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

In the trigone (three portions) and proximal urethra isolated from castrated male pigs, transmural electrical stimulation (0.5-10 Hz) induced no or slight contractions followed by frequency-related relaxations. Atropine suppressed the contraction and potentiated the relaxation. N(G)-nitro-L-arginine methylester (L-NAME), a nitric oxide (NO) synthase inhibitor, depressed or abolished the relaxation induced by low frequency stimulation, but only slightly attenuated the response to high frequency stimulation. L-Arginine reversed the inhibitory effect. L-NAME-sensitive relaxation by 1 Hz stimulation was abolished by 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. Release of NO by nerve stimulation to trigonal strips was determined by increased formation of cyclic GMP in the incubation media containing guanylate cyclase and GTP. L-NAME-resistant relaxation by 10 Hz stimulation was not impaired by ODQ, capsaicin, chymotrypsin, K(+) channel inhibitors and beta-adrenoceptor antagonists. Similar results were obtained in the trigone and urethra from normal male and female pigs. Detrusor muscle responded to nerve stimulation with contraction followed by slight relaxation. Relaxations at 1 and 10 Hz stimulation under treatment with atropine and alpha,beta-methylene ATP were partially attenuated by L-NAME. It is concluded that there is no significant difference in the inhibitory responses, sensitive and resistant to L-NAME, to nerve stimulation in the trigone and proximal urethra from castrated and non-castrated male and female pigs. Relaxations to stimulation at 1 Hz seem to be mediated exclusively by neurogenic NO and cyclic GMP generation, whereas those to 10 Hz stimulation is mainly associated with non-NO relaxing factor(s), peptides, K(+) channel openers and beta-adrenoceptor agonist being unlikely involved.
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PMID:Functional role of inhibitory and excitatory nerves in the porcine lower urinary tract. 1245 May 73

The neurotransmitters mediating relaxation of lower esophageal sphincter (LES) were studied using circular LES strips from adult pigs in organ baths. LES relaxation by sodium nitroprusside (1 nM-3 microM), vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP; 1 nM-1 microM), ATP (10 microM-30 mM), and tricarbonyldichlororuthenum dimer (1 microM-1 mM) was unaffected by tetrodotoxin (1 microM) or l-N(G)-nitroarginine methyl ester (l-NAME; 100 microM). Calcitonin gene-related peptide (CGRP; 1 nM-1 microM) did not affect LES tone. ATP relaxation was blocked by 1 microM apamin and the P2Y(1) antagonist MRS 2179 (N6-methyl 2'-deoxyadenosine 3',5'-bisphosphate; 10 microM). Apamin inhibited PACAP relaxation. VIP and PACAP relaxation was blocked by 10 U/ml alpha-chymotrypsin. L-NAME (-62.52 +/- 13.13%) and 1H-[1,2,4]oxadiazole-[4,3-alpha]quinoxalin-1-one (ODQ; 10 microM, -67.67 +/- 6.80%) similarly inhibited electrical LES relaxation, and apamin blocked non-nitrergic relaxation. Nicotine relaxation (100 microM) was inhibited by L-NAME (-60.37 +/- 10.8%) and ODQ (-41.90 +/- 7.89%), and apamin also blocked non-nitrergic relaxation. Non-nitrergic and apamin-sensitive LES relaxation by electrical stimulation or nicotine was strongly inhibited by MRS 2179, slightly inhibited by alpha-chymotrypsin and the P2X(1,2,3) receptor antagonist NF 279 (8,8 cent-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt; 10 microM), and unaffected by tin protoporphyrin IX (100 microM). Porcine LES relaxation after stimulation of intrinsic inhibitory motor neurons is mediated by two main neuromuscular pathways: nitric oxide through guanylate cyclase signaling and apamin-insensitive mechanisms and by non-nitrergic apamin-sensitive neurotransmission mainly mediated by ATP, ADP, or a related purine acting on P2Y1 receptors and a minor contribution of purinergic P2X1,2,3 receptors and PACAP. Nitrergic and purinergic co-transmitters show parallel effects of similar magnitude without major interplay. Our study shows no role for CGRP and only a minor one for VIP and carbon monoxide in porcine LES relaxation.
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PMID:Pharmacologic characterization of intrinsic mechanisms controlling tone and relaxation of porcine lower esophageal sphincter. 1630 17

