Excitation-contraction coupling in pulmonary vascular smooth muscle involves tyrosine kinase and Rho kinase |
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Authors: | Janssen L J Lu-Chao H Netherton S |
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Affiliation: | Asthma Research Group, McMaster University, Hamilton, Ontario, Canada L8N 3Z5. janssenl@mcmaster.ca |
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Abstract: | We investigated the mechanisms that underlie the responses to norepinephrine (NE) and thromboxane (Tx) A(2) (TxA2) in the canine pulmonary vasculature with fura 2 fluorimetric, intracellular microelectrode, and force transduction techniques. KCl, caffeine, and cyclopiazonic acid elevated intracellular Ca2+ concentration levels and tone, indicating that Ca2+ mobilization is sufficient to produce contraction. However, contractions evoked by NE or the TxA2 mimetic U-46619 were unaffected by nifedipine or by omitting external Ca2+ and were reduced only partially by depleting the internal Ca2+ store; furthermore, NE-evoked depolarization was subthreshold for voltage-dependent Ca2+ currents. Agonist-evoked contractions were insensitive to inhibitors of protein kinase C (calphostin C and chelerythrine), mitogen-activated protein kinase kinase (PD-98059), and p38 kinase (SB-203580) but were abolished by the tyrosine kinase inhibitor genistein and the Rho kinase inhibitor Y-27632. We conclude that, although Ca2+ influx and Ca2+ release are sufficient for contraction, they are not necessary for adrenergic or TxA2 contractions. Instead, excitation-contraction coupling involves the activation of tyrosine kinase and Rho kinase, leading to enhanced Ca2+ sensitivity of the contractile apparatus. |
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