NaHS induces relaxation response in prostaglandin F(2α) precontracted bovine retinal arteries partially via K(v) and K(ir) channels.

Hydrogen sulphide (H2S) is known to be produced endogenously in ocular tissues with the highest levels in the retina and cornea. However, it is yet unclear whether it can modulate retinal arterial tone. Herein, we aimed to investigate the effectiveness and the mechanism of the action of H2S in the isolated bovine retinal arteries. For this purpose, the probable vasorelaxant and inhibitory effects of H2S on vascular reactivity were tested comparatively in the retinal arteries by using the donor, sodium hydrosulphide (NaHS). Thereafter, in relation to the mechanism of action of H2S, the role of nitric oxide (NO) and endothelial vasodilators of cyclooxygenase pathway as well as ATP-sensitive potassium channel (KATP), voltage-dependent potassium channel (Kv), calcium-activated potassium channel (KCa(++)), inwardly rectifying potassium channel (Kir), L-type voltage-dependent calcium channel and adenylate cyclase pathway were evaluated. NaHS (1µM-3mM) displayed prominent relaxations over the concentrations of 300 µM in both PGF2α and K(+) precontracted retinal arteries. Comparatively, in the presence of NaHS (3 mM) pretreatment, the maximum contractile responses and pEC50 values to PGF2α and K(+) were significantly reduced as well. Neither the presence of the known inhibitors of NO synthase, guanylate cyclase, cyclooxygenase, adenylate cyclase, KATP and KCa(++) type K(+) channels, and L-type voltage-dependent calcium channels nor the removal of endothelium, modified the relaxation response to NaHS in retinal arteries. However, a remarkable decrease was observed in the presence of the inhibitors of Kv or Kir type K(+) channels. In addition, administration of l-cysteine (1µM-3mM), the precursor of H2S, induced a modest relaxation response in PGF2α precontracted retinal arteries, which was significantly decreased in the presence of cystathionine-ß-synthase (CBS) inhibitor, aminooxyacetic acid, but was unmodified in the presence of the cystathionine-γ-lyase (CSE) inhibitor, dl-propargylglycine or the deendothelization of retinal arteries. Our findings suggested that H2S might play a substantial role in the regulation of retinal arterial tone possibly by acting on Kv and Kir channels.

Inhibitory role of the endothelium in the response of isolated coronary arteries to platelets.

Aggregating autologous platelets caused contraction of isolated rings of canine left circumflex arteries. The contractions were augmented after removal of the endothelium and were attenuated by serotonergic antagonists. During contraction caused by prostaglandin F2 alpha, aggregating platelets caused a transient increase in tension followed by a profound relaxation of arteries with endothelium, but caused only further contraction of arteries without endothelium. These observations demonstrate the importance of the vascular endothelium in opposing the constriction of coronary vessels caused by 5-hydroxytryptamine and other substances released from aggregating platelets.

F-series prostaglandin function as sex pheromones in the Korean salamander, Hynobius leechii.

In order to test whether prostaglandins (PGs) function as sex pheromones in Hynobius leechii, a salamander that externally fertilizes its eggs, we conducted electro-olfactogram (EOG) studies with 19 PGs, liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses of female and male holding waters, and behavioral tests on selected PGs. Of the 19 PGs tested, only three induced strong EOG responses from both males and ovulated females: 15-epi-prostaglandin F2alpha (15(R)-PGF2alpha), 15-keto-prostaglandin F2alpha (15K-PGF2alpha), and 13,14-dihydro-15-keto-prostaglandin F2alpha (13,14-dh-15K-PGF2alpha). In the LC-MS/MS studies, samples of holding water from ovulated females contained higher concentrations of 15(R)-PGF2alpha, PGF2alpha, and 13,14-dh-15K-PGF2alpha than those from males or oviposited females. In the behavioral tests, only 15(R)-PGF2alpha and ovulated female holding water induced significant reproductive behavior from male salamanders. These results suggest that F-series prostaglandins function as sex pheromones in amphibians.

An investigation into the role of prostaglandins in zebrafish oocyte maturation and ovulation.

