The neurotransmitter serotonin has been critically implicated in the pathogenesis of several mental disorders. The serotonin transporter (5-HTT) is a key regulator of serotonergic neurotransmission and its genetic variability is associated with increased risk of psychopathology. One well known polymorphic locus in the 5-HTT gene affecting its expression is a tandem repeat in the promoter region (5-HTTLPR). It has been reported that 5-HTT is functionally coupled with the neuronal nitric oxide synthase (NOS1 or nNOS), an enzyme catalyzing the production of nitric oxide (NO). We have previously demonstrated that a tandem repeat polymorphism in the promoter of NOS1 exon 1f (Ex1f-VNTR) is associated with sensorimotor gating, a marker of inhibitory processing and a well established endophenotype of several neuropsychiatric disorders. Here we investigated the combined genetic effects of NOS1 Ex1f-VNTR and 5-HTTLPR on sensorimotor gating, measured by prepulse inhibition (PPI) of the acoustic startle reflex, in 164 healthy adults. We found no evidence for the interaction between NOS1 Ex1f-VNTR and 5-HTTLPR on PPI. PPI was associated with NOS1 Ex1f-VNTR, but not 5-HTTLPR. Our data suggest that while NOS1 plays a role in sensorimotor gating, the nitrergic pathway of gating regulation does not involve the action of 5-HTT.

• MeSH
• dospělí MeSH
• exony MeSH
• fenotyp MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin genetika   MeSH
• minisatelitní repetice MeSH
• mladý dospělý MeSH
• prepulsní inhibice genetika   MeSH
• promotorové oblasti (genetika) MeSH
• senzorimotorický kortex fyziologie   MeSH
• synthasa oxidu dusnatého, typ I genetika   MeSH
• úleková reakce genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The sympathetic nerve activity (SNA) is augmented in hypertension. SNA is regulated by neuronal nitric oxide synthase (nNOS) or endothelial nitric oxide synthase (eNOS) activity in hypothalamic paraventricular nuclei (PVN) and/or brainstem rostral ventrolateral medulla. High nNOS or eNOS activity within these brain regions lowers the SNA, whereas low cerebral nNOS and/or eNOS activity causes SNA augmentation. We hypothesize that the decreased cerebral nNOS/eNOS activity, which allows the enhancement of SNA, leads to the augmentation of renal eNOS/nNOS activity. Similarly, when the cerebral nNOS/eNOS activity is increased and SNA is suppressed, the renal eNOS/nNOS activity is suppressed as well. The activation of endothelial alpha(2)-adrenoceptors, may be a possible mechanism involved in the proposed regulation. Another possible mechanism might be based on nitric oxide, which acts as a neurotransmitter that tonically activates afferent renal nerves, leading to a decreased nNOS activity in PVN. Furthermore, the importance of the renal nNOS/eNOSactivity during renal denervation is discussed. In conclusion, the presented hypothesis describes the dual organ-specific role of eNOS/nNOS activity in blood pressure regulation and suggests possible connection between cerebral NOS and renal NOS via activation or inhibition of SNA, which is an innovative idea in the concept of pathophysiology of hypertension.

• MeSH
• hypertenze enzymologie   patofyziologie   MeSH
• krevní tlak * MeSH
• ledviny enzymologie   inervace   MeSH
• lidé MeSH
• mozek enzymologie   MeSH
• oxid dusnatý metabolismus   MeSH
• sympatický nervový systém patofyziologie   MeSH
• synthasa oxidu dusnatého, typ I metabolismus   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

