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Biomedical subjects

J Z Nowak

Publications and source records attributed to J Z Nowak.

At least 55 records · Page 3Linked to original sources
PubMed1994

Clozapine and other neuroleptic drugs antagonize the light-evoked suppression of melatonin biosynthesis in chick retina: involvement of the D4-like dopamine receptor.

The subtype of dopamine receptor mediating the suppressive effect of light on melatonin biosynthesis in chick retina was characterized pharmacologically. Acute exposure of animals to light during the dark phase of the light-dark cycle dramatically decreased melatonin levels and activity of serotonin N-acetyltransferase (NAT; a key regulatory enzyme in melatonin biosynthetic pathway). Various antagonists of dopamine receptors were tested for their ability to block this action of light on the retinal melatonin formation. Intraocular (i. oc.) pretreatment of chicks with neuroleptic drugs--blockers of the D2-family of dopamine receptors, i.e., clotiapine, clozapine (an atypical neuroleptic with high affinity for a D4-subtype dopamine receptor), haloperidol, spiroperidol, sulpiride, and YM-09151-2, significantly antagonized the light-evoked suppression of the nighttime NAT activity of the chick retina in a dose-dependent manner. In contrast, remoxipride (a D2-selective dopamine antagonist), raclopride and (+)-UH-232 (D2/D3-dopamine receptor antagonists), as well as SCH 23390, a blocker of the D1-family of dopamine receptors, were ineffective. Clozapine, haloperidol, spiroperidol and sulpiride also potently antagonized the suppressive action of light on melatonin content of the chick retina. It is suggested that the dopamine receptor mediating the inhibitory effect of light stimulation on the nighttime melatonin biosynthesis in the retina of chick represents a D4-like subtype.

Acetylserotonin O-Methyltransferase↗
PubMed1994

Histamine is a powerful stimulator of cyclic AMP formation in chick pineal gland.

Histamine (HA) potently stimulated both basal and forskolin-activated cAMP formation in chick pineal gland. The action of HA was mimicked by 4-methyl-HA, and to some extent by 2-methyl-HA and 2-thiazolylethylamine (2TEA), but not by dimaprit, (R)-alpha-methyl-HA tele-methyl-HA, and several other imidazole-derivatives. The stimulatory actions of all the compounds were antagonized by ranitidine and tiotidine (HA H2-receptor antagonists), and were not affected by mepyramine and thioperamide (HA H1- and H3-receptor blockers, respectively). These data indicate that the chick pineal probably contains H2-like HA receptors, whose stimulation leads to increases in cAMP production.

Animals↗
PubMed1994

Dopamine receptor regulating serotonin N-acetyltransferase activity in chick retina represents a D4-like subtype: pharmacological characterization.

The dopamine (DA) receptor regulating serotonin N-acetyltransferase (NAT) activity in chick retina was characterized pharmacologically. Intraocular (i.o.) administration of DA significantly decreased the nighttime NAT activity of chick retina. The effect of DA was antagonized by blockers of the D2 family of DA receptors, spiroperidol, YM-09151-2 and clozapine, and it was not affected by SCH23390, a selective antagonist of D1 DA receptor. Several agonists of D2 family of DA receptors given i.o. suppressed the nighttime NAT activity of the chick retina with quinpirole (D3/D4 receptor selective) and bromocriptine (D2/D3 receptor selective) being the most and the least potent drugs, respectively. The rank-order potency of antagonists of D2 family of DA receptors to block the inhibitory effect of quinpirole on the enzyme activity (with clozapine being relatively very potent, and (+)-butaclamol, raclopride and remoxipride-ineffective) match the characteristics of the D4 DA receptor. Moreover, although sulpiride effectively prevented the quinpirole-induced decline in the nighttime NAT activity of the chick retina, there was no marked stereoselectivity in its action. It is suggested that DA receptor regulating NAT activity in chick retina represents a D4-like subtype.

Animals↗
PubMed1994

Stimulatory effect of histamine on cyclic AMP formation in chick pineal gland.

