Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to investigate the role of cardiopulmonary reflex, more specifically the Bezold-Jarisch reflex, in experimental hypertension induced by chronic administration of Nw-nitro-L-arginine methyl ester (L-NAME) (0.5 mg/ml) added to the drinking water for 6 days. The study was performed in male Wistar rats (200-350 g), 9 animals per group. L-NAME ingestion caused a significant increase in resting mean arterial pressure (MAP: 182 +/- 4 mmHg) and heart rate (HR: 447 +/- 20 bpm) when compared to untreated rats (MAP: 112 +/- 3 mmHg and HR: 355 +/- 10 bpm). Cardiopulmonary receptors were chemically stimulated with bolus injections of 5-hydroxytryptamine (5-HT, 4-10 micrograms/kg, iv) followed by measuring the falls in diastolic arterial pressure (DAP) and HR in conscious and freely moving animals. As expected, the responses to intravenous injections of 5-HT consisted of a dose-dependent reduction in HR (from 26 +/- 14 to 175 +/- 25 bpm) and DAP (from 7 +/- 4 to 39 +/- 3 mmHg) in the control rats. Both bradycardia and diastolic hypotension were significantly accentuated in the L-NAME animals (approximately 30%). These data suggest that, in contrast to other models of hypertension, in the present one caused by inhibition of nitric oxide synthesis, the Bezold-Jarisch reflex is exaggerated. This neural dysfunction could be related to changes in the cardiac vagal efferent or effector.
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PMID:Exaggerated Bezold-Jarisch reflex in the hypertension induced by inhibition of nitric oxide synthesis. 858 Aug 77

In humans, the head-up tilted position results in central hypovolaemia which mimicks haemorrhage and is associated with cardiovascular changes that can be divided into two stages. 1) One stage with increase in HR and vascular resistance and a slight increase in MAP. 2) Another stage with decrease in HR, vascular resistance and MAP and appearance of presyncopal symptoms (hypovolaemic shock). The first stage is "sympathoexcitatory" as plasma NA originating from postganglionic vasoconstrictory sympathetic neurons increase. Limb vascular resistance contributes to the increase in TPR at this time. The second stage is "sympathoinhibitory" in nature as plasma NA slightly decreases, or remains unchanged, while plasma A, originating from the adrenal medulla, raises. This pattern is a reflection of a differentiated sympathetic response as an increase in the activity of the nerves innervating the adrenals and decrease in renal sympathetic nerves has been reported by others. There is a decrease in limb as well as total vascular resistance. The secretion of potent vasoactive peptides may contribute to the circulatory changes taken place during head-up tilt. The head-up tilted position is associated with central hypovolaemia which is reliably monitored by electrical impedance. There is a close relation between the increase in thoracic electrical impedance and the decrease in plasma ANP which is regulated by atrial stretch. Also, from recording of technetium labeled red blood cells and measurements of haematocrite the decrease in CBV is reflected by thoracic electrical impedance. In contrast, CVP reflects changes in CBV during the initial head-up tilt only, whereafter CVP usually is unchanged or may even increase. After the initial head-up tilt the decrease in the CBV is caused by further reduction in plasma volume as shown by increase in haematocrite and unchanged distribution of labeled red blood cells. This mechanism is reflected by application of regional electrical impedance measurements at a low and high frequency current. The low frequency current, passing extracellular fluid only, changing more than the high frequency current that passes extra as well as intracellular fluid. Central hypovolaemia was found to stimulate the pituitary-adrenal axis, and the development of hypotension strongly increases plasma ACTH, beta-END, cortisol and PRL. Blocking histaminergic receptors did not change the pituitary-adrenal response to central hypovolaemia, while the sympathoadrenal response was affected by histaminergic receptor blockade. The H2-receptor antagonist cimetidine inhibited plasma A, while the H1-receptor antagonist mepyramine attenuated plasma NA and reduced cardiovascular tolerance, and also induced some sedation. A possible effect of sedation and anxiolysis was investigated by administration of the GABAergic drug diazepam. This drug did not change the cardiovascular response to head-up tilt, but reduced the increase in plasma cortisol. This indicates that the appearance of presyncopal symptoms is not related to "stress" but associated with the cardiovascular effects of central hypovolaemia. Another endogenous substance, serotonin (5-HT), may be also involved in cardiovascular as well as endocrine regulation. We investigated the effect of blocking three main receptors on the development and effects of hypovolaemic shock. Methysergide (5-Ht1+2-receptor antagonist) attenuated plasma NA, beta-END, PRL and PRA during tilt with a slight reduction of cardiovascular tolerance. The 5-HT2-receptor antagonist ketanserin reduced cardiovascular tolerance without significant effects on the hormonal responses. The 5-HT3-receptor antagonist ondansetron inhibited the plasma CGRP and adrenalin response to central hypovolaemia without influencing cardiovascular tolerance. It is concluded that the head-up tilted model in humans can be applied to study cardiovascular and endocrine mechanisms until the development of hypovolaemic shock.(ABSTRACT TRUNCATED)
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PMID:Neuroendocrine mechanisms during reversible hypovolaemic shock in humans with emphasis on the histaminergic and serotonergic system. 880 74

