Pantoprazole decreases gastroesophageal muscle tone in newborn rats

31 Proton pump inhibitors reduce gastric acid secretion and are commonly utilized in 32 the management of gastro-esophageal reflux disease (GERD) across all ages. Yet a 33 decrease in lower esophageal sphincter tone has been reported in vitro in rats 34 through an unknown mechanism, however their effect on the gastroesophageal 35 muscle tone early in life was never studied. Hypothesizing that proton pump 36 inhibitors also reduce gastroesophageal muscle contraction in newborn and juvenile 37 rats, we evaluated the in vitro effect of pantoprazole on gastric and lower 38 esophageal sphincter muscle tissue. Electrical field stimulation (EFS) and carbachol39 induced force were significantly (P<0.01) reduced in the presence of pantoprazole, 40 whereas the drug had no effect on the neuromuscular-dependent relaxation. When 41 administered in vivo, pantoprazole (9 mg/kg) significantly (P<0.01) reduced gastric 42 emptying time at both ages. In order to ascertain the signal transduction pathway 43 responsible for the reduction in muscle contraction, we evaluated the tissue rho44 associated kinase 2 (ROCK-2) and CPI-17 activity. Pantoprazole reduced myosin light 45 chain phosphatase MYPT-1, but not CPI-17 phosphorylation of gastric and lower 46 esophageal sphincter tissue strongly suggesting that it is a ROCK-2 inhibitor. To the 47 extent that these findings can be extrapolated to human neonates, the use of 48 pantoprazole may impair gastric and lower sphincter muscle tone and thus 49 paradoxically exacerbate esophageal reflux. Further studies addressing the effect of 50 proton pump inhibitors on gastroesophageal muscle contraction are warranted to 51 justify its therapeutic use in GERD. 52 Key word(s): Lower esophageal sphincter, gastric emptying time, ROCK-2. 53