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Impaired NO-dependent inhibition of store- and receptor-operated calcium entry in pulmonary vascular smooth muscle after chronic hypoxia

Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico

Submitted 16 August 2004 ; accepted in final form 17 October 2005

We have recently demonstrated that chronic hypoxia (CH) attenuates nitric oxide (NO)-mediated decreases in pulmonary vascular smooth muscle (VSM) intracellular free calcium concentration ([Ca²⁺]_i) and promotes NO-dependent VSM Ca²⁺ desensitization. The objective of the current study was to identify potential mechanisms by which CH interferes with regulation of [Ca²⁺]_i by NO. We hypothesized that CH impairs NO-mediated inhibition of store-operated (capacitative) Ca²⁺ entry (SOCE) or receptor-operated Ca²⁺ entry (ROCE) in pulmonary VSM. To test this hypothesis, we examined effects of the NO donor, spermine NONOate, on SOCE resulting from depletion of intracellular Ca²⁺ stores with cyclopiazonic acid, and on UTP-induced ROCE in isolated, endothelium-denuded, pressurized pulmonary arteries (213 ± 8 µm inner diameter) from control and CH (4 wk at 0.5 atm) rats. Arteries were loaded with fura-2 AM to continuously monitor VSM [Ca²⁺]_i. We found that the change in [Ca²⁺]_i associated with SOCE and ROCE was significantly reduced in vessels from CH animals. Furthermore, spermine NONOate diminished SOCE and ROCE in vessels from control, but not CH animals. We conclude that NO-mediated inhibition of SOCE and ROCE is impaired after CH-induced pulmonary hypertension.

pulmonary hypertension; capacitative calcium entry; uridine 5'-triphosphate; protein kinase G; NiCl₂; SKF-96365; nitric oxide

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