Long-term facilitation of the sensory to motor synapse in Aplysia requires gene expression. While some transcription factors involved in long-term facilitation are phosphorylated by PKA, others lack PKA sites but contain MAP Kinase (MAPK) phosphorylation sites. We now show that MAPK translocates into the nucleus of the presynaptic but not the postsynaptic cell during 5-HT-induced long-term facilitation. The presynaptic nuclear translocation of MAPK is also triggered by elevations in intracellular cAMP. Injection of anti-MAPK antibodies or of MAPK Kinase inhibitors into the presynaptic cell blocks long-term facilitation, without affecting basal synaptic transmission or short-term facilitation. Thus, MAPK appears to be specifically recruited and necessary for the long-term form of facilitation. This mechanism for long-term plasticity may be quite general: cAMP also activated MAPK in mouse hippocampal neurons, suggesting that MAPK may play a role in hippocampal long-term potentiation.
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PMID:MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia. 920 58

The Bezold-Jarisch reflex function was evaluated in rats made hypertensive by the chronic oral intake of a nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, averaging 35 mg/kg/day), for 3, 6, and 12 days (n = 9/group) and in untreated control rats (CR, n = 9/group). L-NAME-treated rats showed a marked hypertension (MAP: 148 +/- 3, 182 +/- 4, and 179 +/- 4 mm Hg, respectively) compared with CR (110 +/- 2 mm Hg). The 6- and 12-day groups showed tachycardia (447 +/- 20 and 466 +/- 13 beats/min, respectively) when compared with CR (355 +/- 10 beats/min). When compared with CR, left ventricular hypertrophy was observed in rats treated with L-NAME for 6 and 12 days. The Bezold-Jarisch reflex, a decrease in heart rate (HR) accompanied by a decrease in diastolic arterial pressure (DAP), was evoked in a dose dependent manner by the intravenous injection of 5-hydroxytryptamine (5-HT, 5 to 10 microg/kg). Relative to responses observed in CR, 5-HT at 10 microg/kg caused a four- to fivefold greater decrease in HR and a two- to threefold greater decrease in DAP in all the L-NAME treatment groups. Using a Langendorff technique, we observed a significant increase in the responsiveness of the pacemaker to acetylcholine (1.25 to 80 microg/mL). These data suggest that the pharmacological inhibition of the nitric oxide synthase causes profound changes in the mechanisms of cardiovascular regulation as shown by a marked enhancement of the Bezold-Jarisch reflex in L-NAME-treated rats. The enhancement of this reflex seems to be in great part due to the hyperresponsiveness of the cardiac pacemaker to cholinergic stimulation.
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PMID:Inhibition of nitric oxide synthase causes profound enhancement of the Bezold-Jarisch reflex. 950 52

