The in vivo effects of milrinone on the airways of cystic fibrosis mice and human subjects

Previous studies have indicated that milrinone, a specific type III phospho diesterase inhibitor, may be able to induce chloride secretion in cystic fi brosis (CF) tissues. We have now assessed the effect of this agent in vivo on the nasal epithelium of CF mutant mice and also in the nose and lungs of human subjects with CF. Wild-type mice showed a small hyperpolarization of the nasal potential difference (PD) in response to milrinone (100 mu M, 1. 6 +/- 0.6 mV, n = 8, P < 0.05). In contrast, CF mice carrying either the mo st common human mutation of the gene for the CF transmembrane regulator (CF TR), Delta 508 (protein mislocalized), or the G551D mutation (protein norma lly localized) failed to demonstrate this response. Milrinone perfused alon e had no significant effect on the baseline nasal PD of human subjects with out CF (14.7 +/- 4.0 mV preperfusion; 15.3 +/- 4.6 mV postperfusion), but s ignificantly (P < 0.05) augmented the hyperpolarization induced by a subseq uently perfused low-chloride solution (with milrinone, 36.8 +/- 3.0 mV, n = 6; without milrinone, 18.1 +/- 2.2 mV, n = 19). In contrast, in human subj ects with CF (n = 6), milrinone alone significantly (P < 0.05) altered the nasal baseline PD (52.2 +/- 3.3 mV preperfusion; 57.4 +/- 4.2 mV, postperfu sion) but not the subsequent responses to the low-chloride solution (with m ilrinone, 1.1 +/- 2.2 mV, n = 4; without milrinone, 0.6 +/- 0.5 mV, n = 28) or to isoproterenol (100 mu M). In a separate study in subjects (n = 6) wi th the Delta 508 mutation, nasal coadministration of milrinone with isoprot erenol produced no effect in the presence of amiloride and a low-chloride s olution (-0.8 +/- 0.5 mV). This was also the case in the nasal epithelium o f CF subjects (n = 4) carrying at least one G551D allele (-0.3 +/- 0.8 mV). Similarly, milrinone did not hyperpolarize the PD of either the tracheal ( n = 6) or segmental (n = 6) airways of CF subjects (Delta 508) when applied topically in vivo in the presence of amiloride, isoproterenol, or adenosin e triphosphate (all 100 mu M) in a low-chloride solution. These data do not support the use of milrinone to induce chloride secretion in CF airways in vivo.