Pantoprazole decreases gastroesophageal muscle tone in newborn rats via rho-kinase inhibition.
Proton pump inhibitors reduce gastric acid secretion and are commonly utilized in the management of gastroesophageal reflux disease across all ages. Yet a decrease in lower esophageal sphincter tone has been reported in vitro in rats through an unknown mechanism; however, their effect on the gastroesophageal muscle tone early in life was never studied. Hypothesizing that proton pump inhibitors also reduce gastroesophageal muscle contraction in newborn and juvenile rats, we evaluated the in vitro effect of pantoprazole on gastric and lower esophageal sphincter muscle tissue. Electrical field stimulation and carbachol-induced force were significantly (P < 0.01) reduced in the presence of pantoprazole, whereas the drug had no effect on the neuromuscular-dependent relaxation. When administered in vivo, pantoprazole (9 mg/kg) significantly (P < 0.01) reduced gastric emptying time at both ages. To ascertain the signal transduction pathway responsible for the reduction in muscle contraction, we evaluated the tissue ROCK-2 and CPI-17 activity. Pantoprazole reduced myosin light chain phosphatase MYPT-1, but not CPI-17 phosphorylation of gastric and lower esophageal sphincter tissue, strongly suggesting that it is a ROCK-2 inhibitor. To the extent that these findings can be extrapolated to human neonates, the use of pantoprazole may impair gastric and lower sphincter muscle tone and thus paradoxically exacerbate esophageal reflux. Further studies addressing the effect of proton pump inhibitors on gastroesophageal muscle contraction are warranted to justify its therapeutic use in gastroesophageal reflux disease.
Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada;
Christopher
C
Welsh
Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; and.
Moshe Yair
MY
Kasirer
Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada;
Jingyi
J
Pan
Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada;
Yulia
Y
Shifrin
Physiology & Experimental Medicine Program, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada; Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; and Department of Physiology, University of Toronto, Toronto, Ontario, Canada jaques.belik@sickkids.ca.
Jaques
J
Belik
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D049630:Esophageal Sphincter, Lower / Q000187:drug effects* / Q000201:enzymology / Q000294:innervation; D005746:Gastric Emptying / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects*; D009124:Muscle Proteins / Q000378:metabolism; D000077402:Pantoprazole; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D054645:Protein Phosphatase 1 / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013270:Stomach / Q000187:drug effects* / Q000201:enzymology / Q000294:innervation; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D009124:Muscle Proteins; D010750:Phosphoproteins; C491519:Ppp1r14a protein, rat; D047428:Protein Kinase Inhibitors; D054328:Proton Pump Inhibitors; D002217:Carbachol; D000077402:Pantoprazole; C580818:ROCK2 protein, rat; D054460:rho-Associated Kinases; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1
ROCK-2; gastric emptying time; lower esophageal sphincter