Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous work has shown that corticosterone, cell-membrane permeant analogs of cGMP, as well as activators of guanylyl cyclase inhibit secretagogue-stimulated ACTH release. In the present study we have examined whether cGMP mediates the inhibitory effect of corticosterone in perifused isolated rat anterior pituitary cells. A brief 22.5-min exposure to corticosterone strongly inhibited ACTH secretion evoked by arginine vasopressin (AVP), 48 mM KC1, and two types of combined stimuli, i.e. 41-residue CRF and AVP (0.05 and 0.5 nM, respectively; CRF/AVP), or ionomycin and phorbol-dibutyrate (200 and 10 nM, respectively; PdBu/IM). The time course of inhibition by corticosterone was similar in all cases; a rapid approximately 30% reduction in ACTH was evident within 25 min, which increased to 60% by 50-70 min and will be referred to as the delayed effect. The corticosteroid inhibition of PdBu/IM-induced ACTH release was fully antagonized by the glucocorticoid/progestin antagonist RU 38486, indicating that it is exerted through type II glucocorticoid receptors. In contrast to corticosterone, the cGMP derivative 8-bromo-cGMP failed to suppress ACTH release evoked by PdBu/IM, whereas it effectively inhibited the action of CRF/AVP. Furthermore, ionomycin reversed the reduction of CRF/AVP-stimulated ACTH release by 8-bromo-cGMP, but had no effect on the delayed inhibition caused by corticosterone. These data indicate that there are two distinct cellular pathways of inhibiting stimulus-evoked ACTH secretion in vitro. One of these is activated by corticosterone, whereas the other involves cGMP as a cellular messenger.
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PMID:Evidence for distinct glucocorticoid and guanine 3',5'-monophosphate-effected inhibition of stimulated adrenocorticotropin release in vitro. 215 98

Only a small number of new drugs have recently become available for gastrointestinal (GI) disorders. This is partly because we await outcomes of research into functional bowel disorder aetiology (e.g., role of microbiota) and of trials to control stress- related or painful GI symptoms (e.g., via CRF(1) receptors or beta(3) adrenoceptors). Nevertheless, only the ClC-2 channel activator lubiprostone has recently reached the clinic, joining the 5-HT(3) antagonist alosetron and the long-established 5-HT(4) agonist and D(2) antagonist metoclopramide; tegaserod, a non-selective ligand, was withdrawn. Interestingly, each has shortcomings, providing opportunities for molecules with 5-HT(4) or motilin receptor selectivity, and for new biology via guanylate cyclase C or ghrelin receptor activation. For translation into new drugs, the molecule must have appropriate efficacy, selectivity and pharmacodynamic properties. It is argued that the compound must then be evaluated in conditions where changes in motility are known to exist, before considering more difficult symptomatic conditions such as irritable bowel syndrome (IBS) or functional dyspepsia (FD), where relationships with disordered motility are unclear. Thus, it may be better to begin studying a gastric prokinetic in diabetics requiring improved glucose control, rather than in FD. Notably, new 5-HT(4) receptor agonists are being evaluated firstly as treatments of constipation, not IBS. New antidiarrhoeal agents should be developed similarly. Thus, progression of new drugs may require initial studies in smaller patient populations where clinical outcome is better defined. Only then can disease-related ideas be properly tested and drugs brought forward for these disorders (with high clinical need) and then, if successful for IBS and FD.
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PMID:Development of drugs for gastrointestinal motor disorders: translating science to clinical need. 1825 67

Organotypic cerebellar cultures were maintained on multi-electrode dishes (MED) with an 8x8 array of electrodes and examined for physiological activity. The cultures remained viable for up to seven months and exhibited spontaneous discharges most likely originating from Purkinje cells. Spike frequencies varied but were mostly around 10-30 Hz and were often stable over weeks with average drifts of <20% per week. Spontaneous firing was significantly reduced by blockers of sodium channels (riluzole) and several potassium channels (iberiotoxin, TEA, 4-amino-pyridine), but blockers of calcium channels, GIRK channels, and SK-type potassium channels were ineffective. Inhibitors of excitatory and inhibitory synaptic transmission made spike discharges more regular. Particularly robust changes in spike frequency were produced by agents that increase cGMP. Bromo-cGMP, the NO donor SNAP, the guanylate cyclase activator YC-1, and the phosphodiesterase inhibitor zaprinast greatly reduced spike frequency. Activation of the metabotropic receptor mGluR1 and inhibition of I(h) channels caused a majority of cells to switch from tonic firing to a cyclic activity mode in which intense firing alternated with silence. Agonists for cholinergic, serotonergic, histamine, opiate, and CRF receptors had no effect, but those for adrenergic and adenosine A1 receptors reduced firing. Moreover, brief application of bromocriptine caused a delayed decrease in firing that reached a minimum after 24 to 48 h and recovered after 1-2 weeks. Taken together, our results demonstrate that long-term cultures maintained on multi-electrode arrays retain many essential features of cerebellar physiology and that they provide a test system that is well suited for broad screening of pharmacological agents as well as for studying long-term effects of drugs, tissue factors, and pathogens.
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PMID:Spontaneous activity in Purkinje cells: multi-electrode recording from organotypic cerebellar slice cultures. 1853 33