Vanecek, Jiri. Cellular Mechanisms of Melatonin Action. Physiol. Rev. 78: 687–721, 1998. — The pi... more Vanecek, Jiri. Cellular Mechanisms of Melatonin Action. Physiol. Rev. 78: 687–721, 1998. — The pineal hormone melatonin is involved in photic regulations of various kinds, including adaptation to light intensity, daily changes of light and darkness, and seasonal changes of photoperiod lengths. The melatonin effects are mediated by the specific high-affinity receptors localized on plasma membrane and coupled to GTP-binding protein. Two different G proteins coupled to the melatonin receptors have been described, one sensitive to pertussis toxin and the other sensitive to cholera toxin. On the basis of the molecular structure, three subtypes of the melatonin receptors have been described: Mel1A, Mel1B, and Mel1C. The first two subtypes are found in mammals and may be distinguished pharmacologically using selective antagonists. Melatonin receptor regulates several second messengers: cAMP, cGMP, diacylglycerol, inositol trisphosphate, arachidonic acid, and intracellular Ca2+concentration...
We have compared melatonin effects in two different cell types in order to determine general intr... more We have compared melatonin effects in two different cell types in order to determine general intracellular mechanisms of its action. In neonatal rat pituitary, melatonin acts via the specific membrane receptors to inhibit GnRH-induced LH release. The melatonin effect disappears in adulthood due to the disappearance of the receptors. The mechanism of the melatonin action involves inhibition of the GnRH induced increase of intracellular calcium ([Ca2+])i. Our observations indicate that melatonin has dual inhibitory effect on GnRH-induced [Ca2+]i: it inhibits mobilisation of Ca2+ from endoplasmic reticulum as well as Ca2+ influx through voltage sensitive channels. Besides, melatonin also decreases basal and GnRH- or forskolin-induced increase of cAMP concentration in the pituitary. Although cAMP is not of primary importance for regulation of LH release, the cAMP decrease may participate in the mechanism of inhibitory melatonin action on LH release. Rat suprachiasmatic nuclei (SCN) have a high density of the melatonin receptors throughout the postnatal life. Cultures of dispersed SCN cells show circadian rhythm of vasopressin (AVP) release, with several fold increase in the middle of the day and decrease during night. Melatonin inhibits the spontaneous AVP release. Melatonin also inhibits the AVP release induced by vasoactive intestinal peptide (VIP). Intracellular mechanisms of the melatonin effect may involve cAMP, because melatonin inhibits the VIP-induced increase of cAMP and increase of cAMP formation by forskolin stimulates AVP release from the cultures. On the other hand, involvement of intracellular calcium in the regulation of AVP release may not be excluded. VIP induces [Ca2+]i increase in 14% of the SCN cells and AVP release is stimulated by Ca2+ ionophore ionomycin. Our observations indicate that some of the mechanisms of melatonin action are similar in the pituitary and SCN.
... VANECEK: Bibliometric analysis of the Czech research publications from 1994 to 2005Scientomet... more ... VANECEK: Bibliometric analysis of the Czech research publications from 1994 to 2005Scientometrics 77 (2008) 357 ... Interdisciplinary Applications (all belonging to the field of Mathematics), Nuclear Physics and Particles & Fields (Physics), Remote Sensing (Space Sciences ...
Our study evaluates results and impacts of the Framework Programs (FP) 5 and 6 in the Czech Repub... more Our study evaluates results and impacts of the Framework Programs (FP) 5 and 6 in the Czech Republic. Publications resulting from the FP projects had 42% higher mean citation rate and 77% more EU-25 collaborations than the Czech standards. Teams participating in the FP are better-than-average, because citation rate of all their papers is 21% higher than the Czech standards. The most striking finding is the marked influence of FP on research direction. After the project start, the participating teams published papers in ten new fields in which they did not publish before the project. In 45 other fields, more than 200% increase of papers was observed.
