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      PGE 2 Action in Human Coronary Artery Smooth Muscle: Role of Potassium Channels and Signaling Cross-Talk

      a,b , a,b , a

      Journal of Vascular Research

      S. Karger AG

      cAMP, Human coronary artery, PGE2 , PKG, BKCa channel

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          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<sub>2</sub> (PGE<sub>2</sub>) on cultured human coronary artery smooth muscle cells (HCASMC). Patch-clamp studies revealed that 10 µ M PGE<sub>2</sub> opens a high-conductance (∼200 pS), calcium-stimulated potassium (BK<sub>Ca</sub>) channel in intact HCASMC. In contrast, PGE<sub>2</sub> had no direct effect on channels in cell-free patches, indicating involvement of a soluble second messenger. Enzyme immunoassay demonstrated that PGE<sub>2</sub> enhances production of cAMP in HCASMC, but does not increase [cGMP]. Furthermore, forskolin, CPT-cAMP, or CPT-cGMP mimicked the stimulatory effect of PGE<sub>2</sub> on BK<sub>Ca</sub> channel activity. Interestingly, the response to PGE<sub>2</sub> 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<sub>2</sub>. These studies suggest a novel PGE<sub>2</sub> action in human arteries: opening of BK<sub>Ca</sub> 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.

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          Most cited references 6

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            Prostaglandin E2 stimulates a Ca2+-dependent K+ channel in human erythrocytes and alters cell volume and filterability.

            To understand the mechanism by which human red blood cells (RBCs) contribute to hemostasis and thrombosis, we have examined the effects of metabolites released by activated platelets on intact RBCs. Prostaglandin E2 (PGE2), a signal molecule produced by activated platelets, was observed to lower the filterability of human erythrocytes by approximately 30% at 10(-10) M. PGE2 also caused a reduction in mean cell volume of approximately 10%. The shrinkage of red cells after PGE2 treatment was confirmed by documenting a decrease in osmotic fragility and an increase in cell density following exposure to the hormone. Careful analysis, however, revealed that only approximately 15% of the erythrocytes responded to stimulation with PGE2. Examination of the cause of cell shrinkage showed that induction of a PGE2-stimulated K+ efflux pathway leading to rapid loss of cellular K+ was responsible. The PGE2-stimulated K+ loss was also observed to be Ca2+-dependent, suggesting the possible involvement of the Gardos channel. Gardos channel participation was supported by the observation that two Gardos channel inhibitors, charybdotoxin and clotrimazole, independently blocked the PGE2-stimulated K+ efflux. Further evidence for Gardos channel activation came from experiments aimed at characterizing the efflux pathway followed by the obligatory counterion. Thus, K+ efflux was readily stimulated even when NO3- was substituted for Cl-, suggesting that neither KCl cotransport nor Na/K/2Cl cotransport plays a prominent role in the PGE2-induced cell shrinkage. Further, the anion transporter band 3 was implicated as the counterion efflux route, since DIDS inhibited the PGE2-stimulated cell volume change without blocking the change in membrane potential. Taken together, we propose that release of PGE2 by activated platelets constitutes part of a mechanism by which activated platelets may recruit adjacent erythrocytes to assist in clot formation.
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              Participation of prostaglandin E2 in the endothelial protective effect of ischaemic preconditioning in isolated rat heart.

              To assess whether the protective effect of ischaemic preconditioning (IPC) on endothelial function in coronary arteries of the rat involves prostaglandins. Isolated rat hearts perfused under constant flow conditions were exposed to 30 min of partial ischaemia (flow-rate 1 ml/min) followed by 20 min of reperfusion, after which coronaries were precontracted with U-46619 0.1 microM, and the coronary response to the endothelium-dependent vasodilator, serotonin (5-HT, 10 microM), was compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 microM). Prostaglandin production was blocked with a perfusion of indomethacin 10 microM started 15 min before IPC or a corresponding sham period and stopped just before the 20-min reperfusion period. In untreated hearts, ischaemia diminished selectively 5-HT-induced vasodilatation, compared to sham hearts. The vasodilatation by SNP was unaffected after ischaemia and reperfusion. IPC (5 min of zero-flow ischaemia followed by 10 min reperfusion before the 30-min partial ischaemia) preserved the vasodilatation produced by 5-HT. Enzymeimmunoassays showed an increased production of PGE2 in the IPC group. Treatment of hearts with indomethacin blocked the protective effect of IPC on the vasodilatation produced by 5-HT and decreased the production of PGE2. A 5-min perfusion with 3 nM PGE2 started 15 min before the partial ischaemia, protected the endothelium. This was blocked by 1 microM chelerythrine, but not by 0.3 microM glibenclamide. These results suggest that IPC affords protection to endothelial function in coronary arteries of the rat partially via the release of PGE2. Under our experimental conditions, the protective effect of PGE2 is mediated by PKC.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2002
                17 January 2003
                : 39
                : 6
                : 477-488
                aDepartment of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Ga., USA, and bDepartment of Physiology, Dalian Medical University, Dalian, People’s Republic of China
                67201 J Vasc Res 2002;39:477–488
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 10, References: 30, Pages: 12
                Research Paper


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