We showed previously that in anaesthetized rats acute noninvasive renal denervation (DNX) induced an increase in arterial blood pressure (MABP), unlike the usual hypotensive effect. Here we aimed to establish the background of such unusual response, especially the role of oxidative stress as suggested by an earlier study. The contribution of oxidative stress was explored by studying the effects on DNX-induced MABP increase of pretreatment with 4-hydroxy-3-methoxyacetophenone (apocynin, APO), a powerful antioxidant and antihypertensive agent, and N(omega)-propyl-L-arginine (L-NPA), a blocker of neuronal nitric oxide synthase (nNOS). In anaesthetized Wistar rats maintained on standard (STD) or high-salt (HS) diet sequential right- and left-side DNX was performed. MABP responses were examined without pretreatment and after APO (20 mg/day on two preceding days) and L-NPA (1 mg/kg/h throughout experiment), given alone or combined. In untreated rats, bilateral DNX increased MABP by 6% on STD and 15% on HS diet (P < 0.01 or less); the difference between MABP responses was highly significant (P = 0.002). In STD rats APO or APO + L-NPA treatment failed to alter post-DNX MABP increases whereas L-NPA alone reversed the response and a significant 7% decrease occurred. In HS rats APO and L-NPA given alone reversed the MABP response and significant decreases of 14% (P = 0.001) and 8% (P = 0.01), were seen. Surprisingly, with L-NPA + APO pretreatment only abolishment (not reversal) of post-DNX pressure increase occurred. The results suggest that both systemic, intrarenal and brain oxidative stress, and excessive nNOS activity, mostly in the brain, determine the unexpected post-DNX pressure increase.

• MeSH
• acetofenony farmakologie   MeSH
• anestezie MeSH
• arginin analogy a deriváty   farmakologie   MeSH
• denervace * MeSH
• krevní tlak * účinky léků   MeSH
• ledviny inervace   MeSH
• oxidační stres * účinky léků   MeSH
• potkani Wistar MeSH
• sodík dietní farmakologie   MeSH
• synthasa oxidu dusnatého, typ I fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Research increasingly suggests that nitric oxide (NO) plays a role in the pathogenesis of schizophrenia. One important line of evidence comes from genetic studies, which have repeatedly detected an association between the neuronal isoform of nitric oxide synthase (nNOS or NOS1) and schizophrenia. However, the pathogenetic pathways linking nNOS, NO, and the disorder remain poorly understood. A deficit in sensorimotor gating is considered to importantly contribute to core schizophrenia symptoms such as psychotic disorganization and thought disturbance. We selected three candidate nNOS polymorphisms (Ex1f-VNTR, rs6490121 and rs41279104), associated with schizophrenia and cognition in previous studies, and tested their association with the efficiency of sensorimotor gating in healthy human adults. We found that risk variants of Ex1f-VNTR and rs6490121 (but not rs41279104) were associated with a weaker prepulse inhibition (PPI) of the acoustic startle reflex, a standard measure of sensorimotor gating. Furthermore, the effect of presence of risk variants in Ex1f-VNTR and rs6490121 was additive: PPI linearly decreased with increasing number of risk alleles, being highest in participants with no risk allele, while lowest in individuals who carry three risk alleles. Our findings indicate that NO is involved in the regulation of sensorimotor gating, and highlight one possible pathogenetic mechanism for NO playing a role in the development of schizophrenia psychosis.

• MeSH
• dospělí MeSH
• exony MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• minisatelitní repetice MeSH
• oxid dusnatý fyziologie   MeSH
• prepulsní inhibice genetika   MeSH
• schizofrenie genetika   MeSH
• senzorický gating genetika   MeSH
• synthasa oxidu dusnatého, typ I genetika   MeSH
• úleková reakce genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.

• MeSH
• aminochinoliny chemická syntéza   farmakologie   MeSH
• Caco-2 buňky MeSH
• enzymatické testy MeSH
• histidin chemie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• permeabilita buněčné membrány účinky léků   MeSH
• skot MeSH
• synthasa oxidu dusnatého, typ I antagonisté a inhibitory   chemie   MeSH
• synthasa oxidu dusnatého, typ II antagonisté a inhibitory   MeSH
• synthasa oxidu dusnatého, typ III antagonisté a inhibitory   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Melatonin, a multitasking indolamine, seems to be involved in a variety of physiological and metabolic processes via both receptor-mediated and receptor-independent mechanisms. The aim of our study was to find out whether melatonin can affect blood pressure (BP), nitric oxide synthase (NOS) activity, eNOS and nNOS protein expressions in rats with metabolic syndrome (SHR/cp). Rats were divided into four groups: 6-week-old male WKY andSHR/cp and age-matched WKY and SHR/cp treated with melatonin (10 mg/kg/day) for 3 weeks. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions were determined in the heart, aorta, brain cortex and cerebellum. MT(1) receptors were analyzed in the brain cortex and cerebellum. In SHR/cp rats, BP was decreased after melatonin treatment. In the same group, melatonin did not affect NOS activity and eNOS protein expression in the heart and aorta, while it increased both parameters in the brain cortex and cerebellum. Interestingly, melatonin elevated MT1 protein expression in the cerebellum. Neuronal NOS protein expression was not changed within the groups. In conclusion, increased NOS activity/eNOS upregulation in particular brain regions may contribute partially to BP decrease in SHR/cp rats after melatonin treatment. Participation of MT(1) receptors in this melatonin action may be supposed.

