Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The blood pressure and respiratory effects of i.v. administration of the tachykinins substance P (SP), physalaemin (P), eledoisin (E) and kassinin (K) and purported antagonists of SP were compared in guinea-pigs anaesthetized with sodium pentobarbital. Tachykinins caused a dose-dependent decrease in diastolic and systolic pressure with systolic pressure decreased more than diastolic. Heart rate was not affected. Duration of response was directly related to dosage. These data are in agreement with observations that tachykinins decrease peripheral vascular resistance in other species. Tachyphylaxis did not develop to the vascular actions of tachykinins. Comparison of ED50's demonstrated a rank order of potency of SP greater than P congruent to E greater than K suggesting that the vascular receptor for SP is of the SP-P type. Analysis of the regression lines for log dose of tachykinin vs. percent decrease in diastolic blood pressure revealed similar slopes for SP and E and for P and K. The maximal response caused by P was greater than that caused by SP, E or K. These observations are not consistent with postulated classifications of tachykinins or tachykinin receptors suggesting that undefined tissue factors may have affected the relative in vivo potencies of these peptides. Apnoea occurred with K and E throughout the effective dosage range. SP caused apnoea only in doses in excess of those causing maximal vasodilation. P did not cause apnoea. These observations suggest that the SP-receptor mediating respiratory depression is of the SP-E type.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of substance P and other tachykinins on arterial pressure in guinea-pigs. 258 Aug 43

The effect of bronchodilators on neurogenic contractions was studied using isolated bronchial strip-chain preparations from guinea-pigs. Electrical field stimulation (8 Hz, 0.5 msec, 30 V, 40 pulses) evoked a biphasic contraction of the bronchial muscle, consisting of an initial phasic component followed by a sustained one which was mediated by cholinergic and peptidergic nerve stimulations, respectively. All the beta-stimulants and xanthines tested caused a concentration-dependent inhibition in the height of the electrically-induced biphasic contraction, with the following order of potency: procaterol greater than fenoterol greater than salbutamol greater than isoproterenol greater than adrenaline greater than enprofylline greater than aminophylline greater than ephedrine. Ipratropium bromide selectively inhibited the electrically-induced cholinergic contraction. Submaximal contractions of the bronchial muscle evoked by exogenous substance P (2 X 10(-7)M) were less potently inhibited by these drugs than those evoked by exogenous acetylcholine (2 X 10(-6)M). These results indicate that in isolated guinea-pig bronchial muscle, bronchodilators may inhibit cholinergic and peptidergic neurotransmissions mainly by postsynaptic depression of the responsiveness and partly by presynaptic reduction of the transmitter release.
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PMID:[Inhibitory effect of bronchodilators on cholinergic and peptidergic contractions of guinea-pig isolated bronchial muscle]. 274 8

The effects of crotoxin, the neurotoxic complex from the venom of the South American rattlesnake Crotalus durissus terrificus on mammalian autonomic neuromuscular transmission, have been investigated. In the longitudinal muscle of the guinea-pig ileum, crotoxin induced a dose-dependent contraction which was followed by relaxation, in spite of the continued presence of the toxin. The contractile response was inhibited by indomethacin, tetrodotoxin, verapamil or nifedipine, but was unaffected by atropine, propranolol, mepyramine or methysergide. In addition, crotoxin caused a presynaptic inhibition of the electrically-evoked twitch of the longitudinal muscle of the guinea-pig ileum. In the guinea-pig vas deferens crotoxin also caused an inhibition of the response to field stimulation. The inhibition was reversible after washing and the preparation remained insensitive to further doses of the toxin. The inhibitory effects of crotoxin were not mediated by noradrenaline and were not due to a non-specific smooth muscle depression, because it was not associated with any reduction in motor responses to acetylcholine, ATP, bradykinin or substance P. Pre-incubation of the guinea-pig vas deferens with indomethacin blocked the inhibitory effects of the toxin. This suggests that the presynaptic activity of crotoxin in the vas deferens might be mediated by prostaglandins.
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PMID:Effects of crotoxin on autonomic neuromuscular transmission in the guinea-pig myenteric plexus and vas deferens. 300 84

