Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was previously shown that the acute administration of adenosine elicits an antidepressant-like effect in the mouse forced swimming test (FST) by a mechanism dependent on the inhibition of the L-arginine-nitric oxide (NO)-guanylate cyclase pathway. Taken into account that the stimulation of this pathway is associated with the activation of K(+) channels, this study investigated the involvement of different types of K(+) channels in the effect of adenosine in the FST. Intracerebroventricular treatment of mice with tetraethylammonium (TEA, a non-specific inhibitor of K(+) channels, 25 pg/site), glibenclamide (an ATP-sensitive K(+) channel inhibitor, 0.5 pg/site), charybdotoxin (a large- and intermediate-conductance calcium-activated K(+) channel inhibitor, 25 pg/site) or apamin (a small-conductance calcium-activated K(+) channel inhibitor, 10 pg/site) was able to potentiate the action of subeffective doses of adenosine (1 mg/kg, i.p.) and fluoxetine (a serotonin reuptake inhibitor, 10 mg/kg, i.p.). Furthermore, the administration of adenosine or fluoxetine and the K(+) channel inhibitors, alone or in combination, did not affect the ambulatory behavior. Moreover, the reduction in the immobility time elicited by active doses of adenosine (10 mg/kg, i.p.) or fluoxetine (32 mg/kg, i.p.) in the FST was prevented by the pretreatment of mice with cromakalim (a K(+) channel opener, 10 microg/site, i.c.v.), without affecting the locomotion in an open-field. Together these results indicate that the modulatory effects of adenosine and fluoxetine on neuronal excitability, via inhibition of K(+) channels, may represent the final pathway of their antidepressant-like effects in the FST.
...
PMID:The inhibition of different types of potassium channels underlies the antidepressant-like effect of adenosine in the mouse forced swimming test. 1729 54

N,N'-Dialkyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines show structural analogy with estrogens and selective estrogen receptor modulators. Because the vasodilator properties of these compounds are unknown, we investigated their potential to relax porcine coronary arteries and determined the mechanism(s) of relaxation. Isolated porcine coronary arterial rings were suspended in organ chambers, precontracted with KCl (30 mM), and the relaxant response was determined by measurement of changes in isometric force. Dependent on the chemical structure, the drugs induced concentration-dependent relaxation in rings with and without endothelium. N,N'-Dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (8) was most potent and showed a 12- to 15-fold higher vasodilatory effect than 17beta-estradiol (E2). The vasorelaxation was independent of endothelium. Calcium concentration-dependent contractions in high-potassium depolarizing medium were insurmountably inhibited by 8. The effect of the L-type Ca2+ channel activator (S)-(-)-Bay K 8644 [(S)-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridine-carboxylic acid methyl ester], which induced a leftward shift of Ca2+ contraction, was blocked by 8. The relaxant response to 8 was unaffected by the estrogen receptor antagonist ICI 182,780 (7alpha-[9-[(4,4,5,5,5-pentafluoropentyl]-sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol) and K+ channel blockers, i.e., TEA, glibenclamide, and 4-aminopyridine. Furthermore, the vasodilatory effect of 8 was unaffected by the adenylyl cyclase inhibitor SQ 22536 [9-(tetrahydro-2-furanyl)-9H-purin-6-amine], the guanylyl cyclase inhibitor ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one], the protein kinase A inhibitor KT 5720 [(9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg: 3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester], the protein kinase G inhibitor KT 5823 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB 203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]. Western blot analysis demonstrated that 8, unlike E2, raloxifene, and tamoxifen, failed to stimulate p38 MAPK. It is concluded that N,N'-dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine induces endothelium-independent relaxation of coronary arteries; the mechanism apparently involves inhibition of L-type Ca2+ channels. The drug may be protective against cardiovascular diseases.
...
PMID:Characterization of the relaxant response to N,N'-dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine in porcine coronary arteries. 1732 23