Pulmonary neuroendocrine cells function as hypoxia-sensitive chemoreceptors, and they release peptides and biogenic amines that are important mediators of pulmonary neonatal adaptation. Some of these products additionally act as autocrine growth factors. Increased numbers of pulmonary neuroendocrine cells have been observed in several smoking-associated pediatric lung disorders such as bronchopulmonary dysplasia, cystic fibrosis, sudden infant death syndrome, and asthma. Disturbed pulmonary neuroendocrine function has been implicated in the etiology of this disease complex. One of the most common smoking-associated lung cancer types, small cell lung carcinoma, expresses phenotypic and functional features of pulmonary neuroendocrine cells. We, as well as others, have shown that the release of the autocrine growth factors 5-hydroxytryptamine (5-HT, serotonin) and mammalian bombesin/gastrin releasing peptide (MB/GRP) by cell lines derived from human small cell lung carcinoma or fetal hamster pulmonary neuroendocrine cells are regulated by a neuronal nicotinic acetylcholine receptor comprised of alpha(7) subunits. In radio-receptor assays, nicotine and the nicotine-derived carcinogenic nitrosamines NNNN. Binding of nicotine or NNK to the alpha(7) receptor resulted in calcium influx and overexpression and activation of the serine-threonine protein kinase Raf-1. In turn, this event lead to overexpression and activation of the mitogen activated (MAP) kinases extracellular signal regulated kinase 1 (ERK1) and extracellular signal regulated kinase 2 (ERK2) and stimulation of DNA synthesis accompanied by an increase in cell numbers in fetal pulmonary neuroendocrine cells and small cell carcinoma cells. Exposure of fetal pulmonary neuroendocrine cells for 6 days to NNK caused a prominant up-regulation of Raf-1. Our findings suggest that chronic exposure to nicotine and NNK in pregnant women who smoke may up-regulate the alpha(7) nicotinic receptor as well as components of its associated mitogenic signal transduction pathway, thus increasing the susceptibilities of the infants for the development of pediatric lung disorders. Similarly, up-regulation of one or several components of this nicotinic receptor pathway in smokers may be an important factor for the development of small cell lung carcinoma.
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PMID:Interaction of tobacco-specific toxicants with the neuronal alpha(7) nicotinic acetylcholine receptor and its associated mitogenic signal transduction pathway: potential role in lung carcinogenesis and pediatric lung disorders. 1077 Oct 23

We have used an antibody that specifically recognizes eukaryotic initiation factor 4E (eIF4E) when it is phosphorylated at Ser(207) to characterize eIF4E phosphorylation in the nervous system of APLYSIA: The level of phosphorylated eIF4E, but not the level of total eIF4E, was significantly correlated with the basal rate of translation measured from different animals. Serotonin (5-HT), a transmitter that regulates the rate of translation in APLYSIA: neurons, had mixed effects on eIF4E phosphorylation. 5-HT decreased eIF4E phosphorylation in sensory cell clusters through activation of protein kinase C. 5-HT increased eIF4E phosphorylation in the whole pleural ganglia. In the APLYSIA: nervous system, eIF4E phosphorylation correlated with phosphorylation of the p38 MAP kinase, but not the p42 MAP kinase (ERK). Furthermore, an inhibitor of the p38 MAP kinase significantly decreased basal eIF4E phosphorylation, but an inhibitor of the MAP or ERK kinase (MEK) did not. Despite the correlation of eIF4E phosphorylation with the basal rate of translation, inhibition of eIF4E phosphorylation by an inhibitor of the p38 MAP kinase did not significantly decrease the rate of translation.
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PMID:Regulation of eukaryotic initiation factor 4E phosphorylation in the nervous system of Aplysia californica. 1089 66

