Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of exo- and endogenous cGMP on the resting activity (RA) of afferent crista fibers were studied in isolated preparations of the statocysts of the cuttlefish Sepia officinalis and the squid Sepioteuthis lessoniana. Bath application of the membrane-permeable cGMP analogs 8-bromo-cGMP (B-cGMP) and N(2),2'-o-dibutyryl 3', 5'-cyclic guanosine monophosphate (dB-cGMP), and of the selective inhibitor of cGMP-phosphodiesterase zaprinast (ZAP), caused an inhibition of RA. The inhibitory effects of B-cGMP and dB-cGMP remained when the preparation was pre-treated with: (i) the guanylate cyclase inhibitors 1H-[1,2,4]oxadiazolo[4,3, -a]quinoxalin-1-one (ODQ) or cystamine (CYS); (ii) the adenylate cyclase inhibitors nicotinic acid (NIC-A), 2',3'dideoxyadenosine (DDA), or MDL-12330A (MDL); (iii) the guanylate cyclase inhibitor methylene blue (M-BLU) and the adenylate cyclase inhibitor MDL combined; or (iv) the nitric oxide (NO) synthase inhibitors N(G)-nitric-L-arginine methyl ester HCl (L-NAME) or N(G)-nitro-L-arginine (L-NOARG). These data indicate that cGMP, as an intracellular messenger, has a tonic inhibitory effect on the RA of afferent crista fibers in cephalopod statocysts.
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PMID:Inhibitory effect of cyclic guanosine 3',5'-monophosphate (cGMP) on the afferent resting activity in the cephalopod statocyst. 1103 90

Gastric ulceration was induced in rats by i.p. injection of the non-steroidal anti-inflammatory drug (NSAID), indomethacin (IND) (30 mg kg(-1)). Pyloric ligation was carried out in each animal before injection to enable collection of the gastric juice. Three hours later, the animals were killed and their stomachs were removed. In the gastric juice, the amounts of mucin, pepsin and HCl were assessed. Gastric mucosa were scrapped for the determination of nitric oxide (NO) (as nitrite) after evaluation of the gastric ulcer index. The influence of arginine (ARG) (300 mg kg(-1)), a NO precursor, N(G)-nitro- l -arginine methyl ester (l -NAME) (50 mg kg(-1)), a non-selective constitutive nitric oxide synthase/inducible nitric oxide synthase (cNOS/iNOS) inhibitor, and the selective iNOS inhibitor aminoguanidine (AMG) (50 mg kg(-1)) were studied. Each NO modulator was injected i.p. 30 min before IND administration. Results indicated that IND elevated gastric acidity by 80% of the normal group, decreased non-significantly mucosal nitrite by 22% and exhibited a remarkably high ulcer index (chi = 17). Neither mucin nor pepsin levels were significantly altered. In comparison with the IND group, pretreatment with l -NAME caused a significant decrease in gastric HCl, further decrease in mucosal nitrite (50% of normal) and a two-fold increase in the ulcer index score (chi = 34), despite the decrease in HCl. AMG did not alter gastric acidity, decreased mucosal nitrite by 38% of the normal value and failed to alter significantly the ulcer index of IND. On the other hand, pretreatment with ARG did not alter the gastric acidity and raised mucosal nitrite by 10% above normal. Surprisingly, ARG improved the gastric ulcer score (chi = 1) almost similar to the normal score (chi = zero). Therefore, this study creates a new pathway for the potential treatment of NSAID gastric ulceration through modulation of NO synthesis, regardless of the effect on gastric acidity.
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PMID:Protective role of nitric oxide in indomethacin-induced gastric ulceration by a mechanism independent of gastric acid secretion. 1139 38

Duodenal HCO3- secretion increases in response to mucosal acidification by luminal acid. Although this process is known to be mediated by endogenous prostaglandins (PGs), the role of nitric oxide (NO) in this response has been little studied. We examined the effects of indomethacin and N(G)-nitro-L-arginine methyl ester (L-NAME) on the acid-induced HCO3- secretion in the rat duodenum, together with those on PGE2 generation as well as luminal release of NO metabolites (NOx). A proximal duodenal loop was perfused with saline, and the HCO3- secretion was measured at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Mucosal acidification was performed by exposing the loop to 10 or 100 mM HCl for 10 min. Acidification of the duodenal mucosa stimulated the HCO3- secretion, with concomitant increase of mucosal PGE2 contents and luminal release of NOx, the response being much greater in case of 100 mM HCl. Indomethacin significantly inhibited the acid-induced HCO3- secretion as well as the PGE2 biosynthetic response, without influence on the NOx release. Pretreatment of the animals with L-NAME attenuated both the increase of mucosal PGE2 contents and luminal release of NOx following the acidification, resulting in a marked inhibition of the acid-induced HCO3- response, and these effects were significantly antagonized by coadministration of L-arginine. Duodenal HCO3- secretion was also increased by mucosal exposure to NOR-3 (a NO donor), with concomitant increase of PGE2 generation, but these effects were mitigated in the presence of indomethacin. In addition, the duodenal damage caused by mucosal perfusion with 100 mM HCl for 4 hr was markedly aggravated by pretreatment with L-NAME as well as indomethacin. These results suggest that both endogenous NO and PGs are involved in the mechanism for the acid-induced duodenal HCO3- secretion, and that NO may increase the HCO3- secretion by stimulating PG generation.
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PMID:Role of endogenous nitric oxide and prostaglandin in duodenal bicarbonate response induced by mucosal acidification in rats. 1141 96