This study explored the potential for ovarian-derived prostaglandins (PGs) to be involved in the regulation of oocyte maturation and ovulation in zebrafish. It was demonstrated that cultured vitellogenic follicles have the capacity to produce prostaglandin E(2) (PGE(2)) and PGF(2alpha) in response to arachidonic acid (AA) in a concentration-dependent manner, and that AA stimulates the in vitro production of 17beta-estradiol (E(2)). The production of AA-stimulated PGF(2alpha) was significantly reduced by treatment with the non-selective cyclooxygenase (COX) inhibitor, indomethacin (INDO). Treatment of full-grown follicles with AA did not induce oocyte maturation as assessed by germinal vesicle breakdown, but INDO significantly decreased the rate of spontaneous maturation. Using Real-Time PCR, it was shown that follicles of different developmental size classes (primary growth and pre-vitellogenic, early-vitellogenic, and mid- to full-grown vitellogenic) express enzymes that release (cytosolic phospholipase A(2) (cPLA(2)); phospholipase Cgamma1) or metabolize (COX-1, COX-2, and prostaglandin synthase-2) AA to PG metabolites. The expression of cPLA(2) was found to be significantly greater in full-grown follicles compared to follicles of the pre- and early-vitellogenic stages. In vivo studies demonstrated that breeding groups of zebrafish exposed to 100 microg/L INDO exhibited reduced spawning rates and clutch sizes compared with control and 1 microg/L INDO exposed fish. In other studies, it was shown that naturally spawning groups of females exhibit increased ovarian levels of PGF(2alpha), E(2), and 17alpha,20beta-dihydroxy-4-pregnen-3-one (a maturation-inducing hormone in zebrafish) near the time of ovulation compared with non-breeding females. Collectively, these experiments indicate that the AA pathway in zebrafish ovaries is involved in the regulation of oocyte maturation and ovulation and a non-selective inhibitor of COX disrupts these processes.

Peptide growth factors in amphibian embryogenesis: intersection of modern molecular approaches with traditional inductive interaction paradigms.

Recent discoveries of the role peptide growth factors (PGFs) play in regulating embryonic patterning and differentiation have profoundly influenced research on the molecular biology of early amphibian embryogenesis. Several PGFs have been recognized to be present as endogenous components of amphibian eggs and early embryos, while other PGFs -- which are known from heterologous systems (e.g., Drosophila) -- exert remarkable effects when injected as either protein or mRNA into eggs/embryos or when added to cultured embryonic tissue. For a variety of reasons (reviewed herein) optimism abounds that an understanding in molecular terms of the classical Spemann and Nieuwkoop tissue interactions which are generally believed to drive embryonic patterning is within reach. A critical assessment of the interpretations of some of the contemporary data on PGFs (included herein) should, however, temper some of that optimism. Likely, multiple rather than single PGFs act in a combinatorial fashion to contribute to individual patterning events. As well, substantial redundancy in PGF regulatory circuits probably exists, so the heavy reliance on tissue culture assays and overexpression studies which characterize much recent research needs to be circumvented. Potential experimental approaches for "next generation" experiments are discussed.

Complementing ODE-Based System Analysis Using Boolean Networks Derived from an Euler-Like Transformation.

In this paper, we present a systematic transition scheme for a large class of ordinary differential equations (ODEs) into Boolean networks. Our transition scheme can be applied to any system of ODEs whose right hand sides can be written as sums and products of monotone functions. It performs an Euler-like step which uses the signs of the right hand sides to obtain the Boolean update functions for every variable of the corresponding discrete model. The discrete model can, on one hand, be considered as another representation of the biological system or, alternatively, it can be used to further the analysis of the original ODE model. Since the generic transformation method does not guarantee any property conservation, a subsequent validation step is required. Depending on the purpose of the model this step can be based on experimental data or ODE simulations and characteristics. Analysis of the resulting Boolean model, both on its own and in comparison with the ODE model, then allows to investigate system properties not accessible in a purely continuous setting. The method is exemplarily applied to a previously published model of the bovine estrous cycle, which leads to new insights regarding the regulation among the components, and also indicates strongly that the system is tailored to generate stable oscillations.

Action of prostaglandin E1 and F2 alpha on the pinocytic activity of horseradish peroxidase in bone-marrow derived macrophages.

The influence of prostaglandin E1 and F2 alpha on the pinocytic activity of bone-marrow macrophages was studied biochemically and morphometrically. The results show that prostaglandin E1 induces 44% inhibition of pinocytosis of horseradish peroxidase; prostaglandin F2 alpha has no significant effect. Morphometrical analysis of electron micrographs demonstrates that inhibition of pinocytosis is connected with diminished average size and raised number of pinocytic vesicles. The influence of prostaglandin E1 on pinocytosis is fully reversible. Further experiments are needed to explore the molecular mechanism of the prostaglandin E1 induced alteration of membrane function.