• MeSH
• aktivace enzymů účinky léků   MeSH
• hypertenze patofyziologie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• melatonin aplikace a dávkování   MeSH
• metabolický syndrom patofyziologie   MeSH
• mozek metabolismus   MeSH
• oxid dusnatý biosyntéza   MeSH
• potkani inbrední SHR MeSH
• synthasa oxidu dusnatého, typ I metabolismus   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• synthasa oxidu dusnatého metabolismus   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability.

• MeSH
• aminopyridiny chemická syntéza   chemie   farmakologie   MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• synthasa oxidu dusnatého, typ I antagonisté a inhibitory   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

We studied the effect of testosterone overdose on the number, distribution and chemical coding of ovarian neurons in the dorsal root ganglia (DRGs) in pigs. On day 3 of the estrous cycle, the ovaries of both the control and experimental gilts were injected with retrograde tracer Fast Blue. From day 4 of the estrous cycle to the expected day 20 of the second studied cycle, the experimental gilts were injected with testosterone, while the control gilts received oil. After the completion of the protocol the Th16-L5 DRGs were collected. Injections of testosterone increased the testosterone (~3.5 fold) and estradiol-17beta (~1.6 fold) levels in the peripheral blood, and reduced the following in the DRGs: the total number of the Fast Blue-positive perikarya, the population of perikarya in the L2-L4 ganglia, and the numbers of SP(+)/CGRP(+), SP(+)/PACAP(+), SP(+)/nNOS(+) and SP(-)/nNOS(+) perikarya. In the testosterone-injected gilts, the populations of SP(+)CGRP(-), small and large androgen receptors-expressing perikarya were increased. These results suggest that elevated androgen levels during pathological states may regulate the transmission of sensory modalities from the ovary to the spinal cord, and antidromic regulation of the ovarian functions.

• MeSH
• androgenní receptory metabolismus   MeSH
• estradiol krev   farmakologie   MeSH
• estrální cyklus MeSH
• estrogeny krev   farmakologie   MeSH
• hypofyzární adenylátcyklázu aktivující peptid metabolismus   MeSH
• imunohistochemie MeSH
• lidé MeSH
• neurony účinky léků   MeSH
• ovarium účinky léků   inervace   MeSH
• peptid spojený s genem pro kalcitonin metabolismus   MeSH
• prasata MeSH
• spinální ganglia cytologie   účinky léků   MeSH
• synthasa oxidu dusnatého, typ I metabolismus   MeSH
• testosteron krev   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.

• MeSH
• aminochinoliny chemie   farmakokinetika   farmakologie   MeSH
• Caco-2 buňky MeSH
• fenylethery chemie   farmakokinetika   farmakologie   MeSH
• inhibitory enzymů chemie   farmakokinetika   farmakologie   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární modely MeSH
• synthasa oxidu dusnatého, typ I antagonisté a inhibitory   metabolismus   MeSH
• synthasa oxidu dusnatého, typ II antagonisté a inhibitory   metabolismus   MeSH
• synthasa oxidu dusnatého, typ III antagonisté a inhibitory   metabolismus   MeSH
• synthasa oxidu dusnatého antagonisté a inhibitory   metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• cévní endotel fyziologie   MeSH
• krevní tlak fyziologie   MeSH
• lidé MeSH
• oxid dusnatý * biosyntéza   fyziologie   MeSH
• oxidační stres fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• synthasa oxidu dusnatého, typ I antagonisté a inhibitory   fyziologie   MeSH
• synthasa oxidu dusnatého, typ III antagonisté a inhibitory   fyziologie   MeSH
• synthasa oxidu dusnatého * antagonisté a inhibitory   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH