Pantoprazole decreases gastroesophageal muscle tone in newborn rats via rho-kinase inhibition

Abstract

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.

Infantile hypertrophic pyloric stenosis (IHPS): A study of its pathophysiology utilizing the newborn hph-1 mouse model of the disease

“…In adult rat (36) and human (39) lower esophageal sphincters, ROCK inhibitors abolish both spontaneous basal and nerveevoked contractions. Recently, we reported a similar response to ROCK-2 inhibition in the newborn rat lower esophageal sphincter (48). In the present study, we documented a direct relationship between pyloric tissue ROCK-2 expression/activity and the magnitude of agonist-induced muscle contraction in newborn mice.…”

Proton Pump Inhibitors in cancer patients: How useful they are? A review of the most common indications for their use

“…The proposed mechanisms for these findings is thought to be the bacterial overgrowth related with the increased gastric pH, and the more frequent occurrence of bacterial aspiration. Adjunctive factors may be a potential decreased muscle tone due to PPIs and an influence on the function of neutrophil and natural-killer cells, which can cause a less efficient clearance of bacteria (Welsh et al, 2014;Gulmez et al, 2007). Taken together these preclinical data suggest that an overuse of PPIs during RT has the potential of increasing the risk of complications.…”

Calcium Sensitization Mechanisms in Gastrointestinal Smooth Muscles

“…Interestingly, the proton pump inhibitor pantoprazole inhibited MYPT1 T853 phosphorylation evoked by CCh in gastric and LES tissue, suggesting that it may also be a ROCK inhibitor, although it had no effect on constitutive MYPT1 or CPI-17 phosphorylation. 114 It has been reported that PDBu-evoked contraction of cells isolated from human IAS smooth muscles are reduced by a ROCK inhibitor, but not by a PKC inhibitor, although PKC was activated, although another study reported that PDBu relaxes opossum IAS smooth muscles and cells isolated from opossum IAS smooth muscles. 97,115 Several of the studies previously mentioned examining CPI-17 and MYPT1 phosphorylation in response to contractile agonists show variable, but significant levels of constitutive CPI-17 and MYPT1 phosphorylation in the un-stimulated control tissues.…”