Experimental models to study the effect of agents on penile erection usually include electrical stimulation of peripheral nerves in anesthetized animals combined with systemic or intracavernous injection of drugs. The objective of this study was to demonstrate that conscious rabbits can be used as a simple and quantitative model for the assessment of compounds that show potential for the treatment of erectile dysfunction. Erection was assessed by measuring the length of uncovered penile mucosa before and after the intravenous (i.v.) administration of agents. Animals did not require anesthesia during the course of the study. The phosphodiesterase 5 (PDE5) inhibitors vardenafil x HCl (hereafter called vardenafil) and sildenafil were given intravenously, and measurements were taken for 0-5 h. The effects of phentolamine and milrinone were also evaluated. Vardenafil (0.1-3 mg/kg) induced dose-dependent penile erections in conscious rabbits following i.v. administration. The efficacy of vardenafil was potentiated, and the minimal effective dose was reduced significantly to 0.01 mg/kg by simultaneous administration of the nitric oxide (NO) donor sodium nitroprusside (SNP). Administration of the NO-synthase inhibitor L-NAME abolished the effect. Sildenafil was effective in this model after i.v. administration. The alpha-adrenergic receptor antagonist phentolamine (0.1, 0.3 and 1 mg/kg i.v.) induced erections with a slower t(max) compared with vardenafil and sildenafil. Intravenous administration of the PDE3 inhibitor milrinone (1 mg/kg i.v.) was less effective than the PDE5 inhibitor vardenafil. The conscious rabbit is a suitable and reliable model for the evaluation of compounds with potential for the treatment of erectile dysfunction. This was demonstrated using compounds that target different signaling pathways that induce smooth muscle relaxation in the penis.
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PMID:A conscious-rabbit model to study vardenafil hydrochloride and other agents that influence penile erection. 1149 80

1. The proton pump inhibitors lansoprazole (LP) and omeprazole (OP) and the cholecystokinin (CCK)-receptor antagonist PD-136450 (PD) provide a broad spectrum of activities in their ability to inhibit gastric acid secretion and protect the stomach against ulcerogens. In the present study, we investigated the protective effects of these compounds against gastric ulcers induced by acidified ethanol (AE) and indomethacin. 2. Both AE (60% ethanol in 150 mmol/L HCl, 1 mL/rat) and indomethacin (30 mg/kg) produced gastric haemorrhagic lesions in the rat 1 and 6 h after oral administration, respectively. 3. The gastric mucosal protective effects of LP (1-20 mg/kg), OP (0.5-10 mg/kg) and PD (1-20 mg/kg), administered either orally or subcutaneously (s.c.) 30 min before the administration of AE or indomethacin, were dose dependent against both models of ulcer induction. 4. To determine whether the cytoprotective effect of LP, OP and PD (each 10 mg/kg) was mediated by endogenous prostaglandins (PG), indomethacin (10 mg/kg, s.c.) was administered 15 min before AE to inhibit prostanoids biosynthesis. Indomethacin reduced the cytoprotective effects of OP, but not LP, administered either orally or s.c. Indomethacin reduced the cytoprotective effect of PD administered orally, although the effect was much less significant than when PD was administered s.c. The results exclude the role of PG in mediating the protective effects of LP, whereas the possibility exists for PG to have a role in mediating the protective effects of OP and PD. 5. To investigate the possible involvement of endogenous nitric oxide (NO) in the cytoprotective action of LP, OP and PD, we treated rats with a selective inhibitor of NO synthesis, namely NG-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg, s.c.). Administration of L-NAME 15 min prior to LP, OP or PD (each 10 mg/kg) orally or s.c. and challenge with AE or indomethacin did not significantly increase the degree of the ulcer index and L-NAME was not able to antagonize the protective effects of LP, OP and PD, thus excluding the role of NO in mediating the protective effects of these drugs. However, the effects of PD in reducing the indomethacin-induced ulcer index were less significant in the presence than the absence of L-NAME (P < 0.05 vs P < 0.001, respectively), suggesting a role for NO. 6. In conclusion, the results of the present study suggest that LP and OP are equally effective against AE- as well as indomethacin-induced gastric ulcers and were more potent than PD in protecting the stomach against ulcer formation. Lansoprazole, OP and PD bring about their cytoprotective action through the reduction of acid secretion and some other unknown mechanisms. However, OP and PD may exert their cytoprotective action through PG and NO pathways.
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PMID:A comparative study on the activity of lansoprazole, omeprazole and PD-136450 on acidified ethanol- and indomethacin-induced gastric lesions in the rat. 1190 79

