Development of secretin-loaded breath test as a pancreatic exocrine function test : from animal model to human chronic pancreatitis

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We purposed to develop the secretin-loaded breath test to assess pancreatic exocrine function test using chronic pancreatitis in male WBN/Kob rats. Using Ubit-IR300,we could measure the ratio of ^<12>CO/^<13>CO from the expiration of rats which were put into the sealed container. At the beginning, we put conscious rats into the sealed container to collect their expiration. We thought that keeping rats in the sealed container caused tremendous stress, including hypo O_2 and hyper CO_2. The followings were our methodological modifications:1)Mixed gas (N_2 80%, O_2 20%) is pumped into the sealed container at a constant flow rate to remove pre-existing CO_2 from the collected air.2)Concentrations of O_2 and CO_2 in the air of the sealed container were monitored to keep O_2 and CO_2 around 20% and below 1%, respectively.3)The exhaust was placed on the lid of the container to remove excess N_2 and O_2.4)The expiration CO_2 with high density was collected from the bottom of the container.We r … More ecognized that the ratios of ^<12>CO/^<13>CO were not significantly lower in 20 and 30 weeks old male WBN/Kob rats than the age-matched male Wistar rats. Since it is reported that pancreatic exocrine function is impaired in 20 and 30 weeks old male WBN/Kob rats, the present breath test has low sensitivity.At the same time, we treated 10 weeks old male WBN/Kob rats with lisinopril, angiotensin-converting enzyme (ACE) inhibitor, in drinking water for 10 weeks and found that lisinopril dramatically attenuated pancreatic inflammation and fibrosis at 20 weeks of age by suppressing transforming growth factor-β1 mRNA. Therefore, we shifted the direction of the experiment and newly aimed to explore the roles of renin-angiotensin system (RAS) in the pathogenesis of chronic pancreatitis in the present model. As a result, both lisinopril, ACE inhibitor, and candesartan, angiotensin II type 1 receptor antagonist (ARB) effectively attenuated pancreatic inflammation and fibrosis in the present model (Gastroenterology 124:1010-1019,2003,J Pharmacol Exp Ther J Pharmacol Exp Ther 307:17-23,2003), demonstrating the important roles of RAS in the pathogenesis of chronic pancreatitis. However, their doses were extremely higher than the clinically used doses. Therefore, we next assessed the effect of combined therapy with ACE inhibitor and ARB. We finally found that combined therapy with ineffective doses of ACE inhibitor and ARB attenuated pancreatic inflammation and fibrosis in the present model. Less