Histamine (HA) potently stimulated cyclic AMP accumulation in intact pineal glands taken from light-exposed chicks. The action of HA was stronger in the presence of forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). The effect of HA was mimicked by HA H1- and H2-receptor-selective agonists in the following order of potency: HA > 4-methylhistamine (H2) > 2-methylhistamine (H1) > 2-thiazolylethylamine (H1) >> dimaprit (H2). The HA H3-receptor-selective agonist (R)alpha-methylhistamine was poorly active. The effect of HA was antagonized by selective H2-receptor blockers (tiotidine > oxmetidine > cimetidine = ranitidine) and was not significantly affected by the selective H1- and H3-receptor blockers mepyramine and thioperamide. A detailed analysis of an antagonistic action of ranitidine (versus HA) revealed a noncompetitive mode of action of the H2 blocker. The stimulatory action of the H1 agonist 2-thiazolylethylamine (both under basal conditions and in the presence of forskolin or IBMX) was not significantly influenced by three H1-receptor-selective blockers (mepyramine, triprolidine, and diphenhydramine), but it was totally counteracted by ranitidine. Using accepted selective agonists and antagonists of the HA H1, H2, and H3 receptor we were unable to identify clearly the receptor subtype mediating the HA action on the cyclic AMP-generating system of the chick pineal. It is suggested that the receptor under consideration may represent either an H2-like (in terms of mammalian criteria) or avian-specific HA receptor. The data suggest that HA may be considered a modulator of the pineal activity in chicks.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Histamine in the central nervous system: its role in circadian rhythmicity.

Histamine is an accepted neurotransmitter and/or neuromodulator in the central nervous system (CNS). Its neuronal system in the brain is well organized, with cell bodies localized in a small area of the posterior hypothalamus. Diverse biological actions of histamine are mediated via three classes of receptors termed H1, H2, and H3. The existence of other histamine receptor subtypes is likely in invertebrates or in birds. This article surveys basic data indicative of a neuroregulator role of histamine in the CNS; it also presents accumulating evidence suggesting that histamine may be related to circadian rhythmicity in the body.

Animals↗
PubMed1993

Intravitreal application of membrane-permeable analogs of cyclic GMP increases serotonin N-acetyltransferase (NAT) activity in retinas of light-exposed chicks: comparison with the effect of cyclic AMP analogs and darkness.

Intravitreal administration of membrane-permeable analogs of cGMP and cAMP markedly enhanced serotonin N-acetyltransferase (NAT) activity in retinas of light-exposed chicks. The effects of cGMP analogs were usually weaker than the actions of cAMP analogs, however, they were more pronounced than the effects of non-cyclic derivative of GMP (i.e., 8-bromo-GMP). Combined treatment with dibutyryl-derivatives of cGMP and cAMP yielded NAT values that were similar to the values produced by the compounds administered separately, whereas NAT activity in chicks receiving a combination of db-cGMP and aminophylline was higher than the enzyme activity produced by the drugs individually. Neither db-cGMP nor aminophylline affected hydroxyindole-O-methyltransferase (HIOMT) activity in retinas of light-exposed chicks. It is hypothesized that cGMP analogs enhance the retinal NAT activity indirectly, via cAMP.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1993

Hydroxyindole-O-methyltransferase activity in ocular and brain structures of rabbit and hen.

Relative activities of hydroxyindole-O-methyltransferase (HIOMT) of some brain and ocular structures of the rabbit and hen were analyzed using different 5-hydroxyindoles, i.e., N-acetylserotonin (NAS), 5-hydroxytryptophol (HTOL), 5-hydroxytryptophan (HTP), 5-hydroxytryptamine (HT), and 5-hydroxy-3-indoleacetic acid (HIAA), as enzyme substrates. Pineal glands of both species, as well as hen retina, are capable of producing, to varying degrees, melatonin, 5-methoxytryptophol, and 5-methoxytryptamine. Hen choroid and iris-ciliary body O-methylated NAS and HTOL, whereas rabbit choroid and, to a much lesser extent, hypothalamus and cerebral cortex all O-methylated only NAS. No measurable HIOMT activity was found in hen brain. NAS was a preferred substrate for HIOMT in the hen tissues, whereas in the rabbit pineal gland NAS and HTOL were equally good substrates for HIOMT. Other tested 5-hydroxyindoles, i.e., HTP, HT, and HIAA, were poor methyl acceptors. Of the tissues examined, the highest HIOMT activity was found in the hen pineal gland, followed by the rabbit pineal gland and hen retina. No significant differences between day and nighttime enzyme activities were observed in the pineal gland and retina of either species. The data suggest that in vertebrates some nervous and ocular tissues possess the potential to produce 5-methoxyindole compounds; however, the HIOMT-catalyzed process shows remarkable substrate-, tissue- and species-dependent variations.

Acetylserotonin O-Methyltransferase↗
PubMed1992

Regulatory mechanisms in melatonin biosynthesis in retina.

The vertebrate retina produces melatonin in a light-dependent rhythmic fashion, synchronized with, but independent from the rhythm of the hormone formation in the pineal gland. This review summarizes the current status of our knowledge on regulatory mechanisms involved in controlling the retinal melatonin biosynthesis. Special emphasis is given to the role and mode of action of dopamine and GABA, two established retinal neurotransmitters, as well as that of second messengers (cyclic AMP, calcium ions). Comparisons are made between lower vertebrates and mammals.