Rabbit isolated ear arteries were perfused at a constant flow and stimulated with field pulses (5 Hz, 5 impulses). Different tachykinins and capsaicin depressed stimulation-induced vasoconstriction, substance P (SP) being the most potent inhibitor. The rank order of potency of the tachykinins was, SP approximately equal to physalaemin approximately equal to eledoisin greater than SP-methyl ester; that of SP and its C-terminal fragments, SP approximately equal to SP-(2-11) approximately equal to SP-(4-11) greater than SP-(6-11). SP-(1-9) was inactive. The SP antagonist (Arg5,D-Trp7,9,Nle11)SP-(5-11) 10 mumol/l shifted the concentration-response curve of SP to the right (pA2 = 5.43), whereas it did not reduce the action of capsaicin. Another SP antagonist (D-Pro4,D-Trp7,9,10)SP-(4-11) 10 mumol/l failed to affect the SP depression. Neither antagonist changed vasoconstriction by itself. Pretreatment of the arteries with a mixture of yohimbine, propranolol, atropine, diphenhydramine, burimamide, methysergide and indomethacin, all 1 mumol/l, did not influence the effect of SP or capsaicin. Only the inhibition by SP, but not that by capsaicin was abolished after mechanical destruction of the endothelium. SP, physalaemin and eledoisin, all 3 mumol/l, reduced vasoconstriction by noradrenaline or histamine; capsaicin 30 mumol/l depressed noradrenaline-induced vasoconstriction. In arteries preincubated with 3H-noradrenaline, electrical stimulation (1 Hz, 120 pulses) triggered an increase in the outflow of tritium and evoked vasoconstriction. SP 1 mumol/l did not change either basal or stimulation-evoked tritium outflow, whereas it reduced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional characterization of substance P receptors in the rabbit ear artery. 301 61

Pretreatment of the guinea-pig ileum with capsaicin resulted consistently in depression of the neurogenic cholinergic contractions induced by the GABAA receptor agonists 3-aminopropane sulphonic acid (3-APS) and muscimol. Since capsaicin acts mainly by releasing and depleting substance P from its stores in intestinal nerves, it is likely that substance P plays a role in the response caused by GABAA-mimetic compounds, On the whole, our results suggest that excitatory responses to 3-APS and muscimol result from both direct and indirect activation of intrinsic intestinal cholinergic neurons innervating smooth muscle cells.
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PMID:Inhibitory action of capsaicin on cholinergic responses induced by GABAA agonists in the guinea-pig ileum. 302 97

The onset of therapeutic effectiveness of carbamazepine is generally very rapid in the treatment of seizure and paroxysmal pain disorders, shows some lag in the treatment of mania, and exhibits the longest lag in depression. These time course variations may indicate that different mechanisms underlie the efficacy of carbamazepine in the differential neuropsychiatric syndromes. Biochemical and pharmacological data suggest that the anticonvulsant effects of carbamazepine are related to "peripheral-type" benzodiazepine and alpha 2-noradrenergic receptor systems and to its ability to stabilize sodium channels. GABAB (baclofen-like) actions appear to be involved in antinociceptive, but not anticonvulsant, effects. The relatively acute time course of antimanic efficacy may be related to the above-mentioned mechanisms or to other effects related to systems postulated to be altered in the manic syndrome. These effects might include carbamazepine's ability to increase acetylcholine in the striatum, decrease probenecid-induced levels of CSF homovanillic acid (HVA) in man and dopamine turnover in animals, decrease CSF norepinephrine in manic patients, inhibit adenylate cyclase activity (in response to norepinephrine, dopamine, adenosine, or ouabain), decrease GABA turnover, or act as a vasopressin agonist. Efficacy in depression may be related to actions in man that take time or chronic drug administration to develop, such as increases in plasma tryptophan, decreases in CSF somatostatin, decreases in thyroid indices, and increases in urinary free cortisol excretion and, in animals, increases in substance P sensitivity and increases in brain adenosine receptors. The ability of carbamazepine to block the development of lidocaine- and cocaine-induced seizures also requires chronic administration, suggesting that these seizure models may provide a unique perspective for understanding mechanisms of time-dependent effects.
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PMID:Time course of clinical effects of carbamazepine: implications for mechanisms of action. 328 May 60

The paper reviews evidence that adjuvant arthritis in the rat is associated with chronic pain and discusses the time course and measurement of this putative pain. The available evidence is consistent with the view that arthritic rats suffer pain, but it appears difficult to formally establish the occurrence of chronic pain in animals. The data suggest the pain to be severe during weeks 2 and 3 and to persist during weeks 4 and 5 after inoculation. The continuing inflammation of joints likely results in movement-induced acutely elicited pains that may persist till about the 8th week. The severe pain during weeks 2 and 3 may be associated with a depression of some drives, and the entire week 2-8 period is likely associated with varying levels of chronic stress. Neurochemical and neurophysiological studies indicate that adjuvant arthritis profoundly influences several of the neurotransmission and neuroendocrine functions of brain and spinal cord; among the affected systems are substance P-ergic, serotonergic and endorphinergic systems. Adjuvant arthritis in the rat constitutes the only laboratory animal model of chronic pain that has been validated to a significant extent. It is suggested that the model be examined further and that additional animal models of chronic pain be developed.
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PMID:Evidence that adjuvant arthritis in the rat is associated with chronic pain. 354 55