Hormonal regulation of epidermal tumor development.

The effects of hormones and hormone-like substances such as thyroxine, estradiol, hydrocortisone, calcitonin, prostaglandins (F2a, A2) or hormone deficiency (hypophysectomy, gonadectomy) on the development of carcinomas in mice and rats induced by 3-methylcholanthrene were investigated. Thyroxine, PGF2a, calcitonin, and estradiol markedly enhanced the development of squamous cell carcinomas and basal cell carcinomas; an inhibition occurred following hydrocortisone, hypophysectomy, and gonadectomy. DNA labeling using [3H]-thymidine and radioautography revealed that DNA synthesis in neoplastic cells is also markedly influenced by the same hormones. Tumor histology and ultrastructure are profoundly affected and an increase of epithelial pearls, hyperchromatic basophilic cells, tonofilaments, polyribosomes, and lysosomes is observed following thyroxine and PGF2a. An increase of keratinization and intramitochondrial granules occurred with estradiol and increased sclerosis followed calcitonin. A marked reduction of cell organelles occurred after hydrocortisone, hypophysectomy, and gonadectomy. Scanning electron microscopy shows salient changes in tumor cytoarchitecture and cell surfaces (blebs, ruffles). These findings demonstrate that hormones can change the development of carcinomas, DNA synthesis as well as their cellular differentiation and consequently may be important modulators of epidermal carcinogenesis.

Inhibition by estradiol of human chorionic gonadotropin-induced progesterone accumulation in isolated human luteal cells: lack of mediation by prostaglandin F.

Estradiol has been previously reported to be a potent inhibitor of hCG-stimulated progesterone accumulation in isolated cells from human corpora lutea of the menstrual cycle. We assessed the role of prostaglandin (PG) in this in vitro estradiol-induced inhibition by measuring PGF and adding a blocker of PG synthesis (indomethacin) to the incubation medium. The inhibition by estradiol of hCG-stimulated progesterone accumulation occurred without any increase in PGF accumulation in the incubations. Furthermore, PGF accumulation was markedly reduced (P less than 0.05) at all concentrations of indomethacin testes (0.1, 1, and 10 microgram/ml), but the inhibitory effect of estradiol on hCG-stimulated progesterone accumulation was not prevented. These data suggest that the inhibitory effect of estradiol observed in vitro is not mediated by PGs.

Role of prostaglandins in acetylcholine-induced contraction of aorta from spontaneously hypertensive and Wistar-Kyoto rats.

Evidence in support of prostaglandin (PG) H2 as the endothelium-derived contracting factor released in response to acetylcholine in vessels from adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) is to a large degree indirect. Therefore, the purpose of the present study was to test the hypothesis that a prostaglandin or prostaglandins other than PGH2 may serve as the endothelium-derived contracting factor that mediates acetylcholine-induced contraction in these vessels. Acetylcholine-induced contraction of endothelium-intact aorta from 7- to 12-month-old SHR and WKY in the presence of the nitric oxide synthase inhibitor N omega-nitro-L-arginine was abolished by indomethacin and only partially decreased by the thromboxane (Tx) A2/PGH2 receptor antagonist SQ29548. Contraction induced by the TxA2/ PGH2 receptor agonist U46619 was abolished by SQ29548. These findings suggest that in endothelium-intact aorta from SHR and WKY, acetylcholine causes the release of a cyclooxygenase product other than PGH2 that induces contraction independently of TxA2/PGH2 receptor activation. To investigate which prostaglandin or prostaglandins could be responsible for the TxA2/PGH2 receptor-independent component, we challenged endothelium-denuded aorta from SHR and WKY with various prostaglandins in the presence of SQ29548. In SQ29548-treated aorta from 7- to 12-month-old rats, maximal contractions to PGF2 alpha, PGE2, and carbacyclin (a PGI2 analogue) were greater than the magnitude of acetylcholine-induced contraction. These findings suggest that PGF2 alpha, PGE2, and/or PGI2 could serve as mediators of the TxA2 receptor-independent component of the acetylcholine-induced contraction. However, in studies with SQ29548-treated aorta from 4- to 6-week-old SHR and WKY (an age at which acetylcholine-induced contraction is known to be absent), maximal contraction to PGF2 alpha and PGE2 was also greater or equivalent to that of SQ29548-treated aorta from 7- to 12-month-old rats, whereas carbacyclin induced negligible contraction. Thus, unlike PGE2 and PGF2 alpha, the age-dependent pattern of contraction induced by carbacyclin closely resembles the pattern induced by acetylcholine. We also measured the levels of PGI2 released in response to acetylcholine and found that they are sufficient to account for the TxA2 receptor-independent component of the acetylcholine-induced contraction. Thus, we propose that PGI2 released in response to acetylcholine may serve as the endothelium-derived contracting factor that elicits the TxA2/PGH2 receptor-independent and dependent components of the acetylcholine-induced contraction.

