Efeitos do novo doador de óxido nítrico [Ru(terpy)(bdq)NO+]3+ sobre o músculo liso traqueal de ratos com asma experimental
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2015-03-26
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Universidade Federal de Goiás
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Nitric oxide is a potent bronchodilator and compounds capable of increasing its supply have demonstrated clinical interest in the treatment of obstructive airways diseases. This study evaluated and compared the mechanisms of relaxation of two nitric oxide donors, ruthenium complex [Ru(terpy)(bdq)NO+]3+ (TERPY) and sodium nitroprusside (SNP) in healthy isolated trachea, Sham group, or experimental model of asthma induced by ovalbumin in rats, OVA group. The isolated trachea was sectioned into rings and contracted with carbachol in an organ chamber for studying relaxation. The relaxing effect of TERPY and SNP was evaluated at increasing concentrations from 10 nM to 100 μM. Thus, we verified the contribution of the different types of K+ channels, the importance of sGC/cGMP pathway, the inhibition of PDEs (for IBMX, amrinone, rolipram and dypiridamole), the influence of the extra and intracellular Ca2+ sources (for cyclopiazonic acid) and the influence of the store and voltage operated calcium channels. Besides inhibition of COX (diclofenac), antagonism of leukotriene receptor (montelukast) and superoxide anion scavenger (TIRON). Analyses were performed under light microscopy for evidence of inflammatory infiltration and bronchoditation by TERPY in slices bronchioles of asthmatic animals. The results verified that sensitization with ovalbumin led to intense inflammatory process and hyperresponsives to carbachol in compared Sham group. TERPY and SNP led to the relaxation of tracheal smooth muscle preparations in a dependent-concentration mode in both groups. However, the maximum effect induced by TERPY was higher than the effect of SNP in Sham and OVA groups. The relaxation mechanism of TERPY in boht groups showed differences. In Sham group, TERPY relaxation by the activation of Kv, Kir, KCa and KATP channels, cGMP-independent mechanisms and by reduction of calcium influx by blocking the store and voltage operated calcium channels. In OVA group, TERPY acts through activation K+ channels, NO/GCs/GMP way and blocking the store and voltage operated calcium channels. The relaxing effect induced by SNP in OVA group was dependent of NO/GCs/GMP pathway, Kv, KCa and BKCa channels and blocking the store and voltage operated calcium channels. However, the activation of the enzyme sGC seems to be reduced in inflamed smooth muscle, as well as the role of the sarcoplasmic reticulum calcium pump. Diclofenac, montelukast and TIRON improved relaxation of the TERPY and SNP in OVA group. The TERPY is able to reverse the contraction of carbachol in asthmatic bronchioles. In conclusion, TERPY and SNP have their mechanisms of relaxation modified by the inflammatory process. However, this modification was not able to alter the pharmacological parameters potency and efficacy to TERPY. Since SNP has less efficacy effect in asthmatic tracheas. This may result from the lower participation of the enzyme sGC and reticular calcium pump, making TERPY a promising drug to reverse the narrowing of the airways.
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CASTRO, P. F. S. Efeitos do novo doador de óxido nítrico [Ru(terpy)(bdq)NO+]3+ sobre o músculo liso traqueal de ratos com asma experimental. 2015. 135 f. Tese (Doutorado em Ciências da Saúde) - Universidade Federal de Goiás, Goiânia, 2015.