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Hypoxia induces hypersensitivity and hyperreactivity to thromboxane receptor agonist in neonatal pulmonary arterial myocytes

Departments of ¹Physiology and ²Pediatrics, University of Manitoba; and ³Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Canada

Submitted 14 July 2005 ; accepted in final form 30 September 2005

PPHN, caused by perinatal hypoxia or inflammation, is characterized by an increased thromboxane-prostacyclin ratio and pulmonary vasoconstriction. We examined effects of hypoxia on myocyte thromboxane responsiveness. Myocytes from 3rd–6th generation pulmonary arteries of newborn piglets were grown to confluence and synchronized in contractile phenotype by serum deprivation. On the final 3 days of culture, myocytes were exposed to 10% O₂ for 3 days; control myocytes from normoxic piglets were cultured in 21% O₂. PPHN was induced in newborn piglets by 3-day hypoxic exposure (FI_O2 0.10); pulmonary arterial myocytes from these animals were maintained in normoxia. Ca²⁺ mobilization to thromboxane mimetic U-46619 and ATP was quantified using fura-2 AM. Three-day hypoxic exposure in vitro results in increased basal [Ca²⁺]_i, faster and heightened peak Ca²⁺ response, and decreased U-46619 EC₅₀. These functional changes persist in myocytes exposed to hypoxia in vivo but cultured in 21% O₂. Blockade of Ca²⁺ entry and store refilling do not alter peak U-46619 Ca²⁺ responses in hypoxic or normoxic myocytes. Blockade of ryanodine-sensitive or IP₃-gated intracellular Ca²⁺ channels inhibits hypoxic augmentation of peak U-46619 response. Ca²⁺ response to ryanodine alone is undetectable; ATP-induced Ca²⁺ mobilization is unaltered by hypoxia, suggesting no independent increase in ryanodine-sensitive or IP₃-linked intracellular Ca²⁺ pool mobilization. We conclude hypoxia has a priming effect on neonatal pulmonary arterial myocytes, resulting in increased resting Ca²⁺, thromboxane hypersensitivity, and hyperreactivity. We postulate that hypoxia increases agonist-induced TP-R-linked IP₃ pathway activation. Myocyte thromboxane hyperresponsiveness persists in culture after removal from the initiating hypoxic stimulus, suggesting altered gene expression.

smooth muscle; pulmonary hypertension; persistent pulmonary hypertension of the newborn

This article has been cited by other articles:

				M. Hinton, A. Gutsol, and S. Dakshinamurti Thromboxane hypersensitivity in hypoxic pulmonary artery myocytes: altered TP receptor localization and kinetics Am J Physiol Lung Cell Mol Physiol, March 1, 2007; 292(3): L654 - L663. [Abstract] [Full Text] [PDF]