We investigated the effects of selective K(+) channel blockers and guanylyl cyclase inhibitor on the rat aorta relaxation induced by the new NO donor cis-[Ru(Cl)(bpy)(2)(NO)](PF(6)) (RUNOCL), following endothelium removal. NO release from RUNOCL was obtained by photo-induction using a visible light system lambda > 380 nm. RUNOCL induced relaxation of phenylephrine contracted aortic rings under light with the maximum effect (ME) of 101.2+/-3.7% and pD(2): 6.62+/-0.16 (n=7), but not in the absence of light. Relaxation stimulated with RUNOCL was also studied on 60 mM of KCl-contracted arteries or after incubation with the non-selective K(+) channel blocker (1 mM TEA) or the selective K(+) channel blockers (3 microM glibenclamide (K(ATP)), 1 mM 4-aminopyridine (K(V), 4-AP), 1 microM apamin (SK(Ca)-APA) or 0.1 microM iberiotoxin (BK(Ca) IBTX). Relaxation induced by RUNOCL was lower in KCl-contracted aortic rings with ME of 68.6+/-10.0% and pD(2): 3.92+/-0.60 (n=4). As compared to Phe-contracted arteries the potency of RUNOCL in inducing rat aorta relaxation was reduced by K(+) channel blockers as demonstrated by the pD(2) values from 6.62+/-0.16 (n=7) (control) to (TEA: 5.32+/-0.108, n=5; IBTX: 5.63+/-0.02 (n=5), APA: 5.73+/-0.13 (n=5)). But the ME was reduced only by IBTX (60.7+/-3.4%). 4-AP and glibenclamide had no effect on the relaxation induced by RUNOCL. The aortic tissue cGMP content increased with RUNOCL under light irradiation from 63.13+/-0.45 fmol/microg to 70.56+/-4.64 fmol/microg of protein (n=4) and the inhibition of guanylyl cyclase with ODQ reduced the ME: 30.1+/-1.6% and pD(2): 6.35+/-0.05 (n=4). Our results suggest that the NO released by photo-induction from RUNOCL induces rat aorta relaxation by activation of K(Ca) by a cGMP-dependent pathway.
...
PMID:Vasorelaxation induced by the new nitric oxide donor cis-[Ru(Cl)(bpy)(2)(NO)](PF(6)) is due to activation of K(Ca) by a cGMP-dependent pathway. 1760 93

In this study, we have investigated the actions of cryptotanshinone, an active, lipophilic component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the ethanol-extractable fraction of the herb. Extraction of the ethanol-soluble fraction from danshen provided a yield of 1%. The amount of cryptotanshinone determined in this ethanol extract was 3.682%, and it was 6 times more potent than the extract in relaxing 5-HT-precontracted coronary artery rings; IC(50) values were 2.65+/-0.15 microg/ml and 15.82+/-1.07 microg/ml, respectively. Involvement of endothelium-dependant mechanisms in their dilator effects were investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 microM), a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium; none of these procedures produced a significant change on their dilator actions. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a beta-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 microM), a guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM), and a potassium channel inhibitor tetraethylammonium (TEA, 100 mM); these also produced no change on their dilator actions. The possible involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT for 5 min prior to adding CaCl(2) to elicit contraction. The danshen ethanol extract (100 microg/ml) abolished the CaCl(2)-induced vasoconstriction, whereas, cryptotanshinone (30 microg/ml) produced 59% inhibition. These findings suggest their vasorelaxant effects are independent of pathways mediated by the endothelium, muscarinic receptors, beta-adrenoceptors, adenylyl cyclase, and guanylyl cyclase, whereas, inhibition of Ca(2+) influx in the vascular smooth muscle cells is important for their vasodilator actions. The high vasodilator potency and the quantity of salvianolic acid B contained in danshen ethanolic extract suggest it is an important constituent in this medicinal herb.
...
PMID:Mechanisms of the dilator action of cryptotanshinone on rat coronary artery. 1796 42

1, 5-Dihydroxy-2, 3-dimethoxy-xanthone (HM-5) is one of the naturally-occurring xanthones of a Tibetan medicinal herb Halenia elliptica. Recently, it has been shown that HM-5 is one of the phase I metabolites of 1-hydroxy-2, 3, 5-trimethoxy-xanthone (HM-1), the major active component of H. elliptica with potent vasorelaxant actions. This study investigated the vasorelaxant effect of HM-5 and its mechanism(s). HM-5 (0.35-21.9 microM) produced a concentration-dependent relaxation in rat coronary artery rings pre-contracted with 1 microM 5-hydroxytryptamine (5-HT), with an EC(50) of 4.40+/-1.08 microM. Unlike HM-1, the effect of HM-5 was endothelial-independent such that removal of the endothelium did not affect its vasodilator potency. Nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME, 100 microM), the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one (ODQ, 10 microM) did not affect the vasodilatory effects of HM-5, thus confirming the non-involvement of endothelium related mechanisms. In endothelium-denuded coronary artery rings, the vasorelaxant effect of HM-5 was inhibited by a potassium channel blocker, TEA (10 mM), and 4-aminopyridine (4-AP, a K(v) blocker; 1 mM) but not by other K+ channel blockers such as iberiotoxin (100 nM), barium chloride (100 microM) and glibenclamide (10 microM). The involvement of Ca2+ channel was studied in artery rings pre-incubated with Ca2+-free buffer (intact endothelium or endothelium-denuded) and primed with 1 microM 5-HT or 60 mM KCl prior to the addition of CaCl2 to elicit contraction. In the 5-HT-primed preparations, HM-5 (34.7 microM) significantly inhibited the CaCl(2)-induced vasoconstriction (89.9% inhibition in intact endothelium artery rings; 83.3% inhibition in endothelium-denuded rings). In the KCl-primed preparations, HM-5 (34.7 microM) produced a 34% inhibition in endothelium-denuded rings. The same concentration of HM-5 inhibited (by 62.3%) the contractile response to 10 microM phorbol 12, 13-diacetate (PDA), a protein kinase C activator, in Ca2+-free solutions. Taken together, this study showed that the mechanisms of the vasorelaxant effects of HM-5 were distinctly different from those of its parent drug HM-1. The vasorelaxant effect of HM-5 was mediated through opening of potassium channel (4-AP) and altering intracellular calcium by partial inhibition of Ca2+ influx through L-type voltage-operated Ca2+ channels and intracellular Ca2+ stores.
...
PMID:Mechanisms of the vasorelaxant effect of 1, 5-dihydroxy-2, 3-dimethoxy-xanthone, an active metabolite of 1-hydroxy-2, 3, 5-trimethoxy-xanthone isolated from a Tibetan herb, Halenia elliptica, on rat coronary artery. 1804 22

