Inhibitors of Na(+)-H+ exchange block stimulus-provoked pineal melatonin synthesis

In rat pinealocytes, amiloride can modulate adrenergic-stimulated cyclic nucleotide accumulation. In this study, the effect of amiloride on melatonin production was characterized. Addition of 5-(N,N-hexamethylene)amiloride, a potent inhibitor of the Na(+)-H+ antiport, dose dependently inhibited norepinephrine- and isoproterenol-stimulated N-acetyltransferase (NAT) activity and melatonin production. Similar inhibition was also observed when pineal melatonin synthesis was stimulated directly with forskolin or dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP), suggesting that the site of inhibition is distal to cAMP accumulation. Similarities between the inhibitory potencies of amiloride derivatives on the Na(+)-H+ antiport and pineal melatonin synthesis indicate that the observed inhibition on pineal melatonin synthesis by amilorides may be secondary to their actions on the Na(+)-H+ antiport. Further studies also indicate that the inhibitory effect of amilorides was not secondary to its cytotoxic actions and that amilorides had no direct antagonistic action on NAT activity. Our findings, therefore, suggest that, in addition to their effects on cyclic nucleotide accumulation, the Na(+)-H+ antiport also plays an important role in the cAMP-mediated melatonin synthesis in the rat pineal gland.

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Monosodium glutamate administration early in life alters pineal melatonin nocturnal profile in adulthood

Melatonin Research ◽

10.32794/mr11250084 ◽

2021 ◽

Vol 4 (1) ◽

pp. 99-114

Author(s):

Janaína B Garcia ◽

Fernanda G Do Amaral ◽

Daniela C Buonfiglio ◽

Rafaela FA Vendrame ◽

Patrícia L Alves ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Pineal Gland ◽

Serum Insulin ◽

Monosodium Glutamate ◽

Female Rats ◽

Pineal Melatonin ◽

Melatonin Synthesis ◽

Male And Female Rats ◽

Melatonin Production

The pineal gland synthesizes melatonin exclusively at night, which gives melatonin the characteristic of a temporal synchronizer of the physiological systems. Melatonin is a regulator of insulin activities centrally and also peripherally and its synthesis is reduced in diabetes. Since monosodium glutamate (MSG) is often used to induce the type 2 diabetic and metabolic syndrome in animal models, the purpose of this work is to evaluate the potential effects of MSG given to neonates on the pineal melatonin synthesis in different aged male and female rats. Wistar rats were subcutaneously injected with MSG (4mg/g/day) or saline solution (0.9%) from the second to eighth post-natal day. The circadian profiles both melatonin levels and AANAT activity were monitored at different ages. Body weight, naso-anal length, adipose tissues weight, GTT, ITT and serum insulin levels were also evaluated. Typical obesity with the neonatal MSG treatment was observed, indicated by a great increase in adipose depots without a concurrent increase in body weight. MSG treatment did not cause hyperglycemia or glucose intolerance, but induced insulin resistance. An increase of melatonin synthesis at ZT 15 with phase advance was observed in in some animals. The AANAT activity was positively parallel to the melatonin circadian profile. It seems that MSG causes hypothalamic obesity which may increase AANAT activity and melatonin production in pineal gland. These effects were not temporally correlated with insulin resistance and hyperinsulinemia indicating the hypothalamic lesions, particularly in arcuate nucleus induced by MSG in early age, as the principal cause of the increase in melatonin production.

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Leptin Modulates Norepinephrine-Mediated Melatonin Synthesis in Cultured Rat Pineal Gland

BioMed Research International ◽

10.1155/2013/546516 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Rodrigo Antonio Peliciari-Garcia ◽

Jéssica Andrade-Silva ◽

José Cipolla-Neto ◽

Carla Roberta de Oliveira Carvalho

Keyword(s):

Pineal Gland ◽

Leptin Receptor ◽

Pineal Melatonin ◽

Melatonin Synthesis ◽

Inducible Camp Early Repressor ◽

Per Se ◽

Isoform B ◽

Rat Pineal Gland

Pineal melatonin synthesis can be modulated by many peptides, including insulin. Because melatonin appears to alter leptin synthesis, in this work we aimed to investigate whether leptin would have a role on norepinephrine- (NE-)mediated melatonin synthesis in cultured rat pineal glands. According to our data, cultured rat pineal glands express leptin receptor isoform b (Ob-Rb). Pineal expression ofOb-RbmRNA was also observedin vivo. Administration of leptin (1 nM) associated with NE (1 µM) reduced melatonin content as well as arylalkylamine-N-acetyl transferase (AANAT) activity and expression in cultured pineal glands. Leptin treatment per se induced the expression of STAT3 in cultured pineal glands, but STAT3 does not participate in the leptin modulation of NE-mediated pineal melatonin synthesis. In addition, the expression of inducible cAMP early repressor (ICER) was further induced by leptin challenge when associated with NE. In conclusion, leptin inhibition of pineal melatonin synthesis appears to be mediated by a reduction in AANAT activity and expression as well as by increased expression ofIcermRNA. Peptidergic signaling within the pineal gland appears to be one of the most important signals which modulates melatonin synthesis; leptin, as a member of this system, is not an exception.