Vasoactive intestinal peptide (VIP) receptor density is high in the pineal gland, which receives ... more Vasoactive intestinal peptide (VIP) receptor density is high in the pineal gland, which receives VIP innervation and responds to VIP with a relatively small increase in cAMP and cGMP levels. In the present study, we show that VIP (5-200 nM) treatment increased the intracellular calcium concentration ([Ca2+]i) in 64% of isolated individual pinealocytes; in comparison, norepinephrine (NE) elevated [Ca2+]i in 93% of the cells and produced more robust responses. Analysis of the role of second messengers indicated that [Ca2+]i was strongly elevated by cGMP analogs, but not by cAMP analogs. The nitric oxide-releasing agent S-nitro-N-acetylpenicillamine and 2,2-diethyl-1-nitroxyhydraxine also elevated [Ca2+]i. Investigation of the mechanisms revealed that responses to VIP or 8-bromo-cGMP involved Ca2+ influx, as did the plateau component of the response to NE; the large rapid component of the response to NE, however, appeared to reflect release from intracellular stores. Pharmacological st...
Physiological research / Academia Scientiarum Bohemoslovaca, 1998
The role of [Ca2+]i and cAMP in transduction of the melatonin inhibitory effect on GnRH-induced L... more The role of [Ca2+]i and cAMP in transduction of the melatonin inhibitory effect on GnRH-induced LH release from neonatal rat gonadotrophs has been studied, because melatonin inhibits the increase of both intracellular messengers. Treatments increasing Ca2+ influx (S(-) Bay K8644 or KCI) or cAMP concentration (8-bromo-cAMP or 3-isobutyl-1-methylxanthine) potentiated the GnRH-induced LH release and partially diminished the inhibitory effect of melatonin. Combination of the treatments increasing cAMP and calcium concentrations blocked completely the melatonin inhibition of LH release. The combined treatment with 8-bromo-cAMP and S(-) Bay K8644 also blocked the melatonin inhibition of GnRH-induced [Ca2+]i increase in 89 % of the gonadotrophs, while any of the treatments alone blocked the melatonin effect in about 25 % of these cells. These observations suggest that a cAMP-dependent pathway is involved in regulation of Ca2+ influx by melatonin and melatonin inhibition of LH release may b...
ABSTRACT We have studied the effects of performance-based research funding introduced to the Czec... more ABSTRACT We have studied the effects of performance-based research funding introduced to the Czech (CZ) R&D system in 2008 on outputs of R&D results. We have analyzed annual changes in number of various types of publications and applications including patents before and after this change. The growth-rate of almost all types of results has accelerated in 2005 or 2006 and the increase continued till 2010. The growth of result quantity in the CZ has been faster than in seven other European countries selected for comparison. Because the accelerated growth has started already before 2008, implementation of the performance-based funding could not have been its cause. Likely cause of the growth could be either the evaluation of R&D institutions introduced in 2004 itself and/or growth of public R&D funding in the past decade. Because the increase of the citation impact of publications lagged behind the increase of their quantity, we conclude that the evaluation is not based on optimal indicators.
In neonatal rat gonadotrophs, melatonin acts through the high-affinity membrane-bound receptors t... more In neonatal rat gonadotrophs, melatonin acts through the high-affinity membrane-bound receptors to inhibit GnRH-induced [Ca2+]i increase. GnRH increases [Ca2+]i primarily by mobilization from the inositol trisphosphate-sensitive pool followed by Ca2+ influx through the voltage-sensitive channels. Melatonin inhibits the GnRH-induced [Ca2+]i increase. When added after the GnRH-induced spike, melatonin decreases [Ca2+]i in 52% of the gonadotrophs. The effect of melatonin is dependent on extracellular Ca2+ and may be mimicked by Ca2+-free medium or verapamil. When added before GnRH, melatonin inhibits the [Ca2+]i spike. This effect of melatonin is independent of extracellular Ca2+ as it persists in Ca2+-free medium. These findings indicate that melatonin blocks Ca2+ mobilization as well as Ca2+ influx in the gonadotrophs.
