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Phosphatidylinositol 3-kinase modulates vascular smooth muscle contraction by calcium and myosin light chain phosphorylation-independent and -dependent pathways

Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102

Submitted 29 May 2003 ; accepted in final form 3 October 2003

Regulation of smooth muscle contraction involves a number of signaling mechanisms that include both kinase and phosphatase reactions. The goal of the present study was to determine the role of one such kinase, phosphatidylinositol (PI)3-kinase, in vascular smooth muscle excitation-contraction coupling. Using intact medial strips of the swine carotid artery, we found that inhibition of PI3-kinase by LY-294002 resulted in a concentration-dependent decrease in the 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 PI3-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 PI3-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 PI3-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 PI3-kinase is involved in Ca²⁺-dependent signaling at the level of receptor-operated calcium channels.

LY-294002; phorbol dibutyrate; SK&F-96365; caffeine; nifedipine; Akt

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