In the present study, the interaction of nitric oxide synthase (NOS) inhibitors, L-NAME (N(G)-nitro-L-arginine methyl ester HCl) and L-NA (N(omega)-nitro-L-arginine), and its precursor, L-arginine (2-(S)-2-amino-5-[(aminoiminomethyl)amino] pentatonic acid), with theophylline on mouse body temperature was studied. Intraperitoneal (i.p.) injection of different doses of theophylline altered body temperature. Lower doses of theophylline (12.5 and 25 mg/kg) increased, but a higher dose (100 mg/kg) reduced, the animals' body temperature. The combination of L-arginine (20 and 40 mg/kg) with the highest dose of theophylline potentiated the hypothermic effect induced by the latter drug, while L-arginine by itself did not alter body temperature. L-NAME (10-80 mg/kg) or L-NA (10 mg/kg) plus a lower dose of theophylline (12.5 mg/kg) reduced the theophylline-induced hyperthermic response. L-NA (1, 5, and 10 mg/kg) in combination with the high dose of theophylline (100 mg/kg) also induced greater hypothermia. Both L-NAME and L-NA by themselves reduced body temperature. It is concluded that nitric oxide (NO) may be involved in the effects of theophylline on body temperature in mice.
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PMID:Role of nitric oxide in systemic effect of theophylline on mouse body temperature. 1222 30

Nitric oxide (NO) is an important regulatory molecule in bone formation and resorption. The purpose of this study was to examine the role of NO in orthodontic tooth movement in rats. We used specific inhibitors of NO synthases (NOS). Upper first molars of 9-week-old male Wistar rats were moved buccally for 21 days. The local administration of N(G)-nitro-L-arginine methyl ester. HCl (L-NAME), a general inhibitor of NOS activity, significantly reduced tooth movement. On the other hand, N(6)-(1-iminoethyl)-L-lysine. 2HCl (L-NIL), a selective inhibitor of the inducible isoform of NOS, had no effect. These results suggest that NO is an important biochemical mediator in the response of periodontal tissue to orthodontic force and is produced primarily through the activity of constitutive NOS.
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PMID:Involvement of nitric oxide in orthodontic tooth movement in rats. 1222 13

Duodenal HCO3- secretion increases in response to luminal acid, mediated by endogenous nitric oxide (NO) as well as prostaglandins (PGs). In this study, we examined the effects of various inhibitors of cyclooxygenase (COX) or NO synthase (NOS) on the acid-induced HCO3- secretion in rats and determined the enzyme isoforms responsible for this response. A proximal duodenal loop was perfused with saline under urethane anesthesia, and the HCO3- secretion was measured at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Mucosal acidification was performed by exposing the loop to 10 mM HCl for 10 min. Indomethacin, SC-560 (a selective COX-1 inhibitor) and rofecoxib (a selective COX-2 inhibitor) were given intraduodenally 1 hr before exposure to 10 mM HCl, while N(G)-nitro-L-arginine methyl ester (L-NAME: a nonselective NOS inhibitor) and aminoguanidine (a relatively selective inhibitor of iNOS) were given subcutaneously 3 hr before the acidification. The mucosal acidification increased the HCO3- secretion, with a rise in mucosal PGE2 content and luminal release of NO. The HCO3- secretory and PGE2 biosynthetic responses were significantly inhibited by indomethacin and SC-560, while rofecoxib had no effect on these responses. On the other hand, L-NAME, but not aminoguanidine, attenuated NO release following the acidification, resulting in inhibition of the acid-induced HCO3- secretion in a L-arginine-sensitive manner. Neither COX-2 nor iNOS mRNAs were observed in the mucosa before and 1 hr after acidification, while the gene expression of COX-1 and nNOS was constitutively detected in the mucosa and appeared to be slightly up-regulated after the acid stimulation. These results suggest that COX-1 and cNOS play as the respective key enzyme responsible for producing PG and NO following the duodenal acidification, both of which are involved in the mechanism for the acid-induced HCO3- secretion in the duodenum.
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PMID:COX and NOS isoforms involved in acid-induced duodenal bicarbonate secretion in rats. 1235 66

