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1 Division of Pulmonary & Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: jsylv{at}jhmi.edu.
Antagonists of myosin light chain kinase (MLCK) and Rho kinase (ROK) are thought to inhibit hypoxic pulmonary vasoconstriction (HPV) by decreasing the concentration of phosphorylated myosin light chains ([P-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 if 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 sarcoplasmic reticulum and Ca2+ entry through both store- and voltage-operated Ca2+ channels in PASMC. Thus, MLCK and ROK antagonists might block HPV by inhibiting Ca2+ signaling, as well as actin-myosin interaction, in PASMC. If effects on Ca2+ signaling were due to decreased [P-MLC], 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.
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