The effects of melatonin on basal and vasoactive intestinal peptide (VIP)-induced cAMP concentrat... more The effects of melatonin on basal and vasoactive intestinal peptide (VIP)-induced cAMP concentration was studied in dispersed cells of the rat suprachiasmatic nuclei (SCN). Our data indicate, that VIP induces a rapid increase of cAMP concentration in the cells followed by a slow and prolonged increase in the medium. The VIP-induced increase was dose-dependent in the range of 1-100 nM. Melatonin had no effect on basal cAMP but inhibited the cAMP increase induced by VIP in a dosedependent manner (EC 50 = 0.21 nM). Our observations indicate that melatonin acts through the inhibition of cAMP in the SCN cells similar as shown in other tissues.
Melatonin inhibits gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) release... more Melatonin inhibits gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) release from neonatal rat anterior pituitary. Melatonin has been shown to decrease the concentration of several second messengers in neonatal pituitary, but it is not known which of them transduces the melatonin effect on LH release. In order to determine the mechanism of melatonin action, we tested the effect of melatonin on GnRH-induced LH release in the presence of specific drugs affecting second messengers. The calcium channel antagonist nifedipine inhibited LH release from cultured pituitary to a similar degree as melatonin and prevented the inhibitory effect of melatonin on LH release. The calcium channel agonist Bay K potentiated the GnRH-stimulated LH release and reduced the inhibitory effect of melatonin on LH release. These data strongly suggest that melatonin inhibits LH release via inhibition of calcium influx through voltage-sensitive channels. The cyclic AMP (cAMP) derivative 8-bromo-cAMP potentiated GnRH stimulation of LH release but did not prevent the melatonin-induced inhibition of LH release. However, when used in combination with Bay K, which reduced only partially the melatonin effect by itself, 8-bromo-cAMP completely blocked the melatonin effect. This observation suggests that decreased cAMP accumulation may also be involved in transduction of the melatonin effect on LH release.
In neonatal rat gonadotropes, melatonin inhibits gonadotropin-releasing-hormone (GnRH)-stimulated... more In neonatal rat gonadotropes, melatonin inhibits gonadotropin-releasing-hormone (GnRH)-stimulated increase in intracellular Ca2+ concentration ([Ca2+]i); in cells transfected with the Mel1a melatonin receptor, however, melatonin has been shown to potentiate agonist-stimulated [Ca2+]i increase. To elucidate this discrepancy, we investigated the effects of melatonin in neonatal gonadotropes over a wide range of melatonin concentrations. Nystatin perforated patch recording of Ca2+-dependent potassium currents was used to monitor GnRH-induced [Ca2+]i changes. In 32% of cells, increasing melatonin concentrations in the range of 1 pM to 100 nM prolonged the latency of, and inhibited GnRH (10 nM)-stimulated [Ca2+]i increases in a concentration-dependent manner. In the remaining 68% of cells, the Ca2+ increase elicited by exposure to 10 nM GnRH was also inhibited by picomolar concentrations of melatonin, but at nanomolar concentrations the inhibitory effect disappeared and melatonin was onl...
In neonatal rat gonadotrophs, melatonin inhibits several GnRH‐induced effects: stimulation of LH ... more In neonatal rat gonadotrophs, melatonin inhibits several GnRH‐induced effects: stimulation of LH release as well as the increase of several second messengers as cAMP, diacylglycerol and [ Ca2+]i . Recently, GnRH has been shown to induce expression of immediate early genes of fos and jun family in adult rat gonadotrophs. The purpose of this study was to determine, whether melatonin inhibits the GnRH‐induced induction of cFos in neonatal rat pituitary cells.