1. The mechanism of stimulation of noradrenaline (NA) release by nicotine (NIC) was investigated in human cerebral cortex slices preloaded with 3H-noradrenaline. 2 NIC (10-1000 micro M) increased 3H-NA release in a concentration-dependent manner. 3. NIC (100 micro M)-evoked 3H-NA release was largely dependent on external Ca2+, and was attenuated by omega-conotoxin GVIA (0.1 micro M) but not by nitrendipine (1 micro M). 4. Tetrodotoxin (1 micro M) and nisoxetine (0.1 micro M) attenuated the NIC (100 micro M)-evoked release of 3H-NA. 5. Mecamylamine (10 micro M), dihydro-beta-erythroidine (10 micro M) and d-tubocurarine (30 micro M), but not alpha-bungarotoxin (alpha-BTX, 0.1 micro M), attenuated the NIC (100 micro M)-evoked release of 3H-NA. 6. NIC (100 micro M)-evoked release of 3H-NA was not affected by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 30 micro M) and D(-)-2-amino-5-phosphonopentanoic acid (D-AP5, 100 micro M), but attenuated by MK-801 (10 micro M). MK-801 (0.1-1000 micro M) displaced the specific binding of 3H-nisoxetine with K(i) values of 91.2 micro M. NIC (100, 300 and 1000 micro M) did not induce 3H-D-aspartate release in human cerebral cortex slices. 7. NIC (100 micro M)-evoked release of 3H-NA was attenuated by 7-nitroindazole (10 micro M), N(G)-nitro-L-arginine methyl ester HCl (L-NAME, 30 micro M), N(G)-monomethyl-L-arginine acetate (L-NMMA, 300 micro M). [(3)H]-NA release induced by NIC (100 micro M) was attenuated by methylene blue (3 micro M) and 1H-[1,2,4]oxadiazole[4,3-alpha]quinoxalin-1-one (ODQ, 10 micro M), and enhanced by zaprinast (30 micro M). 8. In conclusion, NIC stimulates the release of 3H-NA through activation of alpha-BTX-insensitive nicotinic acetylcholine receptors in the human cerebral cortex slices and this action of NIC is associated with modulation of the NO/cGMP pathway.
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PMID:Mechanism of nicotine-evoked release of 3H-noradrenaline in human cerebral cortex slices. 1242 79

We compared the HCO3(-) secretory response to capsaicin and mucosal acidification in rat duodenums, especially the relation to vanilloid receptor type 1 (VR1). A proximal duodenal loop was perfused with saline, and the HCO3(-) secretion was measured at pH 7.0 using a pH-stat method and by adding 10 mM HCl. The secretion was stimulated by exposing the loop to capsaicin (0.03-0.3 mg/ml) or 10 mM HCl for 10 min. Indomethacin subcutaneously or ruthenium red intravenously, a nonspecific VR1 antagonist, was given 60 or 10 min, respectively, before exposure to capsaicin or acid, while L-NAME was given intravenously 3 hr before these treatments. Capsazepine, another VR1 antagonist, was coapplied to the loop for 10 min with capsaicin or acid. Luminal application of capsaicin increased the secretion of HCO3(-) in a dose-dependent manner; this effect was markedly attenuated by chemical ablation of capsaicin-sensitive afferent neurons (CSN) as well as pretreatment with ruthenium red or capsazepine, and significantly mitigated by indomethacin or L-NAME (in an L-arginine-sensitive manner). The HCO3(-) secretion was also stimulated by mucosal acidification, and this response was attenuated by both capsaicin pretreatment, indomethacin and L-NAME, but not ruthenium red or capsazepine. Mucosal application of capsaicin as well as acid increased the mucosal PGE2 content, and these effects were both significantly attenuated by indomethacin and L-NAME. These results suggest that both capsaicin and acid cause the CSN-dependent increase in duodenal HCO3(-) secretion mediated by NO and PG, yet the mode of their action differs in terms of the ruthenium red or capsazepine sensitivity. Although luminal H+ plays a modulatory role in duodenal HCO3(-) secretion, it is unlikely that the action results from the interaction of H+ with the ruthenium red- or capsazepine-sensitive site of VR1.
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PMID:Stimulation by capsaicin of duodenal HCO3(-) secretion via afferent neurons and vanilloid receptors in rats: comparison with acid-induced HCO3(-) response. 1456 Oct 13


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