Serotonin [5-hydroxytryptamine (5-HT)]-mediated cardiac valvular disease has been commonly observed in patients with carcinoid tumors. Previous research by others using reverse transcriptase-polymerase chain reaction demonstrated that aortic valve cells expressed predominantly 5-HT(2A/2B) receptors (5-HT(2A)R). Related investigations by our group using sheep aortic valve interstitial cell (SAVIC) cultures demonstrated that 5-HT both up-regulates transforming growth factor (TGF)-beta1 expression and activity, and also results in increased phospholipase C (PLC) activity. Thus, the present study investigated the hypothesis that the 5-HT signaling pathway in SAVICs involves 5-HT(2)Rs with associated G-protein signal transduction. The objectives were to functionally characterize in SAVIC cultures the native serotonin receptor subtypes using specific agonists and antagonists, and to delineate the serotonin-signaling pathway. 5-HT administration caused a marked stimulation of PLC activity. SAVIC studies of specific agents that target the 5-HT(2)R subtypes indicate that this response seemed to be mediated predominantly by 5-HT(2A)Rs. Furthermore, the sheep 5-HT(2A)R was identified by reverse transcriptase-polymerase chain reaction with sequence confirmation including comparisons to pig and human 5-HT(2A)R. Extracellular signal-regulated kinase (Erk 1/2) is a signaling molecule downstream from the 5-HT(2A)R. Both a protein kinase C inhibitor, GF109203X, and a Src inhibitor, PP1, attenuated 5-HT-stimulated Erk 1/2 activation. However, a 5-HT(2A)R antagonist, MDL 100907, inhibited 5-HT up-regulation of PLC and TGF-beta1, while having far less pronounced effects on Erk 1/2. In conclusion, these studies of the signal transduction activity of SAVICs in response to 5-HT have demonstrated that the 5-HT(2A)Rs are the most functionally active of the 5-HT(2)Rs in this cell type. Furthermore, 5-HT(2A)Rs are also involved in 5-HT up-regulation of active TGF-beta. 5-HT also mediated strong Erk 1/2 signaling via the MAP-kinase pathway, which was only in part because of 5-HT(2A)R activity. Thus, major 5-HT Erk 1/2 signaling beyond that controlled by 5-HT(2)Rs must involve other serotonin receptor types and/or secondary signaling events.
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PMID:Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells. 1246 35

Superficial vein pathology involves both mechanical (hyperpressure and distension) and inflammatory mechanisms. Conflicting results exist about the role of NO in the venous hyporeactivity induced by inflammation. In order to clarify this point, we aimed to investigate the effects of sepsis on cutaneous vein responsiveness in vivo and the possible contributions of constitutive and inducible NOS to the changes of venous contractility. Saphenous vein diameter was recorded by an ultrasonic echo-tracking device in pentobarbital-anaesthetised rabbits. Bacterial lipopolysaccharide (LPS) was administered i.v. at 20 mg/kg/15 min, inducing a progressive fall in mean arterial blood pressure after 2-3 h. The effects of LPS on saphenous vein responsiveness to noradrenaline (2 microg/kg i.v.) were measured simultaneously. In some rabbits, veins were removed for immunochemistry to detect iNOS staining. The venoconstriction to noradrenaline was already significantly reduced at 30 min after LPS (6+/-1% instead of 19+/-1% before LPS) and was completely abolished 3 h after LPS. A reduction of the venoconstriction induced by sumatriptan, a 5-HT(1B/D) agonist, (100 microg/kg, 11+/-1% after saline n=5) was also observed 180 min after LPS infusion (3+/-1%, n=4). The venodilatations induced by acetylcholine or sodium nitroprusside injected locally into the vein were not altered by LPS. When administered 90 min after LPS infusion, the NOS inhibitor L-NAME but not the selective iNOS inhibitor L-NIL (10 mg/kg) induced a recovery of the venoconstriction. Preventive perfusion with L-NAME (10 mg/kg/2 h) reduced the initial hyporeactivity to noradrenaline (30 to 60 min), but accelerated the lethal fall in MAP. L-NIL (10 mg/kg/2 h), to a lesser extent than L-NAME, also reduced the initial hyporeactivity to noradrenaline; in contrast to L-NAME, L-NIL also delayed the complete loss of noradrenaline constriction and improved animal survival. In control animals, neither L-NAME nor L-NIL modified the venoconstriction induced by noradrenaline. iNOS staining was observed in the saphenous vein endothelium after LPS. The experimental model developed in these experiments allows the study of venous responsiveness during sepsis in vivo. Our results show that LPS administration reduces saphenous vein contractility to both adrenergic and serotoninergic constrictor agents. The data suggest that both endothelial and inducible NO are involved in the loss of venous reactivity but these enzymes exert contrasting effects on blood pressure changes.
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PMID:Cutaneous venous dysfunction studied in vivo in the LPS-treated rabbit: implication of NO in saphenous vein hyporeactivity. 1267 58