Partial characterization of a uteroglobin-like protein in the human uterus and its temporal relationship to prostaglandin levels in this organ.

During the past decade several corticosteroid-dependent, low mol wt proteins with phospholipase-A2 (PLA2) inhibitory activity have been described. This family of proteins is collectively known as lipocortins. Blastokinin or uteroglobin (utg), a progesterone-induced protein, first discovered in the pregnant rabbit uterus, is also a potent PLA2 inhibitor, but genetically distinct from lipocortins. Although utg has been found in rabbits, its presence in humans has not been well established. Here, we present biochemical, immunological, and immunohistological evidence for the detection of a utg-like protein in the human uterus. Since inhibition of PLA2 may modulate tissue eicosanoid levels and since rabbit utg has been reported to be a potent PLA2 inhibitor, we also studied the temporal relationship between utg and tissue prostaglandin E2 and F2 alpha levels in estrogen- and progesterone-dominated endometrial tissue. We found an inverse temporal relationship between utg-like protein and eicosanoid levels in this organ. Since some eicosanoids (e.g. prostaglandins, leukotrienes, etc.) are known to be involved in smooth muscle contractility and inflammatory processes, our findings may help to understand the pathogenesis of some human disorders in which abnormal eicosanoid production occurs.

Relationship between zinc and prostaglandin metabolisms in plasma and small intestine of rats.

The effect of zinc nutriture on levels of prostaglandin (PG) E2, F2 alpha and 6-keto-PGF1 alpha in the plasma and small intestine of rats, and that of PGE2 and PGF2 alpha on unidirectional uptake of 65Zn by everted gut sac of rats was determined. When zinc was given intraperitoneally, plasma PGE2 and intestinal PGF2 alpha levels increased, while the intestinal PGE2 and the plasma PGF2 alpha and 6-keto-PGF1 alpha levels decreased in accordance with the amount of zinc given. Oral administration of excess zinc increased intestinal PGE2, PGF2 alpha and 6-keto-PGF1 alpha levels and the plasma 6-keto-PGF1 alpha levels. The intestinal levels of PGE2 increased significantly only in rats on zinc excess diet, and of PGF2 alpha only in rats on a zinc deficient diet. The plasma PGE2 levels in rats on both zinc deficient and zinc excess diets increased but PGF2 alpha levels in zinc deficient rats were greatly reduced compared to controls. Unidirectional zinc uptake by everted gut sac of the rat is also enhanced by PG metabolites. These results are consistent with the view that PGs participate in regulating the zinc transport mechanism in small intestine.

A chemotactic role for prostaglandins released from polymorphonuclear leucocytes during phagocytosis.

1. Prostaglandin E1 is chemotactic at concentrations down to 10 ng/ml for rabbit polymorphonuclear (PMN) leucocytes. Prostaglandins E2 and F2alpha have little or no chemotactic effect at concentrations up to 10 mug/ml. 2. Washed PMN leucocytes produced a chemotactic agent during phagocytosis, but not in the presence of indomethacin (28 muM). 3. Phagocytosing PMN leucocytes produce up to ten times as much prostaglandin as do resting cells. Some of this is prostaglandin E1 as judged by thin layer chromatography and differential bioassay. This prostaglandin production by PMN leucocytes is abolished by indomethacin (28 muM). 4. Ultrasonicated suspensions of PMN leucocytes produced prostaglandin from arachidonic aicd. This synthesis is inhibited by indomethacin. 5. Homogenates of PMN leucocytes which have been pre-incubated withe bacteria for 30 min show more prostaglandin synthetase activity than homogenates from PMN leucocytes which have not been exposed to bacteria. 6. It is concluded that in some forms of inflammation, prostaglandin E1 may play a controlling role in cellular migration. 7. PMN leucocytes may contribute to the generation of prostaglandins found in some inflammatory lesions.