Acetylserotonin O-Methyltransferase↗
PubMed1992

Melatonin increases serotonin N-acetyltransferase activity and decreases dopamine synthesis in light-exposed chick retina: in vivo evidence supporting melatonin-dopamine interaction in retina.

The administration of melatonin, either peripherally (0.01-10 mg/kg) or intraocularly (0.001-10 mumol/eye), to light-exposed chicks dose-dependently increased serotonin N-acetyltransferase (NAT) activity in retina but not in pineal gland. The effect of melatonin was slightly but significantly reduced by luzindole (2-benzyl-N-acetyltryptamine), and not affected by two other purported melatonin antagonists, N-acetyltryptamine and N-(2,4-dinitrophenyl)-5-methoxytryptamine (ML-23). The elevation of the enzyme activity induced by melatonin was substantially stronger than that evoked by 5-hydroxytryptamine, N-acetyl-5-hydroxytryptamine, or 5-methoxytryptamine. The melatonin-evoked rise in the retinal NAT activity was counteracted by two dopamine D2 receptor agonists, quinpirole and apomorphine, and prevented by the dopamine D2 receptor blocker spiroperidol, and by an inhibitor of dopamine synthesis, alpha-methyl-p-tyrosine. Melatonin (0.1-10 mg/kg i.p.) dose-dependently decreased the levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), as well as the DOPAC/dopamine ratio, in chick retina but not in forebrain. The results obtained (1) indicate that melatonin in vivo potently inhibits dopamine synthesis selectively in retina, and (2) suggest that the increase in retinal NAT activity evoked by melatonin in light-exposed chicks is an indirect action of the compound, and results from the disinhibition of the NAT induction process from the dopaminergic (inhibitory) signal. The results provide in vivo evidence supporting the idea (derived on the basis of in vitro findings) that a mutually antagonistic interaction between melatonin and dopamine operates in retinas of living animals.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Calcium channel blockers in vivo inhibit serotonin N-acetyltransferase (NAT) activity in chicken retina stimulated by darkness and not by agents elevating intracellular cyclic AMP level.

The molecular mechanism underlying the role of calcium influx in the regulation of retinal serotonin N-acetyltransferase (NAT) activity was studied in vivo in chickens. Systemic administration of organic antagonists of voltage-sensitive calcium channels (VSCC), i.e., nimodipine and nifedipine, resulted in a marked suppression of the nocturnal increase of NAT activity in chicken retina. In contrast, NAT activity stimulated by nonhydrolysable analogs of cyclic AMP (dibutyryl-cyclic AMP and 8-bromo-cyclic AMP), forskolin, a direct activator of adenylate cyclase, and by phosphodiesterase inhibitors (aminophylline and 3-isobutyl-1-methylxanthine), was not significantly affected by various tested VSCC antagonists. The inhibitory effect of nimodipine on the dark-dependent increase in NAT activity of chicken retina was abolished by Bay K 8644, a selective VSCC agonist. The results presented in this paper indicate an important role of calcium influx through L-type of VSCC in the induction of NAT activity in chicken retina, and suggest that a requirement of calcium ions in the process of NAT induction in the retina may be primarily at the level of cyclic AMP production.

Animals↗
PubMed1992

Serotonin N-acetyltransferase (NAT) induction in mammalian retina: role of cyclic AMP and calcium ions.

In retinas and pineal glands of rat, rabbit and hen, activities of the penultimate (and key regulatory) enzyme in melatonin biosynthesis, serotonin N-acetyltransferase (NAT), display distinct diurnal variations, with high and low values during dark and light phase of a 12-h dark: 12-h light illumination cycle. Two-hour incubation (during daytime hours in light) of isolated pineal glands of the studied vertebrates, or the retinas, with 50 microM forskolin (plus 100 microM 3-isobutyl-1-methylxanthine, IBMX-a phosphodiesterase inhibitor), and 1 mM dibutyryl-cAMP, markedly increased the tissue NAT activity. The same procedures significantly enhanced the enzyme activity of rat retina in light, however, only during nighttime hours. The forskolin (+ IBMX)-induced increase of NAT activity in rat retina was significantly lower in a calcium-free medium, and substantially enhanced when calcium concentration was raised from 1.3 mM to 3.9 mM. Treatment of rats with IBMX or aminophylline, and rabbits with aminophylline, increased NAT activity in their pineal glands irrespective of the time of the day, whereas both phosphodiesterase inhibitors significantly increased the enzyme activity of rat retina only when injected during the subjective dark hours. It is concluded that, by analogy to vertebrate pineal gland, in vertebrate retina an increase of NAT activity (and consequently melatonin formation), stimulated both physiologically (i. e. at night), or pharmacologically, involves a cAMP- and calcium dependent process of the enzyme induction.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Calcium channel drugs affect nocturnal serotonin N-acetyltransferase (NAT) activity in rat pineal gland.