We previously reported that five repeated pulses of 5-HT lead to down-regulation of the TM-apCAM isoform at the surface of Aplysia sensory neurons (SNs). We here examined whether apCAM down-regulation is required for 5-HT-induced long-term facilitation. We also analyzed the role of the cytoplasmic and extracellular domains by overexpressing various apCAM mutants by DNA microinjection. When TM-apCAM was up-regulated in SNs by DNA microinjection, five pulses of 5-HT failed to produce either synaptic facilitation or an enhancement of synaptic growth, suggesting that down-regulation of apCAM is required for 5-HT-induced EPSP enhancement and new varicosity formation. However, disrupting the extracellular domain function of overexpressed apCAM with a specific antibody restored 5-HT-induced excitatory postsynaptic potential increase but not synaptic growth. The overexpression of the MAP Kinase mutant of TM-apCAM, which is not internalized by 5-HT, inhibited new varicosity formation, but did not inhibit excitatory postsynaptic potential increase. Deletion mutants containing only the cytoplasmic portion of apCAM blocked 5-HT-induced synaptic growth but not excitatory postsynaptic potential increase. Thus, our data suggest that TM-apCAM may act as a suppressor of both synaptic-strength enhancement in pre-existing synapses and of new synaptic varicosity formation in the nonsynaptic region, via different mechanisms.
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PMID:Role of Aplysia cell adhesion molecules during 5-HT-induced long-term functional and structural changes. 1525 21

The present study quantified the cleaved form of the microtubule-associated protein tau (cleaved MAP-tau, C-tau), a previously demonstrated marker of CNS toxicity, following the administration of monoamine-depleting regimens of the psychostimulant drugs amphetamine (AMPH), methamphetamine (METH), +/-3,4-methylenedioxymethamphetamine (MDMA), or para-methoxyamphetamine (PMA) in an attempt to further characterize psychostimulant-induced toxicity. A dopamine (DA)-depleting regimen of AMPH produced an increase in C-tau immunoreactivity in the striatum, while a DA- and serotonin (5-HT)-depleting regimen of METH produced an increase in the number of C-tau immunoreactive cells in the striatum and CA2/CA3 and dentate gyrus regions of the hippocampus. MDMA and PMA, two psychostimulant drugs that produce selective 5-HT depletion in the striatum, had no effect on C-tau immunoreactivity in the striatum or hippocampus. Furthermore, 5,7-dihydroxytryptamine (5,7-DHT), an established 5-HT selective neurotoxin, did not produce an increase in C-tau immunoreactivity. Dual fluorescent immunocytochemistry with antibodies to glial fibrillary acidic protein (GFAP) and C-tau indicated that C-tau immunoreactivity was present in astrocytes, not neurons, suggesting that increased C-tau may be an alternative indicator of reactive gliosis. The present results are consistent with previous findings that the DA-depleting psychostimulants AMPH and METH produce reactive gliosis whereas the 5-HT-depleting drugs MDMA and PMA, as well as the known 5-HT selective neurotoxin 5,7-DHT, do not produce an appreciable glial response.
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PMID:The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain. 1708 36


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