We have previously shown that exposure of rats to constant light (LL) induced a decrease in NO sy... more We have previously shown that exposure of rats to constant light (LL) induced a decrease in NO synthase (NOS) activity in the pineal gland. We present here the evidence that chronic (5 days) norepinephrine (NE) or isoproterenol treatment prevents the effect of LL and enhances pineal NOS activity in LL animals. This effect of NE appears to be mediated by beta-adrenoceptors, because it was not mimicked by the alpha-agonist phenylephrine. Pineal NOS activity was reduced in 16-h light/8-h dark animals treated for 4 days with the beta-adrenergic antagonist propranolol but not with the alpha 1-antagonist prazosin, indicating again an involvement of beta-adrenergic receptor in the control of NOS. Treatment with adrenergic antagonists did not affect cortical NOS activity, suggesting that the control of NOS is different in these two tissues or that the pineal expresses a specific isoform of the enzyme. Taken together, these data suggest that NE controls NOS in the pineal gland through beta-adrenergic receptors. To our knowledge, this represent the first demonstration of a regulation of NOS by a neurotransmitter in the CNS, as assayed under Vmax conditions.
ABSTRACT The adrenergic control of cAMP and 3',5'-cyclic GMP (cGMP) in dispersed ... more ABSTRACT The adrenergic control of cAMP and 3',5'-cyclic GMP (cGMP) in dispersed adult rat pinealocytes was investigated. Norepinephrine treatment increased cAMP and cGMP content 60- and 400-fold, respectively; both alpha- and beta-adrenoceptors had to be activated for these responses to occur. Beta-Adrenergic stimulation alone produced only about 6- and 2-fold increase in cAMP and cGMP content, respectively. Alpha-Adrenergic stimulation, which alone had no effect on either cyclic nucleotide concentration, markedly amplified the beta-adrenergic stimulation of both cAMP and cGMP. The relative potency of alpha-adrenergic agonists and antagonists indicates the alpha 1-subclass of adrenoceptors is involved. A role of alpha 1-adrenoceptors in the control of pineal cAMP is consistent with published evidence of the presence of alpha 1-adrenoceptors on pinealocytes and their role in the regulation of N-acetyltransferase activity and melatonin production.
Vanecek, Jiri. Cellular Mechanisms of Melatonin Action. Physiol. Rev. 78: 687–721, 1998. — The pi... more Vanecek, Jiri. Cellular Mechanisms of Melatonin Action. Physiol. Rev. 78: 687–721, 1998. — The pineal hormone melatonin is involved in photic regulations of various kinds, including adaptation to light intensity, daily changes of light and darkness, and seasonal changes of photoperiod lengths. The melatonin effects are mediated by the specific high-affinity receptors localized on plasma membrane and coupled to GTP-binding protein. Two different G proteins coupled to the melatonin receptors have been described, one sensitive to pertussis toxin and the other sensitive to cholera toxin. On the basis of the molecular structure, three subtypes of the melatonin receptors have been described: Mel1A, Mel1B, and Mel1C. The first two subtypes are found in mammals and may be distinguished pharmacologically using selective antagonists. Melatonin receptor regulates several second messengers: cAMP, cGMP, diacylglycerol, inositol trisphosphate, arachidonic acid, and intracellular Ca2+concentration...
We have compared melatonin effects in two different cell types in order to determine general intr... more We have compared melatonin effects in two different cell types in order to determine general intracellular mechanisms of its action. In neonatal rat pituitary, melatonin acts via the specific membrane receptors to inhibit GnRH-induced LH release. The melatonin effect disappears in adulthood due to the disappearance of the receptors. The mechanism of the melatonin action involves inhibition of the GnRH induced increase of intracellular calcium ([Ca2+])i. Our observations indicate that melatonin has dual inhibitory effect on GnRH-induced [Ca2+]i: it inhibits mobilisation of Ca2+ from endoplasmic reticulum as well as Ca2+ influx through voltage sensitive channels. Besides, melatonin also decreases basal and GnRH- or forskolin-induced increase of cAMP concentration in the pituitary. Although cAMP is not of primary importance for regulation of LH release, the cAMP decrease may participate in the mechanism of inhibitory melatonin action on LH release. Rat suprachiasmatic nuclei (SCN) have a high density of the melatonin receptors throughout the postnatal life. Cultures of dispersed SCN cells show circadian rhythm of vasopressin (AVP) release, with several fold increase in the middle of the day and decrease during night. Melatonin inhibits the spontaneous AVP release. Melatonin also inhibits the AVP release induced by vasoactive intestinal peptide (VIP). Intracellular mechanisms of the melatonin effect may involve cAMP, because melatonin inhibits the VIP-induced increase of cAMP and increase of cAMP formation by forskolin stimulates AVP release from the cultures. On the other hand, involvement of intracellular calcium in the regulation of AVP release may not be excluded. VIP induces [Ca2+]i increase in 14% of the SCN cells and AVP release is stimulated by Ca2+ ionophore ionomycin. Our observations indicate that some of the mechanisms of melatonin action are similar in the pituitary and SCN.
