PGE2 action in human coronary artery smooth muscle:: Role of potassium channels and signaling cross-talk

Cyclic AMP-stimulating agents are powerful vasodilators, but our knowledge of the signal transduction mechanisms of these agents, particularly in human arteries, is limited. We now report direct molecular effects of prostaglandin E-2 (PGE(2)) on cultured human coronary artery smooth smooth muscle cells (HCASMC). Patch-clamp studies revealed that 10 muM PGE(2) opens a high-conductance (similar to 200 pS), calcium-stimulated potassium (BKCa) channel in intact HCASMC. In contrast, PGE2 had no direct effect on channels in cell-free patches, indicating involvement of a soluble second messenger. Enzyme immunoassay demonstrated that PGE(2) enhances production of cAMP in HCASMC, but does not increase [cGMP]. Furthermore, forskolin, CPT-cAMP, or CPT-cGMP mimicked the stimulatory effect of PGE(2) on BKCa channel activity. Interestingly, the response to PGE(2) was unaffected by inhibiting the cAMP-dependent protein kinase, but was antagonized by inhibitors of the cGMP-dependent protein kinase (PKG). Furthermore, cAMP-stimulated PKG activity mimicked the effect of PGE(2). These studies suggest a novel PGE(2) action in human arteries: opening of BKCa channels via cAMP cross-activation of PKG in HCASMC. It is proposed that this signaling mechanism may mediate the vasodilatory response to cAMP-dependent agents in the human coronary and other vascular beds. Copyright (C) 2002 S. Karger AG, Basel.