We investigated the mechanisms of the relaxant action of genistein, an isoflavone, phytoestrogen and non-specific protein tyrosine kinase inhibitor. Changes in tension of guinea pig tracheal segments were isometrically recorded on a polygraph. Genistein concentration-dependently relaxed histamine (30 microM)-, carbachol (0.2 microM)-, KCl (30 mM)- and leukotriene D4 (10 nM)-induced precontractions and inhibited cumulative histamine- and carbachol-induced contractions in a non-competitive manner. Genistein also concentration-dependently and non-competitively inhibited the cumulative, Ca2+-induced contractions in the depolarized (K+, 60 mM) trachealis. The remaining nifedipine (10 microM)-induced tension of the histamine (30 microM)-induced precontraction was further relaxed by genistein, suggesting that regardless of whether voltage-dependent calcium channels are blocked genistein may have other mechanisms of relaxant action. These other mechanisms of the relaxant effect of genistein appeared to be epithelium-independent and were not affected by the presence of propranolol (1 microM), 2',5'-dideoxyadenosine (10 microM), methylene blue (25 microM), glibenclamide (10 microM), Nomega-nitro-L-arginine (20 microM) or alpha-chymotrypsin (1 U/mL), suggesting that the mechanisms are unrelated to activation of the beta-adrenoceptor, of adenylate cyclase, of guanylate cyclase, of adenosine triphosphate-sensitive potassium channel opening, of nitric oxide formation or of neuropeptide release, respectively. However, genistein (17.5-35 microM) produced parallel, leftward shifts in the concentration-response curves of forskolin and nitroprusside and significantly increased the pD2 values of these two agonists. Both genistein and 3-isobutyl-1-methylxanthine at various concentrations (10-300 microM) concentration-dependently and significantly inhibited cAMP- and cGMP-phosphodiesterase (PDE) activities of the trachealis. The -log IC50 values of genistein were estimated to be 4.28 and 4.17, respectively. The above results reveal that the mechanisms of the relaxant action of genistein may be due to its non-selective inhibition of both PDE activities. IBMX:3-ixobutyl-1-methylxanthine VDCCs:voltage-dependent calcium channels cAMP:adenosine 3',5'-cyclic monophosphate cGMP:guanosine 3',5'-cyclic monophosphate ATP:adenosine triphosphate PDE:phosphodiesterase LTD4:leukotriene D4L-NNA:Nomega-nitro-L-arginine DMSO:dimethyl sulfoxide EGTA: N,N,N',N'-tetraacetic acid ANOVA:analysis of variance.
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PMID:Relaxation of isolated guinea pig trachea by genistein via inhibition of phosphodiesterase. 1739 3

The present study was designed to characterize the urinary bladder-derived relaxant factor that was demonstrated by acetylcholine-induced relaxation response in a coaxial bioassay system consisting of rat bladder as the donor organ and rat anococcygeus muscle as the assay tissue. The concentration-dependent relaxation to acetylcholine (10 nM-1 mM) was inhibited by atropine but was not altered by the antagonists of calcitonin gene-related peptide (CGRP 8-37), vasoactive intestinal peptide (VIP 6-28), tachykinin NK1 (L-732138), tachykinin NK2 (MEN-10376), tachykinin NK3 (SB-218795), purinergic P2 (PPADS) and adenosine (CGS 15943) receptors as well as alpha-chymotrypsin. Adenylate cyclase inhibitor SQ-22536 and protein kinase A inhibitor KT-5720 significantly inhibited the acetylcholine response while guanylate cyclase inhibitor ODQ, and protein kinase C inhibitor H-7 did not have any effect. The P2X agonist alpha,beta-methylene ATP (10 nM-0.1 mM) also produced concentration-dependent relaxation response that was inhibited by PPADS, SQ-22536 and KT-5720 in the coaxial bioassay system. In bladder strips, acetylcholine and alpha,beta-methylene ATP elicited concentration-dependent contractions that were not altered in the presence of SQ-22536 and KT-5720. In conclusion, the urinary bladder-derived relaxant factor that was recognized by the coaxial bioassay system is neither a peptide of the bladder neurons nor a purinergic mediator but adenylate cyclase and protein kinase A are involved in its release and/or relaxant effect. Furthermore, activation of purinergic P2X receptors besides the muscarinic receptors leads to the release of this factor.
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PMID:Rat urinary bladder-derived relaxant factor: studies on its nature and release by coaxial bioassay system. 1862 Oct 43


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