... VANECEK: Bibliometric analysis of the Czech research publications from 1994 to 2005Scientomet... more ... VANECEK: Bibliometric analysis of the Czech research publications from 1994 to 2005Scientometrics 77 (2008) 357 ... Interdisciplinary Applications (all belonging to the field of Mathematics), Nuclear Physics and Particles & Fields (Physics), Remote Sensing (Space Sciences ...
Our study evaluates results and impacts of the Framework Programs (FP) 5 and 6 in the Czech Repub... more Our study evaluates results and impacts of the Framework Programs (FP) 5 and 6 in the Czech Republic. Publications resulting from the FP projects had 42% higher mean citation rate and 77% more EU-25 collaborations than the Czech standards. Teams participating in the FP are better-than-average, because citation rate of all their papers is 21% higher than the Czech standards. The most striking finding is the marked influence of FP on research direction. After the project start, the participating teams published papers in ten new fields in which they did not publish before the project. In 45 other fields, more than 200% increase of papers was observed.
Vasoactive intestinal peptide (VIP) receptor density is high in the pineal gland, which receives ... more Vasoactive intestinal peptide (VIP) receptor density is high in the pineal gland, which receives VIP innervation and responds to VIP with a relatively small increase in cAMP and cGMP levels. In the present study, we show that VIP (5-200 nM) treatment increased the intracellular calcium concentration ([Ca2+]i) in 64% of isolated individual pinealocytes; in comparison, norepinephrine (NE) elevated [Ca2+]i in 93% of the cells and produced more robust responses. Analysis of the role of second messengers indicated that [Ca2+]i was strongly elevated by cGMP analogs, but not by cAMP analogs. The nitric oxide-releasing agent S-nitro-N-acetylpenicillamine and 2,2-diethyl-1-nitroxyhydraxine also elevated [Ca2+]i. Investigation of the mechanisms revealed that responses to VIP or 8-bromo-cGMP involved Ca2+ influx, as did the plateau component of the response to NE; the large rapid component of the response to NE, however, appeared to reflect release from intracellular stores. Pharmacological st...
Physiological research / Academia Scientiarum Bohemoslovaca, 1998
The role of [Ca2+]i and cAMP in transduction of the melatonin inhibitory effect on GnRH-induced L... more The role of [Ca2+]i and cAMP in transduction of the melatonin inhibitory effect on GnRH-induced LH release from neonatal rat gonadotrophs has been studied, because melatonin inhibits the increase of both intracellular messengers. Treatments increasing Ca2+ influx (S(-) Bay K8644 or KCI) or cAMP concentration (8-bromo-cAMP or 3-isobutyl-1-methylxanthine) potentiated the GnRH-induced LH release and partially diminished the inhibitory effect of melatonin. Combination of the treatments increasing cAMP and calcium concentrations blocked completely the melatonin inhibition of LH release. The combined treatment with 8-bromo-cAMP and S(-) Bay K8644 also blocked the melatonin inhibition of GnRH-induced [Ca2+]i increase in 89 % of the gonadotrophs, while any of the treatments alone blocked the melatonin effect in about 25 % of these cells. These observations suggest that a cAMP-dependent pathway is involved in regulation of Ca2+ influx by melatonin and melatonin inhibition of LH release may b...