Nitrative stress is an important regulator of vascular tone. We have recently described that trans-arachidonic acids (TAA) are major products of NO(2)(.)-mediated isomerization of arachidonic acid in cell membranes and that nitrative stress increases TAA levels leading to neural microvascular degeneration. In the present study, we explored whether TAA exert acute effects on neuromicrovascular tone and investigated potential mechanisms thereof. TAA induced an endothelium-dependent vasorelaxation of rat brain pial microvasculature. This vasorelaxation was independent of nitric oxide, prostanoids, lipoxygenase products, and CYP(450) metabolite trans-hydroxyeicosatetraenoic acids. However, inhibition of heme oxygenase (using zinc protoporphyrin IX) and of dependent soluble guanylate cyclase (sGC; using ODQ) significantly diminished (by approximately 70%) the TAA-induced vasorelaxation. Consistent with these findings, TAA stimulated heme oxygenase (HO)-2-dependent bilirubin (using siRNA HO-2) and cGMP formation, and the HO product carbon monoxide (using CO-releasing CORM-2) reproduced the sGC-dependent cGMP formation and vasorelaxation. Further exploration revealed that TAA-induced vasorelaxation and bilirubin formation (HO activation) were nearly abrogated by large-conductance calcium-dependent potassium channels (BK(Ca)) (using TEA and iberiotoxin). Opening of BK(Ca) with the selective activator NS1619 induced a concentration-dependent vasorelaxation, which was inhibited by HO and sGC inhibitors. Coimmunoprecipitation suggested a molecular complex interaction between BK(Ca) and HO-2 (but not HO-1). Collectively, these findings identify new properties of TAA, specifically cerebral vasorelaxation through interactive activation of BK(Ca) with HO-2 and, in turn, sGC. Our findings provide new insights into the characterization of nitrative stress-derived TAA products, by showing they can act as acute mediators of nitrative stress on neurovascular tone.
...
PMID:trans-Arachidonic acids induce a heme oxygenase-dependent vasorelaxation of cerebral microvasculature. 1808 39

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.
...
PMID:Spontaneous activity in Purkinje cells: multi-electrode recording from organotypic cerebellar slice cultures. 1853 33

Nicotine causes vasodilation in the renal vasculature through as yet unidentified mechanism. This study investigated the role of endothelial and non-endothelial factors in the vasodilatory action of nicotine in the rat isolated kidney. Nicotine vasodilation in phenylephrine-preconstricted perfused kidneys was evaluated in the absence and presence of drugs that interfere with nitric oxide synthase (NOS), K+ channels, cholinergic or adrenergic activity. Nicotine infusion (5 x 10(-5), 1 x 10(-4), and 5 x 10(-4) M) produced concentration-dependent decreases in the renal perfusion pressure, which continued for 20 min with a peak depressor effect observed at approximately 3 min. Nicotine vasodilation was associated with increases in norepinephrine and NO metabolites (nitrite/nitrate, NOx) levels in the renal effluent. Chemical denudation of the endothelium with 3-[(3-cholamidopropyl)-dimethyl-ammonio]-1-propane-sulfonate (CHAPS), or inhibition of NOS (NG-nitro-L-arginine, L-NNA), or guanylate cyclase (methylene blue) almost abolished the renal vasodilatory action of nicotine. Nicotine vasodilation was also significantly attenuated after selective blockade of ATP-sensitive (K(ATP), glibenclamide) or inward rectifier (Kir, BaCl2) K+ channels but remained unaltered after blockade of large-conductance calcium-activated (BKCa, tetraethylammonium, TEA) or voltage-dependent (Kv, 4-aminopyridine) K+ channels. Hexamethonium (ganglionic blocker), propranolol (beta-adrenceptor blocker), guanethidine (adrenergic neuron blocker), atropine (muscarinic antagonist) or the use of kidneys preconstricted with 80 mM KCl reduced the vasodepressor action of nicotine. Finally, exposure to diclophenac or neostigmine had no effect on nicotine vasodilation. Together, these findings implicate endothelial NOS and KATP and Kir channels in the renal vasodepressor effect of nicotine. Further, the sympathetic-dependent NO-mediated neurogenic vasodilation apparently contributes, at least partly, to nicotine vasodilation.
...
PMID:Pharmacological characterization of cellular mechanisms of the renal vasodilatory effect of nicotine in rats. 1853 47

