and 12 days, respectively, with daily subcutaneous injections of 15 or 40 g/100 g body weight of dexamethasone (Dx) were investigated. Morphometry showed that PNM counteracted Dx-induced adrenal atrophy, by preventing the decrease in volume and number of the parenchymal cells. PNM raised aldosterone and corticosterone production of adrenal quarters from Dx-treated rats, but it did not evoke significant changes in the plasma concentrations of the two hormones. The preventive effect of PNM was only partial and almost exclusively evident in rats administered the lower dose of Dx. In light of these findings the following conclusions are drawn: (i) PNM is able to partially overcome the Dx-induced inhibition of the rat hypothalamo-pituitary-adrenal axis, probably by stimulating the pituitary release of AVP and ACTH, that in turn enhance adrenocortical growth; (ii) the PNM-induced improvement of the secretory capacity of atrophic adrenocortical cells is not sufficient to raise the blood level of corticosteroid hormones; and (iii) Dx exerts a direct inhibitory action on adrenocortical cells, which is not counteracted by PNM.

Pneumadin (PNM), a decapeptide isolated from mammalian lungs, has previously been found not to affect corticosterone release from dispersed rat adrenocortical cells, but to enhance it in vivo, probably by stimulating the pituitary release of ACTH and arginine-vasopressin (AVP). The present study shows that the administration of PNM markedly raised corticosterone production by rat adrenal slices containing medullary chromaffin cells, and that this effect was prevented by antagonists of both ACTH and AVP receptors. The conclusion is drawn that PNM elicits the intra-adrenal release of ACTH and AVP, which in turn stimulates glucocorticoid secretion by adrenocortical cells in a paracrine manner.

The effects of a prolonged administration of bradykinin (BK) and/or D-Arg, [Hyp3, D-Phe7]-BK, a specific antagonist of BK receptors (BK-A) (daily subcutaneous injections of 4 nmol/rat for 6 days) on the function of the pituitary-adrenocortical axis were investigated. BK did not change plasma aldosterone concentration (PAC), but markedly lowered that of corticosterone (PBC) and consequently induced a compensatory hypersecretion of ACTH by the pituitary gland. BK-A did not apparently affect the function and growth of the adrenal gland, but, when administered together with BK, markedly raised both PAC and PBC, and provoked a significant atrophy of the adrenal gland, probably due to loss of parenchymal cells. Taken together, these rather puzzling findings do not appear to provide clear evidence for the involvement of BK in the physiological regulation of adrenocortical growth and steroidogenic capacity in rats.

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Pneumadin (PNM) is a biologically active decapeptide, originally isolated from mammalian lungs, that has been previously found to acutely stimulate pituitary-adrenocortical axis in rats. The effects of 2-day PNM administration on the atrophic adrenal cortices of rats treated for 8 days with dexamethasone (DX) were investigated. PNM significantly raised adrenal weight and the average volume of adrenocortical cells. The decapeptide strikingly increased ACTH plasma concentration; however, the blood levels of aldosterone and corticosterone, as well as steroid output by adrenal quarters were not apparently affected. In light of these findings the following conclusions can be drawn: (i) PNM enhances the growth of adrenal cortex in DX-administered rats by a mechanism involving the stimulation of ACTH release; and (ii) PNM treatment is probably too short to allow DX-atrophied adrenocortical cells to re-acquire all their differentiated secretory capacities.

The effects of neuromedin-K (NMK) on the rat hypothalamo-pituitary-adrenal (HPA) axis were studied both in vivo and in vitro. A subcutaneous injection of 1 nmol/100 g NMK evoked a rise in plasma ACTH level at 30 min, increased plasma corticosterone (B) concentration (PBC) at 60 and 120 min, and did not alter plasma aldosterone (ALDO) concentration (PAC). The administration of 3 nmol/100 g NMK induced a rise in plasma ACTH level at 120 min and a drop of PBC at 30 min; it increased PBC and PAC at 60 and 120 min. NMK did not affect basal B secretion of dispersed zona fasciculata/reticularis (ZF/R) cells, but markedly enhanced basal ALDO production by dispersed zona glomerulosa (ZG) cells (minimal and maximal effective concentrations were 10(-9) M and 10(-7) M). Video-imaging analysis showed that NMK (10(-8) M) increased intracellular Ca2+ concentration in dispersed ZG cells, but not in ZF/R ones. These findings indicate that NMK exerts a complex modulatory action on the rat HPA axis: low doses of NMK appear to evoke a transient stimulation of ACTH release, while high doses seem to exert a short-term inhibition of glucocorticoid synthesis followed by the compensatory hypersecretion of ACTH; moreover, elevated doses of NMK also exert a strong ALDO secretagogue action by acting directly on the ZG cells.