ABSTRACT We have studied the effects of performance-based research funding introduced to the Czec... more ABSTRACT We have studied the effects of performance-based research funding introduced to the Czech (CZ) R&D system in 2008 on outputs of R&D results. We have analyzed annual changes in number of various types of publications and applications including patents before and after this change. The growth-rate of almost all types of results has accelerated in 2005 or 2006 and the increase continued till 2010. The growth of result quantity in the CZ has been faster than in seven other European countries selected for comparison. Because the accelerated growth has started already before 2008, implementation of the performance-based funding could not have been its cause. Likely cause of the growth could be either the evaluation of R&D institutions introduced in 2004 itself and/or growth of public R&D funding in the past decade. Because the increase of the citation impact of publications lagged behind the increase of their quantity, we conclude that the evaluation is not based on optimal indicators.
In neonatal rat gonadotrophs, melatonin acts through the high-affinity membrane-bound receptors t... more In neonatal rat gonadotrophs, melatonin acts through the high-affinity membrane-bound receptors to inhibit GnRH-induced [Ca2+]i increase. GnRH increases [Ca2+]i primarily by mobilization from the inositol trisphosphate-sensitive pool followed by Ca2+ influx through the voltage-sensitive channels. Melatonin inhibits the GnRH-induced [Ca2+]i increase. When added after the GnRH-induced spike, melatonin decreases [Ca2+]i in 52% of the gonadotrophs. The effect of melatonin is dependent on extracellular Ca2+ and may be mimicked by Ca2+-free medium or verapamil. When added before GnRH, melatonin inhibits the [Ca2+]i spike. This effect of melatonin is independent of extracellular Ca2+ as it persists in Ca2+-free medium. These findings indicate that melatonin blocks Ca2+ mobilization as well as Ca2+ influx in the gonadotrophs.
The effects of melatonin on basal and vasoactive intestinal peptide (VIP)-induced cAMP concentrat... more The effects of melatonin on basal and vasoactive intestinal peptide (VIP)-induced cAMP concentration was studied in dispersed cells of the rat suprachiasmatic nuclei (SCN). Our data indicate, that VIP induces a rapid increase of cAMP concentration in the cells followed by a slow and prolonged increase in the medium. The VIP-induced increase was dose-dependent in the range of 1-100 nM. Melatonin had no effect on basal cAMP but inhibited the cAMP increase induced by VIP in a dosedependent manner (EC 50 = 0.21 nM). Our observations indicate that melatonin acts through the inhibition of cAMP in the SCN cells similar as shown in other tissues.
Melatonin inhibits gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) release... more Melatonin inhibits gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) release from neonatal rat anterior pituitary. Melatonin has been shown to decrease the concentration of several second messengers in neonatal pituitary, but it is not known which of them transduces the melatonin effect on LH release. In order to determine the mechanism of melatonin action, we tested the effect of melatonin on GnRH-induced LH release in the presence of specific drugs affecting second messengers. The calcium channel antagonist nifedipine inhibited LH release from cultured pituitary to a similar degree as melatonin and prevented the inhibitory effect of melatonin on LH release. The calcium channel agonist Bay K potentiated the GnRH-stimulated LH release and reduced the inhibitory effect of melatonin on LH release. These data strongly suggest that melatonin inhibits LH release via inhibition of calcium influx through voltage-sensitive channels. The cyclic AMP (cAMP) derivative 8-bromo-cAMP potentiated GnRH stimulation of LH release but did not prevent the melatonin-induced inhibition of LH release. However, when used in combination with Bay K, which reduced only partially the melatonin effect by itself, 8-bromo-cAMP completely blocked the melatonin effect. This observation suggests that decreased cAMP accumulation may also be involved in transduction of the melatonin effect on LH release.
