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1 Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: robert.moreland{at}drexel.edu.
Regulation of smooth muscle contraction involves a number of signaling mechanisms that include both kinase and phosphatase reactions. The goal of this study was to determine the role of one such kinase, phosphatidylinositol 3-kinase (PI 3-kinase) in vascular smooth muscle excitation contraction coupling. Using intact medial strips of the swine carotid artery, we found that inhibition of PI 3-kinase by LY 294002 resulted in a concentration dependent decrease in contractile response to both agonist stimulation and membrane depolarization dependent contractions and a decrease in Ca2+ dependent myosin light chain (MLC) phosphorylation, the primary step in the initiation of smooth muscle contraction. Inhibition of PI 3-kinase also depressed phorbol dibutyrate induced contractions which are not dependent on either Ca2+ or MLC phosphorylation, but are dependent on protein kinase C. To determine the Ca2+ dependent site of action of PI 3-kinase, we determined the effect of several inhibitors of calcium metabolism on LY 294002 dependent inhibition of contraction. These inhibitors included nifedipine, SK&F 96365, and caffeine. Only SK&F 96365 blocked the LY 294002 dependent inhibition of contraction. Interestingly, all compounds blocked the LY 294002 dependent inhibition of MLC phosphorylation. Our results suggest that activation of PI 3-kinase is involved in a Ca2+ and MLC phosphorylation independent pathway for contraction likely to involve protein kinase C. In addition, our results also suggest that activation of PI 3-kinase is involved in Ca2+-dependent signaling at the level of the receptor operated calcium channels.
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