Induction of heme oxygenase in guinea‐pig stomach: roles in contraction and in single muscle cell ionic currents

Abstract

The role of heme oxygenase reaction products in modulation of stomach fundus excitability was studied. The presence of constitutive heme oxygenase 2 was verified in myenteric ganglia by immunohistochemistry. The role of inducible heme oxygenase isoenzyme was investigated after invivo treatment of animals with CoCl2 (80 mg kg-1 b.w) injected subcutaneously 24 h before they were killed. This treatment resulted in increased production of bilirubin and positive staining for the inducible isoform in stomach smooth muscle and vast induction in the liver. In both control and treated animals haemin, applied to the bath as a substrate of heme oxygenase caused significant decrease of prostaglandin F2alpha-induced tone, and ameliorated the relaxatory response of the fundic strips to electrical field stimulation. Both effects were antagonized by Sn-protoporphyrin IX, competitive heme oxygenase inhibitor, and were found to be neuronally dependent. In single freshly isolated smooth muscle cells from control animals haemin caused a concentration-dependent increase of the whole cell K+ currents, which was not affected by Sn-protoporphyrin IX, cyclic guanosine monophosphate (cGMP)-dependent protein kinase or guanylyl cyclase antagonists, but was reversed by various antioxidants and abolished by an NO scavenger. In cells from treated animals the K+ current increasing effect of haemin did not depend on the presence of antioxidants, but was abolished by protein kinase G and guanylyl cyclase inhibitors, depletors of intracellular Ca2+ pools or Sn-protoporphyrin IX. Biliverdin did not affect contraction or ionic currents. Thus, this is the first study demonstrating that heme oxygenase is an inducible enzyme in guinea-pigs, which exerts a modulatory role on gastric smooth muscle excitability via carbon monoxide production.

Calcium-dependent changes in potassium currents in guinea-pig coronary artery smooth muscle cells after acute cobalt loading in vivo

“…1), consistent with our earlier study [17]. This suggests that HO-1 cannot be induced in guinea-pig coronary artery SMCs by acute cobalt poisoning, although such induction is observed in guinea-pig stomach fundus [23] and liver [24] under the same conditions. The presence of HO-2 isoenzyme in this tissue has already been documented [17].…”

“…Is HO-1 expression induced in coronary artery SMCs by acute cobalt loading (given that such has been demonstrated in vivo in other SMCs, as well as in the liver, kidney, stomach and heart [22,23,24])? 2.…”

A Model of Slow Wave Propagation and Entrainment Along the Stomach

“…32 In guinea pig gastric SMCs, a cGMP-and PKG-dependent vectorial intracellular mobilization of Ca 2+ ions has been suggested to cause the augmentation of the K + currents. 18 In human intestinal myocytes, on the other hand, no change in intracellular Ca 2+ levels was noted after the application of exogenous CO, 13 supporting previous suggestions that the augmentation of the K + currents appears to be due to voltage dependent and not Ca 2+ -activated K + channels. 11 Here it was assumed that CO affected voltage dependent and large conductance Ca 2+ -activated K + channels (BK) were activated by CO as BK channels are also believed to exhibit voltage dependence.…”

“…Recent experimental evidence has suggested that ICC in the GI tract, in particular the ICC-MY, produce CO through a heme-oxygenase-2 (HO-2)-mediated pathway. 18,31 Experimental observations from genetically modified HO-2-null mice showing a lack of a membrane potential gradient 12 appear to suggest a relationship between the RMP and CO concentration gradients. However, the mechanism through which CO causes membrane hyperpolarization in GI SMCs is yet to be fully elucidated.…”

Protective role of hemeoxygenase-1 in gastrointestinal diseases

“…In diabetic gastroparesis there was a decrease in HO-1 + CD206 + macrophages and an increase in oxidative stress that was associated with low expression of the receptor tyrosine kinase KIT in interstitial cells of Cajal (ICC) resulting in delayed gastric emptying [78,81]. In a non-obese diabetic (NOD) model of diabetic gastroparesis, hemin treatment protected ICC by decreasing reactive oxygen species and restoring KIT expression [82].…”