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J Pharmacol Exp Ther. 2018 Nov;367(2):194-202. doi: 10.1124/jpet.118.249581. Epub 2018 Aug 14.

Impairment of Nitric Oxide Pathway by Intravascular Hemolysis Plays a Major Role in Mice Esophageal Hypercontractility: Reversion by Soluble Guanylyl Cyclase Stimulator.

Author information

1
Hematology and Hemotherapy Center (F.H.S., K.Y.F., C.F.F.-P., F.F.C.) and Department of Pharmacology, Faculty of Medical Sciences (E.C.A., F.B.C.), University of Campinas, Campinas, São Paulo, Brazil; and Division of Hematology, University of Washington, Seattle, Washington (K.Y.F.) fabiohsilva87@gmail.com.
2
Hematology and Hemotherapy Center (F.H.S., K.Y.F., C.F.F.-P., F.F.C.) and Department of Pharmacology, Faculty of Medical Sciences (E.C.A., F.B.C.), University of Campinas, Campinas, São Paulo, Brazil; and Division of Hematology, University of Washington, Seattle, Washington (K.Y.F.).

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) patients display exaggerated intravascular hemolysis and esophageal disorders. Since excess hemoglobin in the plasma causes reduced nitric oxide (NO) bioavailability and oxidative stress, we hypothesized that esophageal contraction may be impaired by intravascular hemolysis. This study aimed to analyze the alterations of the esophagus contractile mechanisms in a murine model of exaggerated intravascular hemolysis induced by phenylhydrazine (PHZ). For comparative purposes, sickle cell disease (SCD) mice were also studied, a less severe intravascular hemolysis model. Esophagus rings were dissected free and placed in organ baths. Plasma hemoglobin was higher in PHZ compared with SCD mice, as expected. The contractile responses produced by carbachol (CCh), KCl, and electrical-field stimulation (EFS) were superior in PHZ esophagi compared with control but remained unchanged in SCD mice. Preincubation with the NO-independent soluble guanylate cyclase stimulator 3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (BAY 41-2272; 1 μM) completely reversed the increased contractile responses to CCh, KCl, and EFS in PHZ mice, but responses remained unchanged with prior treatment with NO donor sodium nitroprusside (300 μM). Protein expression of 3-nitrotyrosine and 4-hydroxynonenal increased in esophagi from PHZ mice, suggesting a state of oxidative stress. In endothelial nitric oxide synthase gene-deficient mice, the contractile responses elicited by KCl and CCh were increased in the esophagus but remained unchanged with the intravascular hemolysis induced by PHZ. In conclusion, our results show that esophagus hypercontractile state occurs in association with lower NO bioavailability due to exaggerated hemolysis intravascular and oxidative stress. Moreover, our study supports the hypothesis that esophageal disorders in PNH patients are secondary to intravascular hemolysis affecting the NO-cGMP pathway.

PMID:
30108160
DOI:
10.1124/jpet.118.249581

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