In neonatal rat gonadotropes, melatonin inhibits gonadotropin-releasing-hormone (GnRH)-stimulated... more In neonatal rat gonadotropes, melatonin inhibits gonadotropin-releasing-hormone (GnRH)-stimulated increase in intracellular Ca2+ concentration ([Ca2+]i); in cells transfected with the Mel1a melatonin receptor, however, melatonin has been shown to potentiate agonist-stimulated [Ca2+]i increase. To elucidate this discrepancy, we investigated the effects of melatonin in neonatal gonadotropes over a wide range of melatonin concentrations. Nystatin perforated patch recording of Ca2+-dependent potassium currents was used to monitor GnRH-induced [Ca2+]i changes. In 32% of cells, increasing melatonin concentrations in the range of 1 pM to 100 nM prolonged the latency of, and inhibited GnRH (10 nM)-stimulated [Ca2+]i increases in a concentration-dependent manner. In the remaining 68% of cells, the Ca2+ increase elicited by exposure to 10 nM GnRH was also inhibited by picomolar concentrations of melatonin, but at nanomolar concentrations the inhibitory effect disappeared and melatonin was onl...
In neonatal rat gonadotrophs, melatonin inhibits several GnRH‐induced effects: stimulation of LH ... more In neonatal rat gonadotrophs, melatonin inhibits several GnRH‐induced effects: stimulation of LH release as well as the increase of several second messengers as cAMP, diacylglycerol and [ Ca2+]i . Recently, GnRH has been shown to induce expression of immediate early genes of fos and jun family in adult rat gonadotrophs. The purpose of this study was to determine, whether melatonin inhibits the GnRH‐induced induction of cFos in neonatal rat pituitary cells.
We have previously shown that exposure of rats to constant light (LL) induced a decrease in NO sy... more We have previously shown that exposure of rats to constant light (LL) induced a decrease in NO synthase (NOS) activity in the pineal gland. We present here the evidence that chronic (5 days) norepinephrine (NE) or isoproterenol treatment prevents the effect of LL and enhances pineal NOS activity in LL animals. This effect of NE appears to be mediated by beta-adrenoceptors, because it was not mimicked by the alpha-agonist phenylephrine. Pineal NOS activity was reduced in 16-h light/8-h dark animals treated for 4 days with the beta-adrenergic antagonist propranolol but not with the alpha 1-antagonist prazosin, indicating again an involvement of beta-adrenergic receptor in the control of NOS. Treatment with adrenergic antagonists did not affect cortical NOS activity, suggesting that the control of NOS is different in these two tissues or that the pineal expresses a specific isoform of the enzyme. Taken together, these data suggest that NE controls NOS in the pineal gland through beta-adrenergic receptors. To our knowledge, this represent the first demonstration of a regulation of NOS by a neurotransmitter in the CNS, as assayed under Vmax conditions.
ABSTRACT The adrenergic control of cAMP and 3',5'-cyclic GMP (cGMP) in dispersed ... more ABSTRACT The adrenergic control of cAMP and 3',5'-cyclic GMP (cGMP) in dispersed adult rat pinealocytes was investigated. Norepinephrine treatment increased cAMP and cGMP content 60- and 400-fold, respectively; both alpha- and beta-adrenoceptors had to be activated for these responses to occur. Beta-Adrenergic stimulation alone produced only about 6- and 2-fold increase in cAMP and cGMP content, respectively. Alpha-Adrenergic stimulation, which alone had no effect on either cyclic nucleotide concentration, markedly amplified the beta-adrenergic stimulation of both cAMP and cGMP. The relative potency of alpha-adrenergic agonists and antagonists indicates the alpha 1-subclass of adrenoceptors is involved. A role of alpha 1-adrenoceptors in the control of pineal cAMP is consistent with published evidence of the presence of alpha 1-adrenoceptors on pinealocytes and their role in the regulation of N-acetyltransferase activity and melatonin production.
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Papers by Jiri Vanecek