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1 Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: shimodal{at}welch.jhu.edu.
Endothelin-1 (ET-1), a potent vasoconstrictor, is believed to contribute to the pathogenesis of hypoxic pulmonary hypertension. Previously we demonstrated that contraction induced by ET-1 in intrapulmonary arteries (IPA) from chronically hypoxic (CH) rats occurred independently of changes in intracellular Ca2+ concentration ([Ca2+]i), suggesting that ET-1 increased Ca2+-sensitivity. The mechanisms underlying this effect are unclear, but could involve the activation of myosin light chain kinase (MLCK), Rho kinase, protein kinase C (PKC), or tyrosine kinases (TK), including those from the Src family. In this study, we examined the effect of pharmacologic inhibitors of these kinases on maximum tension generated by IPA from CH rats (10% O2 for 21 days) in response to ET-1. Experiments were conducted in the presence of nifedipine, an L-type Ca2+ channel blocker, to isolate the component of contraction that occurred without a change in [Ca2+]i. The mean change in tension caused by ET-1 (10-8M) expressed as a percent of the maximum response to KCl was 184.0±39.0%. This response was blocked >90% by the Rho kinase inhibitors Y-27632 and HA-1077, and the TK inhibitors, genistein, tyrphostin A23, and PP2. In contrast, staurosporine and GF109203X, inhibitors of PKC, had no significant inhibitory effect on the tension generated in response to ET-1. We conclude that the component of ET-1-induced contraction that occurs without a change in [Ca2+]i in IPA from CH rats requires activation of Rho kinase and TKs, but not PKC.
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