The effects of different organic compounds that block and increase Ca2+ influx through the voltage-sensitive calcium channels (VSCC) on the nocturnal serotonin N-acetyltransferase (NAT) activity was investigated in vivo in rats. Systemic administration of VSCC antagonists, i.e. nimodipine, nifedipine, verapamil and diltiazem, resulted in a marked suppression of the nighttime pineal NAT activity. Bay K 8644, a VSCC agonist, injected to rats before the time of the light offset of the light-dark cycle significantly enhanced the nocturnal increase of the pineal NAT activity. Although Bay K 8644 given during the dark phase of an imposed illumination cycle had little effect on the nocturnal pineal NAT activity, it antagonized the nimodipine- and verapamil-induced decrease in the enzyme activity. These results support the role of Ca2+ influx through the VSCC in the nocturnal increase of NAT activity in the pineal gland of rat.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Cyclic AMP generating systems in vertebrate retina: effects of histamine and an established retinal modulator, dopamine.

Histamine (HA), 1-1000 microM, significantly stimulated both basal and forskolin-activated cAMP generation in chicken and adult hen retina. The action of HA was reproduced by the selective H2-receptor agonists dimaprit and 4-methyl-histamine, but not by the selective H1-receptor agonist 2-thiazolylethylamine, and it was antagonized by the specific H2-receptor blockers cimetidine and tiotidine, but not by the H1-receptor blocker mepyramine. In parallel experiments, dopamine, an established retinal neuromodulator acting through the D1-type of receptor, also stimulated basal and forskolin-driven adenylate cyclase activity in homogenate of chicken retina. It is suggested that chicken retina contains HA H2-receptors which are positively coupled to the adenylate cyclase system.

Adenylyl Cyclases↗
PubMed1991

Dark-induced supersensitivity of dopamine D-1 and D-2 receptors in rat retina.

Light deprivation of rat retina leads to a rapid (within 6 h) development of a state of supersensitivity (upregulation) of dopamine D-1 receptors (positively coupled to adenylate cyclase), which are essentially involved in the modulation by light of the electrical activity and communication between horizontal cells. In contrast, the supersensitivity of D-2 receptors (negatively coupled to cAMP generating system) appears to develop only after 2 days (better after 4 days) of dark adaptation, although these receptors are linked to multiple light-dependent retinal functions. These results suggest the existence of different mechanisms of sensory adaptation for these two subtypes of dopamine receptors.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Regulation of melatonin biosynthesis in vertebrate retina: involvement of dopamine in the suppressive effects of light.

The article shortly reviews literature data and presents our new findings on the regulation of melatonin biosynthesis and level in the vertebrate retina. Special emphasis is given to the role of dopamine as a mediator of the inhibitory effect of light on melatonin synthesis in retinas of lower vertebrates. Other discussed problems include (1) the role of cyclic AMP and calcium ions in the induction of serotonin N-acetyltransferase (NAT; the key regulatory enzyme in melatonin biosynthetic pathway), and (2) feedback regulations and metabolism of retinal melatonin. The presented experimental evidence, compared with similar data obtained for the pineal gland, suggests the existence in the vertebrates retina of some specific for this tissue factors, that locally regulate and control the level of retinal melatonin.

Acetylserotonin O-Methyltransferase↗
PubMed1990

Calcium influx through voltage-sensitive calcium channels regulates in vivo serotonin N-acetyltransferase (NAT) activity in hen retina and pineal gland.

The involvement of transmembrane transport of Ca2+ in regulation of retinal and pineal serotonin N-acetyltransferase (NAT) activity was studied in vivo in hens. Intramuscular administration to hens of organic antagonists of voltage-sensitive calcium channels (VSCC), nimodipine, nifedipine and verapamil, resulted in a marked inhibition of the nocturnal increase of NAT activity in retina and pineal gland. In both tissues the inhibitory effect of nimodipine on the night-time rise of NAT activity was abolished by Bay K 8644, a VSCC agonist. Bay K 8644 administered to hens at the end of the light phase of the light-dark cycle significantly enhanced the dark-dependent increase in retinal and pineal NAT activity. It is suggested that the nocturnal increase of NAT activity in hen retina and pineal gland is similarly regulated in vivo by Ca2+ influx through the VSCC.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