EFFECT OF INHALED THIORPHAN, A NEUTRAL ENDOPEPTIDASE INHIBITOR, ON THE BRONCHODILATOR RESPONSE TO INHALED ATRIAL-NATRIURETIC-PEPTIDE (ANP)

Background - The hormone atrial natriuretic peptide (ANP) causes bronc hodilation and partially protects against direct and indirect bronchia l challenges. Both in vitro and in vivo studies have found that the pr otective effect of ANP against bronchoconstrict ion is enhanced by inh ibition of the enzyme neutral endopeptidase (NEP). It was hypothesised that pretreatment with thiorphan, an NEP inhibitor, might enhance the bronchodilator response to inhaled ANP. Methods - In a randomised dou ble blind placebo controlled crossover study, six asthmatic patients ( one woman) of mean (SD) age 47.3 (3.8) years and forced expiratory vol ume in one second (FEV(1)) 1.91 (0.42) 1, 55 (3.8)% predicted, were st udied. All were shown at screening to have at least a 25% improvement in FEV(1) to inhaled salbutamol. On five study visits the patients rec eived either thiorphan 1 mg (in 2 ml) followed by ANP 5 mg or placebo (saline), or placebo (saline) followed by ANP (5 mg), placebo or salbu tamol 5 mg. Spirometric parameters were measured after each inhalation and thereafter for the next two hours. Results - ANP alone caused a b ronchodilator response up to 15 minutes when compared with placebo or thiorphan alone with a mean (SE) change in FEV(1) of 16.8 (8.1)% and 1 6.1 (6.8)% at 10 and 15 minutes from baseline, respectively. Prior inh alation of thiorphan prolonged the duration of the bronchodilator effe ct of ANP up to 60 minutes with a mean (SE) change in FEV(1) of 23.1 ( 3.4)% at 60 minutes. There was no difference in the maximum degree of bronchodilation following the administration of ANP alone compared wit h the combination of thiorphan and ANP. The degree and duration of the bronchodilator response produced by ANP, or the combination of the NE P inhibitor and ANP, were less than that produced by salbutamol. Concl usions - These results confirm that, at least in part, the bronchodila tor response to inhaled ANP is modulated by NEP. Analogues of ANP whic h are stable to NEP may have greater bronchodilator activity than ANP in the treatment of asthma.