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Kinetic changes of melatonin release in rat pineal perifusions at different circadian stages. Effects of corticosteroids

Acta Endocrinologica ◽

10.1530/acta.0.1290081 ◽

1993 ◽

Vol 129 (1) ◽

pp. 81-88 ◽

Cited By ~ 22

Author(s):

Zi-Yan Zhao ◽

Yvan Touitou

Keyword(s):

Inhibitory Effect ◽

Dark Phase ◽

Melatonin Secretion ◽

Light Phase ◽

Light Onset ◽

Progressive Decline ◽

Pineal Melatonin ◽

High Concentrations ◽

Kinetics Of ◽

Melatonin Production

The kinetic characteristics of melatonin release were documented in perifused pineal glands removed from rats sacrificed at six circadian stages (light/dark =12:12): three during the light phase, i.e. 3, 7 and 11 hours after light onset (HALO), and three during the dark phase, i.e. 15, 19 and 23 HALO. Whatever the circadian stage, the melatonin release decreased during the first 3–4 h and then remained fairly constant and roughly similar up to 8 h of perifusion. However, the kinetics of the release in the first 3 h differed in perifusions of pineal glands removed during the light (progressive decline during 3 h) as compared to perifusions of pineal glands removed during the dark (sharp decline during the first hour and then a progressive decline until reaching a constant level after 3 h). As the effects of steroid administration on melatonin secretion are a matter of controversy, we also studied the direct effects and their circadian stage dependence, if any, of corticosterone, deoxycorticosterone and dexamethasone on melatonin secretion by pineal glands removed 7 HALO (about the middle of the light phase) and 19 HALO (about the middle of the dark phase). High concentrations of corticosterone (0.8 × 10−1 mol/l) and dexamethasone (0.4×10−3 mol/l) resulted in a significant (p<0.001) inhibitory effect on melatonin production (about a 50% and a 30% decrease, respectively) whatever the circadian stage, whereas lower concentrations (10−4–10−5 mol/l of both steroids did not affect melatonin production. In addition, neither pharmacological (1.06 × 10−5 mol/l) nor physiological (for the rat) concentrations (2.1 × 10−7 mol/l) of deoxycorticosterone had any significant effect on pineal melatonin production. These data clearly show the time dependence of the kinetics of melatonin release and an effect of adrenocortical steroids on pineal melatonin production that may be quite different according to the steroid and dosage.

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Ticlopidine and Clopidogrel (SR 25990C) Selectively Neutralize ADP Inhibition of PGE1-Activated Platelet Adenylate Cyclase in Rats and Rabbits

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647481 ◽

1991 ◽

Vol 65 (02) ◽

pp. 186-190 ◽

Cited By ~ 61

Author(s):

G Defreyn ◽

C Gachet ◽

P Savi ◽

F Driot ◽

J P Cazenave ◽

...

Keyword(s):

Platelet Aggregation ◽

Adenylate Cyclase ◽

Direct Effect ◽

Cyclic Nucleotide ◽

Camp Accumulation ◽

Rabbit Platelets ◽

Camp Levels ◽

Kinetics Of ◽

Camp Elevation ◽

Rat Platelets

SummaryTiclopidine and its potent analogue, clopidogrel, are powerful inhibitors of ADP-induced platelet aggregation. In order to improve the understanding of this ADP-selectivity, we studied the effect of these compounds on PGE1-stimulated adenylate cyclase and on the inhibition of this enzyme by ADP, epinephrine and thrombin. Neither drug changed the basal cAMP levels nor the kinetics of cAMP accumulation upon PGEj-stimulation in rat or rabbit platelets, which excludes any direct effect on adenylate cyclase or on cyclic nucleotide phosphodiesterase. However, the drop in cAMP levels observed after addition of ADP to PGEr stimulated control platelets was inhibited in platelets from treated animals. In contrast, the drop in cAMP levels produced by epinephrine was not prevented by either drug in rabbit platelets. In rat platelets, thrombin inhibited the PGEX-induced cAMP elevation but this effect seems to be entirely mediated by the released ADP. Under these conditions, it was not surprising to find that clopidogrel also potently inhibited that effect of thrombin on platelet adenylate cyclase. In conclusion, ticlopidine and clopidogrel selectively neutralize the ADP inhibition of PGEr activated platelet adenylate cyclase in rats and rabbits.