This study investigated the mechanisms involved in the antinociceptive action induced by diphenyl diselenide ((PhSe)(2)) in the formalin test. Mice were pre-treated with (PhSe)(2) by the oral route (0.1-100 mg kg(-1)), 30 min before formalin injection. To address some of the mechanisms by which (PhSe)(2) inhibits formalin-induced nociception mice were treated with different drugs. The antinociceptive effect of (PhSe)(2) was shown in the first and second phases of the formalin test. The antinociceptive effect caused by (PhSe)(2) (10 mg kg(-1), p.o.) was prevented by intrathecal injection of K(+) channel blockers such as apamin and charybdotoxin (small- and large-conductance Ca(2+)-activated K(+) channel inhibitors, respectively) and tetraethylammonium (TEA, a non-selective voltage-dependent K(+) channel inhibitor), but not glibenclamide (an ATP-sensitive K(+) channel inhibitor). The antinociceptive action caused by (PhSe)(2) (10 mg kg(-1), p.o.) was also blocked by a nitric oxide (NO) synthase inhibitor (N(omega)-nitro-L-arginine, L-NOARG) and the soluble guanylate cyclase inhibitors 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and methylene blue. These results suggest the participation of NO/cyclic GMP/Ca(2+) and K(+) channel pathways in the antinociceptive effect caused by (PhSe)(2).
...
PMID:Mechanisms involved in the antinociceptive effect caused by diphenyl diselenide in the formalin test. 1900 Mar 74

The relaxation mechanisms of tetrandrine (Tet) on the rabbit corpus cavernosum tissue in vitro were investigated. Strips of rabbit corpus cavernosum were mounted in organ chambers. The effects of Tet were examined on isolated muscle strips pre-contracted with phenylephrine (PE) alone, in the presence of N(W)-nitro-L-arginine (LNNA, a nitric oxide synthase inhibitor), 1-H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one(ODQ, a guanylyl cyclase inhibitor), indomethacin (cyclooxygenase inhibitor), tetraethylammonium (TEA, Ca(2+)-activated K(+) channel blocker), 4-aminopiridine (4-AP, voltage dependent K(+) channel blocker) and glibenclamide (ATP sensitive K(+)channel blocker). The effects of Tet on KCl-induced contraction of isolated muscle strips were also investigated. The procedure of calcium absence-calcium addition was designed to observe the effect of Tet on the two components of the contractile responses to PE based on the source of Ca(2+) (extracellular vs. intracellular). Corpus cavernosum strips showed relaxation in response to Tet (10(-8) approximately 10(-3) mol L(-1)) in a concentration-dependent manner with an IC(50) of 3.73 x 10(-5) mol L(-1). However, they were not affected by LNNA, ODQ, indomethacin and K(+)-channel blockers. Tet (10 micromol L(-1), 30 micromol L(-1)) concentration dependently reduced the maximal contraction response of isolated strips induced by KCl to (73.0 +/- 3.8) and (41.5 +/- 3.4)%, respectively (p < 0.01). In the procedure of calcium absence-calcium addition, Tet 100 micromol L(-1) inhibited both intracellular calcium-dependent and extracellular calcium-dependent contraction induced by PE (20 micromol L(-1)) (p < 0.05). The inhibition ratios were (23.8 +/- 7.1) and (40.7 +/- 11.2)%, respectively. The results of the present study suggest that Tet possesses a relaxant effect on rabbit corpus cavernosum tissues, which is attributable to the inhibition of extracellular Ca(2+) influx and the inhibition of release of intracellular-stored Ca(2+), but not mediated by the release of nitric oxide, prostaglandins or by the activation of potassium channels.
...
PMID:The relaxation mechanisms of tetrandrine on the rabbit corpus cavernosum tissue in vitro. 1917 19


<< Previous 1 2 3 4 5 6 7 Next >>

---