Tyrosine Kinase Inhibitors Are Potent Acute Pulmonary Vasodilators in Rats
- 1 October 2011
- journal article
- Published by American Thoracic Society in American Journal of Respiratory Cell and Molecular Biology
- Vol. 45 (4), 804-808
- https://doi.org/10.1165/rcmb.2010-0371oc
Abstract
Tyrosine kinase inhibitors are promising for the treatment of severe pulmonary hypertension. Their therapeutic effects are postulated to be due to inhibition of cell growth-related kinases and attenuation of vascular remodeling. Their potential vasodilatory activities have not been explored. Vasorelaxant effects of the tyrosine kinase inhibitors imatinib, sorafenib, and nilotinib were examined in isolated pulmonary arterial rings from normal and pulmonary hypertensive rats. Phosphorylation of myosin light chain phosphatase and myosin light chain was assessed by Western blots. Acute hemodynamic effects of imatinib were tested in the pulmonary hypertensive rats. In normal pulmonary arteries, imatinib reversed serotonin- and U46619-induced contractions in a concentration-dependent and endothelium-independent manner. Sorafenib and nilotinib relaxed U46619-induced contraction. Imatinib inhibited activation of myosin phosphatase induced by U46619 in normal pulmonary arteries. All three tyrosine kinase inhibitors concentration-dependently and completely reversed the spontaneous contraction of hypertensive pulmonary arterial rings unmasked by inhibition of nitric oxide synthase. Acute intravenous administration of imatinib reduced high right ventricular systolic pressure in pulmonary hypertensive rats, with little effect on left ventricular systolic pressure and cardiac output. We conclude that tyrosine kinase inhibitors have potent pulmonary vasodilatory activity, which could contribute to their long-term beneficial effect against pulmonary hypertension. Vascular smooth muscle relaxation mediated via activation of myosin light chain phosphatase (Ca(2+) desensitization) appears to play a role in the imatinib-induced pulmonary vasodilation.Keywords
This publication has 31 references indexed in Scilit:
- Imatinib in Pulmonary Arterial Hypertension Patients with Inadequate Response to Established TherapyAmerican Journal of Respiratory and Critical Care Medicine, 2010
- Thromboxane A2-induced Bi-directional Regulation of Cerebral Arterial TonePublished by Elsevier BV ,2009
- Nilotinib: A second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemiaClinical Therapeutics, 2008
- Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertensionBritish Journal of Pharmacology, 2008
- Physiologic Properties and Regulation of the Actin Cytoskeleton in Vascular Smooth MuscleJournal of Cardiovascular Pharmacology and Therapeutics, 2008
- Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertensionPhysiological Genomics, 2008
- Rho Kinase–Mediated Vasoconstriction Is Important in Severe Occlusive Pulmonary Arterial Hypertension in RatsCirculation Research, 2007
- Therapeutic potential of the epidermal growth factor receptor transactivation in hypertension: a convergent signaling pathway of vascular tone, oxidative stress, and hypertrophic growth downstream of vasoactive G-protein-coupled receptors?This paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.Canadian Journal of Physiology and Pharmacology, 2007
- Discovery and development of sorafenib: a multikinase inhibitor for treating cancerNature Reviews Drug Discovery, 2006
- Treatment of Pulmonary Arterial HypertensionNew England Journal of Medicine, 2004