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)

The vascular relaxant effect of salbutamol and its dependence on the endothelium were studied in the isolated dog coronary artery, precontracted with prostaglandin F2 alpha. Salbutamol induced a concentration-dependent relaxation which was partially inhibited by removal of endothelial cells. Atenolol 10(-6) mol/l, a beta 1-selective antagonist, inhibited the relaxant effect of salbutamol both in the presence and in the absence of endothelium. Conversely, ICI 118,551 10(-6) mol/l, a beta 2-selective antagonist, antagonized the response to salbutamol only in intact vessels. Methylene blue amplified markedly the relaxation to salbutamol but only in denuded rings. Therefore, the vasodilating effect of salbutamol on large coronary arteries seems to result from the stimulation of both, beta 1-receptors on smooth muscle cells and beta 2-receptors on endothelial cells, demonstrating the existence of the two types of adrenoceptors in the wall of large dog coronary arteries. In addition, the effect obtained with methylene blue in this study shed some doubts on its specificity as a guanylate cyclase inhibitor.
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PMID:Study of the vasodilating activity of salbutamol on dog coronary arteries. Unexpected effects of methylene blue. 167 90

1. We have investigated the bronchodilator potential of type V phosphodiesterase (PDE V) inhibitors in anaesthetized ventilated guinea-pigs using the potent and selective PDE V inhibitor, SK&F 96231. We have compared its activity to that of salbutamol, the PDE III inhibitors, siguazodan and SK&F 95654 and to the PDE IV inhibitor rolipram. 2. Administered as an i.v. infusion SK&F 96231 (0.6 and 1 mg kg-1 min-1, i.v.) caused a slowly developing inhibition of histamine (100 nmol kg-1, i.v.)-induced bronchoconstriction and elevated tracheal cyclic GMP levels in the anaesthetized guinea-pig. SK&F 96231 (0.1 and 0.3 mg kg-1 min-1, i.v.) was without effect on histamine-induced bronchoconstriction. In the presence of a sub-threshold infusion of SNP (0.1 mumol kg-1 min-1, i.v.) there was a marked enhancement of SK&F 96231-induced inhibition of histamine responses such that at infusion rates that were ineffective alone, SK&F 96231 caused a > 50% inhibition of histamine responses. The stimulation of tracheal cyclic GMP accumulation by SK&F 96231 was also potentiated. 3. Administered directly into the airway, SK&F 96231 (300 micrograms in 5 mg lactose carrier) was largely without effect on histamine-induced bronchoconstriction (4.9 +/- 1.9% inhibition). In the presence of SNP (0.1 mumol kg-1 min-1, i.v.) or isosorbide dinitrate (200 micrograms administered by insufflation into the trachea) there was a marked potentiation of the inhibitory activity of SK&F 96231 (40 +/- 4% and 62 +/- 1.8% respectively). 4. Salbutamol and rolipram (3-300 microg by insufflation) caused a dose-related inhibition of histamine responses with a maximum of 91 +/- 2% and 59 +/- 10% respectively. The PDE III inhibitor, siguazodan,was without effect on histamine responses but they were reduced (27.7 +/- 4.8% at 300 microg) by SK&F95654. There was a marked enhancement of the inhibitory activity of rolipram in the presence of SK&F 95654.5. We conclude that SK&F 96231 has weak anti-spasmogenic activity in the guinea-pig in vivo, we suggest that this is primarily a consequence of a low endogenous guanylate cyclase activity in the airway. The potentiation of the anti-spasmogenic activity of SK&F 96231 by SNP suggests that a combination of PDE V inhibitor and guanylate cyclase agonist might provide significant bronchodilator activity.6. We have established that PDE IV inhibitors are bronchodilators when administered directly into the airway of anaesthetized guinea-pigs but that PDE III inhibitors are only weakly active. The marked enhancement of the inhibitory activity of rolipram by the PDE III inhibitor, SK&F 95654, indicates that inhibitors of both PDE III and PDE IV might offer greater potential as bronchodilators than inhibitors of either isoenzyme alone.
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PMID:Pulmonary effects of type V cyclic GMP specific phosphodiesterase inhibition in the anaesthetized guinea-pig. 803 6

We investigated the effect of chronic hypoxia (10% O(2) for 14 days) on airway responsiveness in rats. Chronic hypoxia significantly (P<0. 05, P<0.01, P<0.01, respectively) attenuated contractions evoked by methacholine (10(-9)-3x10(-4) M), endothelin-1 (10(-10)-3x10(-7) M) and potassium chloride (10(-3)-7x10(-2) M) in rat isolated trachea. To investigate this attenuation, we studied the effect of epithelial removal, indomethacin (3x10(-6) M), and L-nitro arginine methyl ester (L-NAME, 10(-4) M), on contractile responses in control and chronically hypoxic rat trachea. Indomethacin did not alter contractions evoked by methacholine or endothelin-1 in control or hypoxic rats. In contrast, epithelial removal and L-NAME both significantly potentiated responses to methacholine and endothelin-1 in trachea from control and chronically hypoxic rats. In separate experiments, tracheal rings were first contracted with methacholine (10(-6) M) and then relaxed, either by the nitric oxide donor sodium nitroprusside or by the beta(2)-adrenoceptor agonist, salbutamol. Sodium nitroprusside was significantly (P<0.001) more effective at reversing induced tone in tracheal rings from chronically hypoxic than control rats. Salbutamol, however, was equally effective in chronically hypoxic and control rats. These results suggest that, in trachea from both control and chronically hypoxic rats, contractile responses to methacholine and endothelin-1 are inhibited by nitric oxide, probably released from the epithelium. The attenuation of contractile responses in airways from chronically hypoxic rats may be due to an enhanced guanylyl cyclase activity and hence, an increased response to nitric oxide.
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PMID:Chronic exposure to hypoxia attenuates contractile responses in rat airways in vitro: a possible role for nitric oxide. 1059 42