The intrathecal (i.t.) administration of morphine inhibits nociceptive motor responses and activity in ascending axons evoked by stimulation of nociceptive afferent nerve fibers (nociceptive sensory response) in the rat. The i.t. administration of cholecystokinin octapeptide and ceruletide inhibits nociceptive motor responses, but does not affect ascending nociceptive activity. This shows that drug-induced depression of nociceptive motor responses is not always associated with depression of the nociceptive sensory response of the spinal cord. The microiontophoretic application of substance P excites single dorsal horn neurons that respond to noxious stimulation, whereas the i.t. administration of substance P inhibits both nociceptive motor and sensory responses. Thus, the results obtained from the i.t. administration of a drug may differ from those obtained from its application to single spinal neurons. Diazepam inhibits spinal reflexes and may reduce pain sensation in humans. To assess whether a spinal action is involved in the pain-relieving effect of diazepam, experiments were carried out on spinalized rats in which activity evoked by the stimulation of nociceptive and nonnociceptive afferent nerve fibers of the sural nerve was recorded from single ascending axons below the site of spinal cord transection. Diazepam, 20 micrograms i.t., reduced activity evoked by afferent A delta and C fiber stimulation and by stimulation of afferent A beta fibers. The depressant effect caused by diazepam, 2 mg/kg i.v., on C fiber-evoked ascending activity was reduced by the i.t. injection of the benzodiazepine antagonist, Ro 15-1788 (40 micrograms), an imidazodiazepine. It is concluded that the depression by diazepam of C fiber-evoked ascending activity contributes to pain relief caused by the drug.
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PMID:Depression of nociceptive sensory activity in the rat spinal cord due to the intrathecal administration of drugs: effect of diazepam. 609 60

Urethane (50 mM) produced a non-selective antagonism of depolarizations evoked by excitant amino acids or carbachol recorded from ventral roots of isolated spinal cord preparations of the frog or immature rat. Depolarizing responses to substance P or eledoisin-related-peptide were either unaffected or potentiated by this concentration of urethane. The threshold level for depression of dorsal to ventral root transmission was 10 mM urethane and transmission was completely blocked at 70-100 mM urethane. It is suggested that post-junctional blockade of the actions of excitant amino acids may be important in the anaesthetic action of urethane.
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PMID:Effect of urethane on synaptic and amino acid-induced excitation in isolated spinal cord preparations. 612 91

The prevalence of severe dementia in the United States is about 1.3 million cases, of which at least 50 to 60% are of the Alzheimer type. Severe dementia of the Alzheimer type is found rarely in a clearly dominant pattern, although often one or more relatives are affected. Down's syndrome in adults is often associated with Alzheimer changes. The diagnosis is a clinicopathological one; there is a considerable error rate in the clinical diagnosis early in the course of the disease, especially in regard to dementia in depression. The differential diagnosis involves a great many disorders, including multi-infarct dementia, tumors, subdural hematomas, and others. Physiological aspects of Alzheimer's disease include a diffusely slow electroencephalogram, reduced cerebral blood flow, and particular patterns noted on positron emission tomographic scanning. The latter technique has also demonstrated that oxygen extraction is normal in Alzheimer's disease, thus excluding ischemia from possible pathogenetic factors. Morphological changes, that is, the presence of plaques and tangles, are widely distributed in neocortex, paleocortex, and many deep gray areas down through the pontine tegmentum, but largely exclude the basal ganglia, thalamus, and substantia nigra. Numerous plaques without neocortical tangles are found in many demented persons older than 75 years. A severe loss of large neocortical neurons is characteristic of the disease. The chemical nature of the paired helical filaments that make up the neurofibrillary tangle has not yet been ascertained. Neurons are markedly deficient in the basal forebrain nuclei, and this deficiency may account for the severe diminution of choline acetyltransferase and acetylcholine in the neocortex and paleocortex. Muscarinic cholinergic receptors are present in normal amounts. Norepinephrine is reduced in some cases, and somatostatin in most. Substance P is low in severe cases. The etiology of the disorder is unknown and the role of aluminum is disputed. Management of patients with Alzheimer's disease is difficult, and neuroleptics are to be used with great caution because of their side effects. Substrate therapy has not been effective; physostigmine improves memory but is not suitable for general use. Trophic factors, gangliosides, and aluminum chelation are being investigated for use in pharmacological intervention.
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PMID:Senile dementia of the Alzheimer type. 613 75


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