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Ca²⁺ signaling in hypoxic pulmonary vasoconstriction: effects of myosin light chain and Rho kinase antagonists

Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 9 April 2007 ; accepted in final form 12 June 2007

Antagonists of myosin light chain (MLC) kinase (MLCK) and Rho kinase (ROK) are thought to inhibit hypoxic pulmonary vasoconstriction (HPV) by decreasing the concentration of phosphorylated MLC at any intracellular Ca²⁺ concentration ([Ca²⁺]_i) in pulmonary arterial smooth muscle cells (PASMC); however, these antagonists can also decrease [Ca²⁺]_i. To determine whether MLCK and ROK antagonists alter Ca²⁺ signaling in HPV, we measured the effects of ML-9, ML-7, Y-27632, and HA-1077 on [Ca²⁺]_i, Ca²⁺ entry, and Ca²⁺ release in rat distal PASMC exposed to hypoxia or depolarizing concentrations of KCl. We performed parallel experiments in isolated rat lungs to confirm the inhibitory effects of these agents on pulmonary vasoconstriction. Our results demonstrate that MLCK and ROK antagonists caused concentration-dependent inhibition of hypoxia-induced increases in [Ca²⁺]_i in PASMC and HPV in isolated lungs and suggest that this inhibition was due to blockade of Ca²⁺ release from the sarcoplasmic reticulum and Ca²⁺ entry through store- and voltage-operated Ca²⁺ channels in PASMC. Thus MLCK and ROK antagonists might block HPV by inhibiting Ca²⁺ signaling, as well as the actin-myosin interaction, in PASMC. If effects on Ca²⁺ signaling were due to decreased phosphorylated myosin light chain concentration, their diversity suggests that MLCK and ROK antagonists may have acted by inhibiting myosin motors and/or altering the cytoskeleton in a manner that prevented achievement of required spatial relationships among the cellular components of the response.

isolated rat lung; pulmonary vascular resistance; angiotensin II; vascular smooth muscle; calcium channels

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