Effects of phosphoinositide 3-kinase on endothelin-1-induced activation of voltage-independent Ca2+ channels and vasoconstriction

• Published in: Biochemical pharmacology 2004-07, Vol.68 (2), p.215-221
• Main Authors: KAWANABE, Yoshifumi, HASHIMOTO, Nobuo, MASAKI, Tomoh
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Androstadienes - pharmacology; Animals; Basilar Artery - cytology; Biological and medical sciences; Calcium - metabolism; Calcium Channels - metabolism; Chromones - pharmacology; Drug Interactions; Endothelin-1 - pharmacology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Enzyme Inhibitors - pharmacology; Imidazoles - pharmacology; In Vitro Techniques; Isoquinolines - pharmacology; Medical sciences; Morpholines - pharmacology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - pharmacology; Rabbits; Vasoconstriction - drug effects; Vasoconstriction - physiology
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2004.03.025

We recently demonstrated that endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channel (designated NSCC-1 and NSCC-2) and a store-operated Ca(2+) channel (SOCC) in rabbit basilar artery (BA) vascular smooth muscle cells (VSMCs). In this study, we investigated the effects of phosphoinositide 3-kinase (PI3K) on ET-1-induced activation of these channels and BA contraction by using PI3K inhibitors, wortmannin and LY 249002. To determine which Ca(2+) channels are activated via PI3K, monitoring of intracellular Ca(2+) concentration was performed. Role of PI3K in ET-1-induced vasoconstriction was examined by tension study using rabbit BA rings. Only NSCC-1 was activated by ET-1 in wortmannin- or LY 294002-pretreated VSMCs. In contrast, addition of these drugs after ET-1 stimulation did not suppress Ca(2+) influx. Wortmannin inhibited the ET-1-induced contraction of rabbit BA rings that depends on the Ca(2+) influx through NSCC-2 and SOCC. The IC(50) values of wortmannin for the ET-1-induced Ca(2+) influx and vasoconstriction were similar to those for the ET-1-induced PI3K activation. These results indicate that (1) NSCC-2 and SOCC are stimulated by ET-1 via PI3K-dependent cascade, whereas NSCC-1 is stimulated via PI3K-independent cascade; (2) PI3K is required for the activation of the Ca(2+) entry, but not for its maintenance; and (3) PI3K is involved in the ET-1-induced contraction of rabbit BA rings that depends on the extracellular Ca(2+) influx through SOCC and NSCC-2.