The possible roles of histamine, 5-hydroxytryptamine and prostaglandin F2alpha as mediators of the acute pulmonary effects of endotoxin.

1 In an attempt to investigate the possible role of released vasoactive substances in mediating the pulmonary pressor responses to E. coli endotoxin, cats were pretreated with histamine, 5-hydroxytryptamine (5-HT) or prostaglandin antagonists, with a histamine depleting agent (compound 48/80) or with an inhibitor of prostaglandin synthetase (sodium meclofenamate).2 The administration of endotoxin (2 mg/kg) resulted in a rapidly developing pulmonary hypertension (pressure twice normal after 2-3 min), increases in right atrial and intratracheal pressures, systemic hypotension and bradycardia. These effects were unaffected by methysergide in a dose sufficient to prevent the effects of intravenously administered 5-HT.3 Endotoxin responses were also unaffected by a combination of mepyramine and burimamide in doses sufficient to reduce markedly the effects of intravenously-administered histamine. In cats pretreated (chronically or acutely) with compound 48/80, endotoxin induced a transient pulmonary pressor response which was not maintained.4 The pulmonary and systemic responses to endotoxin were prevented by the prior administration of the prostaglandin antagonist, polyphloretin phosphate and by pretreatment with the prostaglandin synthetase inhibitor, sodium meclofenamate.5 It is concluded that a pulmonary vasoconstrictor prostaglandin is involved in the acute response to endotoxin in the cat.

Renal blood flow autoregulation and renal venous prostaglandins in the pump-perfused canine kidney (in situ).

1. Renal autoregulation of blood flow was re-examined in the pump-perfused canine kidney and concentrations of prostaglandins E and F in the renal venous plasma were measured by radioimmunoassay. 2. At low perfusion pressures, below the range of autoregulation, prostaglandin E and F concentrations rose and calculated prostaglandin E secretion rate fell. 3. Meclofenamate (10 mg/kg i.v.) reduced renal blood flow and prostaglandin E and F secretion rates, but did not abolish autoregulation. 4. Renal prostaglandins do not appear to mediate autoregulation in the kidney but may affect the level at which flow is controlled.

Inhibition of growth hormone release by prostaglandins in immature domestic fowl (Gallus domesticus).

The effect of prostaglandin (PG) E1, PGE2 and PGF2 alpha on GH secretion has been assessed in immature domestic fowl. The intravenous or subcutaneous administration of PGE1 and PGE2 (at a dose of approximately 200 microgram/kg) to 2-, 6- and 8-week-old cockerels consistently lowered plasma GH concentrations. This inhibition in GH secretion was observed for at least 40 min after administration of PGE1 and PGE2. The same dose of PGF2 alpha suppressed plasma GH levels in 2- and 6- week-old birds but the magnitude and duration of this response was less than that induced by PGE1 and PGE2. At this dose, administration of PGE1 and PGE2 resulted in overt signs of distress (e.g. gaping, panting, eye closure and postural instability) within 5-10 min of injection and the birds appeared to be sedated thereafter. Prostaglandin F2 alpha and lower doses of PGE1 and PGE2 did not have any apparent effect on behavior. These results suggest that prostaglandins inhibit GH secretion in birds although this may reflect a non-specific stress response.

Plasma progesterone levels in guinea-pigs actively immunized against prostaglandin F2alpha, hysterectomized or treated with intra-uterine indomethacin.

Five guinea-pigs actively immunized against a prostaglandin F2alpha(PGF2alpha)-bovine serum albumin conjugate showed elongated oestrous cycles. During these, corpora lutea were maintained in a functional secretory state as indicated by plasma progesterone levels. The results are compatible with the view that the PGF2alpha antibodies neutralized the PGF2alpha released from the uterus and thus prevented its normal luteolytic effect. Similar patterns of progesterone secretion were observed in two hysterectomized animals and in two animals with intra-uterine implants of indomethacin.

Parturition in goats: studies on the interactions between the foetus, placenta, prostaglandin F and progesterone before parturition, at term or at parturition induced prematurely by corticotrophin infusion of the foetus.