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THE ANTAGONISTIC ACTION OF METHYLTHIOURACIL ON THE INHIBITORY EFFECT OF THYROXIN ON SERUM LIPASE

Acta Endocrinologica ◽

10.1530/acta.0.0010248 ◽

1948 ◽

Vol 1 (3) ◽

pp. 248-257 ◽

Cited By ~ 1

Author(s):

GEORGE KLEIN

Keyword(s):

Inhibitory Effect ◽

Serum Lipase ◽

Antagonistic Action

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Adenosine A1 receptor-mediated inhibition of vasopressin action in inner medullary collecting duct

AJP Renal Physiology ◽

10.1152/ajprenal.1994.266.5.f791 ◽

1994 ◽

Vol 266 (5) ◽

pp. F791-F796 ◽

Cited By ~ 11

Author(s):

R. M. Edwards ◽

W. S. Spielman

Keyword(s):

Receptor Agonist ◽

Collecting Duct ◽

Basolateral Membrane ◽

Inhibitory Effect ◽

Dependent Manner ◽

Camp Accumulation ◽

Concentration Dependent Manner ◽

Cgs 21680 ◽

Camp Generation ◽

A1 Receptor

We examined the effects of adenosine and adenosine analogues on arginine vasopressin (AVP)-induced increases in osmotic water permeability (Pf; micron/s) and adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in rat inner medullary collecting ducts (IMCDs). When added to the bath, the A1 receptor agonist N6-cyclohexyladenosine (CHA) produced a rapid and reversible inhibition of AVP-stimulated (10 pM) Pf (1,781 +/- 195 to 314 +/- 85 microns/s at 0.3 microM CHA; n = 9). The inhibitory effect of CHA was concentration dependent, with a 50% inhibitory concentration of 10 nM. The effect of CHA was inhibited by prior exposure of IMCDs to the A1 receptor antagonist 1,3-dipropylxanthine-8-cyclopentylxanthine (DP-CPX; 1 microM) or by preincubation with pertussis toxin. CHA had no effect on cAMP-induced increases in Pf. In addition to CHA, adenosine and the nonselective agonist 5'-(N-ethylcarboxamido)-adenosine (NECA) inhibited AVP-dependent Pf by > or = 70%, whereas the A2 receptor agonist CGS-21680 had no effect. Luminal adenosine (0.1 mM) had no effect on basal or AVP-stimulated Pf. CHA, NECA, and adenosine but not CGS-21680 inhibited AVP-stimulated cAMP accumulation in a concentration-dependent manner (50% inhibitory concentrations 0.1–300 nM). The inhibitory effect of CHA on AVP-stimulated cAMP accumulation was attenuated by DPCPX. We conclude that adenosine, acting at the basolateral membrane, inhibits AVP action in the IMCD via interaction with A1 receptors. The inhibition occurs proximal to cAMP generation and likely involves an inhibitory G protein.

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Mechanisms of cyclic nucleotide-induced relaxation in canine tracheal smooth muscle

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1995.268.3.l407 ◽

1995 ◽

Vol 268 (3) ◽

pp. L407-L413 ◽

Cited By ~ 2

Author(s):

I. McGrogan ◽

S. Lu ◽

S. Hipworth ◽

L. Sormaz ◽

R. Eng ◽

...

Keyword(s):

Smooth Muscle ◽

Cyclic Nucleotide ◽

Cyclopiazonic Acid ◽

Inhibitory Effect ◽

Beta Agonist ◽

Cyclic Monophosphate ◽

Median Effective Concentration ◽

Camp Levels ◽

Ca2 Channels

The effects of exogeneous cyclopiazonic acid (CPA, 10 microM), a selective inhibitor of the sarcoplasmic reticulum (SR) Ca2+ adenosinetriphosphatase, on cyclic nucleotide-induced relaxations of canine airway smooth muscle were examined. Strips of tracheal muscle were precontracted with carbachol (50% median effective concentration, 0.1 microM) or with 60 mM KCl. The beta-agonist isoproterenol (ISO, 10 microM) relaxed the tissue by approximately 50%. The relaxation was reduced in the presence of CPA when L-type Ca2+ channels were available but not when these were blocked by 0.1 microM nifedipine. Forskolin (1.0 microM), an adenylate cyclase activator, was less effective at inhibiting the contraction than ISO, and addition of CPA did not block its inhibitory effect as effectively as when ISO was used. Radioimmunoassay indicated that both these agents raised adenosine 3',5'-cyclic monophosphate (cAMP) levels to the same degree. Very little relaxation of the precontracted smooth muscle was elicited by 3 mM 8-bromo-adenosine 3',5'-cyclic monophosphate (8-BrcAMP), and addition of CPA had no effect. Sodium nitroprusside (100 microM) and 8-bromo-guanosine 3',5'-cyclic monophosphate (10 mM) inhibited contraction to a greater degree than any agent that raised cAMP. These inhibitions were greatly reduced in the presence of CPA when L-type Ca2+ channels were available. We conclude that pumping of Ca2+ into SR plays a major role guanosine 3',5'-cyclic monophosphate-produced but not cAMP-induced relaxation; L-type Ca2+ channels must be available for the relaxant role of Ca2+ pumping into the SR to be expressed; and ISO-induced relaxation may not involve primarily elevation of the cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

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