Hypoxic Depression of Pacemaker Activity of Interstitial Cells of Cajal: A Threat of Gastrointestinal Dysmotility and Necrosis. A Simulation Study

Hypoxic-ischemic injury is a known risk factor of necrotizing enterocolitis (NEC), an inflammatory bowel disease of neonates, one of the most common causes of intestinal failures associated with total bowel and/or segmental disorders of intestinal motility. The gastrointestinal motility is based, to a significant extent, on pacemaker action of the interstitial cells of Cajal (ICCs) on intestinal smooth muscle cells (SMCs). We explored how the hypoxia affects ICC pacemaker activity manifested in oscillations of the cell membrane potential E-m and intracellular calcium concentration [Ca2+](i), factors determined by interplay of calcium-handling mechanisms of the endoplasmic reticulum (ER) and mitochondria. The hypoxic action was simulated by a reduction of the mitochondrial bulk membrane potential (Delta psi*) or maximal rates of Ca2+-ATPase pumps of the plasmalemma or ER (PMCA or SERCA, respectively). Loss of Delta psi* resulted, first, in an increase in the oscillation period and, finally, in the transition of ICCs to the down-state with resting E-m and basal [Ca2+](i) levels. Depression of SERCA brought the ICC to the downstate with small-amplitude oscillations of E-m and [Ca2+](i) near the resting/basal levels. Suppression of the PMCA pump caused transition of ICCs into the up-state characterized by a persistent depolarization shift of the E-m and [Ca2+](i) significantly exceeding the down-state levels. Hence, hypoxic suppression of any of the above energy-consuming mechanisms led, thought in different ways, to the cessation of ICC pacemaker activity, which may have crucial pathological consequences for ICC-driven periodic contractions of electrically coupled SMCs; this can be manifested as gastrointestinal dysmotility and/or NEC.