Mechanisms of relaxations of bovine isolated bronchioles by the nitric oxide donor, GEA 3175

Abstract

1 The present study was designed to investigate the eects and mechanisms of relaxation induced by the nitric oxide (NO) donor, GEA 3175 (a 3-aryl-substituted oxatriazole derivative) on bovine bronchioles (eective lumen diameter 200 ± 800 mm) suspended in microvascular myographs for isometric tension recording. 2 In segments of bovine bronchioles contracted to 5-hydroxytryptamine, GEA 3175 (10 78 ± 10induced concentration-dependent reproducible relaxations. These relaxations were slow in onset compared to other NO-donors such as 3-morpholinosydonimine-hydrochloride (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP).3 In 5-hydroxytryptamine-contracted preparations the order of relaxant potency (pD 2 ) was: salbutamol (7.80)4GEA 3175 (6.18)4SIN-1 (4.90)4SNAP (3.55). In segments contracted to acetylcholine, the relaxant responses were reduced and GEA 3175 relaxed the bronchioles with pD 2 =4.41+0.12 and relaxations of 66+10% (n=4), while SNAP and salbutamol caused relaxations of 19+6% (n=4) and 27+6% (n=8) at the highest concentration used, respectively. and iberiotoxin (10 78 M), did inhibit the relaxations to GEA 3175. The combination of apamin and charybdotoxin did not induce an additional inhibitory eect on the relaxations to GEA 3175 compared to charybdotoxin alone. 6 In preparations where a concentration-response curve to GEA 3175 or NO was ®rst obtained in the presence of LY 83583, incubation with charybdotoxin (10 77 M) did produce an additional inhibitory eect of the relaxations. However, in the presence of ODQ (3610 76 M), iberiotoxin (10 78 M) did not produce additional reduction of the NO-or GEA 3175-induced relaxations. 7 The present results suggest that the slow-releasing NO-donor GEA 3175 is more potent than the traditional NO donors in inducing relaxations of bovine bronchioles. GEA 3175, as for exogenously added NO, elicits relaxations through a cyclic GMP-dependent mechanism followed by opening of large conductance Ca 2+ -activated K + -channels.

A Nitric Oxide-Releasing Salbutamol Elicits Potent Relaxant and Anti-Inflammatory Activities

“…In contrast, ODQ had no significant effects on both NCX-950 and salbutamol concentration-response curves, suggesting that NO is not a major component in the relaxant effect of NCX-950. However, ODQ did not cause total inhibition of the relaxation of isolated airways induced by GEA 3175 or sodium nitroprusside, two other NO donors (Hernandez et al, 1998;Hjoberg et al, 1999). These results may also support the existence of additional mechanisms, other than guanylyl cyclase activation, for NO-induced smooth muscle relaxation.…”

Mechanisms underlying epithelium-dependent relaxation in rat bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries

“…The lungs were immediately removed and placed in a 4°C physiological saline solution (PSS). Bronchioles and pulmonary arteries of third and fourth order were carefully dissected under a microscope by removing the surrounding tissue as previously described (24).…”

Nitric oxide modulators: An emerging class of medicinal agents

“…The active compounds GEA 3162 and GEA 3175 (fig. 5) have been shown to produce NO-dependant pharmacological effects such as vasodilator, antiplatelet, fibrinolytic[32] and antibacterial activities[33] as well as inhibit neutrophil functions[34], suppress tumor cell growth[35], regulate glycosaminoglycan synthesis in articular cartilage[36], inhibit oxidation of low density lipoprotein[37] and induce relaxation of bronchioles[38] and trachea[39]. GEA compounds consume oxygen only when used at high concentrations and thereby an oxygen dependant mechanism of NO release, similar to that found in SIN-1, is unlikely in these cases[40].…”