Mechanisms of endothelin-1-induced contraction in pulmonary arteries from chronically hypoxic rats
- 1 February 2006
- journal article
- Published by American Physiological Society in American Journal of Physiology-Lung Cellular and Molecular Physiology
- Vol. 290 (2), L284-L290
- https://doi.org/10.1152/ajplung.00449.2004
Abstract
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, Rho kinase, PKC, or tyrosine kinases (TKs), including those from the Src family. In this study, we examined the effect of pharmacological inhibitors of these kinases on maximum tension generated by IPA from CH rats (10% O2for 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 markedly inhibited by the Rho kinase inhibitors Y-27632 and HA-1077 and the TK inhibitors genistein, tyrphostin A23, and PP2. In contrast, staurosporine and GF-109203X, 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+]iin IPA from CH rats requires activation of Rho kinase and TKs, but not PKC.Keywords
This publication has 36 references indexed in Scilit:
- Chronic hypoxia augments protein kinase G-mediated Ca2+ desensitization in pulmonary vascular smooth muscle through inhibition of RhoA/Rho kinase signalingAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2004
- Chronic hypoxia causes angiogenesis in addition to remodelling in the adult rat pulmonary circulationThe Journal of Physiology, 2002
- Identification of Calponin as a Novel Substrate of Rho-KinaseBiochemical and Biophysical Research Communications, 2000
- ETA receptors are the primary mediators of myofilament calcium sensitization induced by ET‐1 in rat pulmonary artery smooth muscle: a tyrosine kinase independent pathwayBritish Journal of Pharmacology, 1999
- NO: COPD and beyondThorax, 1997
- Nuclear Signaling by Endothelin-1 Requires Src Protein-tyrosine KinasesPublished by Elsevier BV ,1996
- Phosphorylation of Calponin Mediated by Protein Kinase C in Association with Contraction in Porcine Coronary ArteryBiochemical and Biophysical Research Communications, 1995
- Augmented agonist-induced Ca(2+)-sensitization of coronary artery contraction in genetically hypertensive rats. Evidence for altered signal transduction in the coronary smooth muscle cells.JCI Insight, 1994
- Pulmonary Vascular Reactivity to Endothelin-1 in Normal and Chronically Pulmonary Hypertensive RatsJournal of Cardiovascular Pharmacology, 1991
- Myosin light chain and caldesmon phosphorylation in arterial muscle stimulated with endothelin-1Journal of Molecular and Cellular Cardiology, 1990