Relationships between foetal corticosteroid concentrations, utero-ovarian prostaglandin F (PGF) and maternal peripheral progesterone have been examined in detail in goats shortly before spontaneous parturition at term. Foetal corticosteroids increased during the last 13-11 days of gestation and particularly sharply during the last 3 days and even during advanced labour. About 24 h before parturition, acute releases of PGF were evident in the vein draining the pregnant uterine horn, and these corresponded closely to the time of luteal regression. Further release of PGF occured when progesterone declined to low levels, probably reflecting in the course of labour. The changes observed before premature parturition, induced by infusing ACTH into foetal goats, were similar except for the more rapid increase in foetal corticosteoid concentrations. Immature neonates born after ACTH treatment were viable, placental delivery was normal and lactogenesis occurred in the mothers indicating that the treatment promoted full expression of the critical perinatal events. The early, acute releases of PGF were ipsilateral to the ACTH-infused foetus and were luteolytic provided the corpora lutea were also on that side. Luteolysis failed or was abnormally delayed if the corpora lutea were contralateral and prolonged ACTH treatment of the foetuses in such cases caused foetal death probably because of premature failure of the placenta. Similar findings were noted if ACTH infusion of the foetus was accompanied by simultaneous progesterone treatment of the mothers in order block the induction of labour. It was suggested that placental changes occurring during foetal hypercortisolism might be caused by increased placental oestrogen synthesis and the effect of this on the foeto-maternal junction along with a stimulatory action on PG synthesis in the maternal placenta. Experimental disruption of the normal sequence of events, when labour was blocked by progesterone, proved to be lethal to the foetus if the loss of placental integrity progressed sufficiently. The chain of regulatory signals linking increased activity of the foetal adrenal with parturition thus appears to involve stimulation of oestrogen biosynthesis, PGF release from the maternal placenta and the start of physical changes at the placental junction. Provided the foetus and corpora lutea are ipsilateral, the early releases of PGF effect luteolysis and a withdrawal of progesterone from the maternal circulation. When progesterone concentrations are sufficiently low, labour is initiated and its progress reflected by further release of PGF. The control mechanisms, which also provide for the final maturation of the foetus, clearly enable a close synchronization of the various perinatal events which are essential for the transition from foetal to postnatal life.

Involvement of prostaglandins in the inhibition of growth hormone production in cultured pituitary cells by insulin.

The effect of insulin was tested on the rate of synthesis and release of growth hormone in cultured rat anterior pituitary cells. Concentrations of insulin between 10(-9) and 10(-7) mol/l (6--600 ng/ml or 0.15--15 mu./ml) inhibited synthesis of growth hormone; 10(-8) mol insulin/l was most effective. The effect was observed after a time-lag of at least 1 h. Insulin at concentrations between 3 x 10(-9) mol/l and 3 x 10(-7) mol/l also inhibited growth hormone secretion in 30 min incubations. The most effective insulin concentration in this case was 3 x 10(-8) mol/l. Insulin (10(-9)-10(-7) mol/l) also decreased the intracellular content of prostaglandins E and F. The effect was rapid, reaching a maximum after 30 min. Indomethacin, an inhibitor of prostaglandin synthetase, dramatically lowered the concentration of prostaglandins in the cells within 30 min; growth hormone synthesis was also decreased, but not until after 2 h of incubation. The results suggest that an initial response to insulin treatment is a lowering of intracellular levels of prostaglandins, which may then mediate a decrease in growth hormone synthesis, after a 1--2 h delay.

Molecular mechanisms of neuroendocrine integration in the central nervous system: an approach through the study of the pineal gland and its innervating sympathetic pathway.

In the brain specialized cells known as 'neuroendocrine transducers' translate an input of neural activity into a hormonal output, e.g. oxytocin released into the blood stream. Other, more typical neurons make the reverse conversion constituting chemoreceptors which transform the hormonal 'language' into changes in their firing rate ('endocrine-neural' transduction). 'Endocrine-endocrine' transducing events occur at the level of the neurosecretory cells that translate a hormonal signal into another, different, hormone output. This article reviews the molecular aspects of several neuroendocrine integrative processes in the hypothalamus, the pineal gland and the cervical sympathetic pathway. The discussed results indicate that the pineal gland and its innervating sympathetic neurons located in the superior cervical ganglia constitute an easy-to-manipulate model system for the study of basic neuroendocrine mechanisms because: (i) receptors for various hormones exist in the mammalian pineal and sympathetic ganglia; (ii) the pattern of pineal steroid metabolism resembles that of the neuroendocrine hypothalamus; (iii) pineal estrophilic and androphilic receptors as well as the pattern of steroid metabolism are modulated by the sympathetic nerves; (iv) neuronal activity in the cervical sympathetic pathway is modified by hormone treatment at preganglionic, ganglionic and postganglionic sites.