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Featured researches published by Shiling Hu.


European Journal of Pharmacology | 1993

Activation of K+ channel in vascular smooth muscles by cytochrome P450 metabolites of arachidonic acid

Shiling Hu; Helen S. Kim

Arachidonic acid can be oxidatively metabolized by cytochrome P450 epoxygenase to four regioisomeric epoxyeicosatrienoic acids (5,6-; 8,9-; 11,12-; 14,15-EET), which exhibit vasorelaxant effects in vivo and in vitro with unknown mechanisms. In this study, the patch-clamp method was used to examine the effects of EETs on the Ca(2+)-activated K+ channel in cells from rabbit portal vein, rat caudal artery, guinea pig aorta and porcine coronary artery. In all four cell types, EETs in the bath activated the K+ channel in cell-attached patches by increasing the single channel open-state probability. Potencies of the four EETs did not differ significantly for each cell type. The concentrations for doubling open-state probability were 0.1 microM in portal vein and coronary artery, 0.3-1 microM in aorta and 1-3 microM in caudal artery. In caudal artery cells, K+ channel activation by 3 microM 5,6- and 1 microM 11,12-EET was blocked and reversed by glyburide at 0.5 microM. In aorta, coronary artery, and caudal artery cells, micromolar EETs induced a dose-dependent and reversible augmentation of whole-cell K+ current by 50-120% and a 5-12 mV hyperpolarization. EETs on the cytosolic side of inside-out patches produced little or no potentiation of K+ channels, implying an interaction of receptor-mediated nature. Thus, EETs may promote vasodilation by functioning as endogenous K+ channel openers.


European Journal of Pharmacology | 1991

Dual action of endothelin-1 on the Ca2+-activated K+ channel in smooth muscle cells of porcine coronary artery

Shiling Hu; Helen S. Kim; Arco Y. Jeng

The effects of endothelin-1 (ET-1) on the activity of the large Ca2(+)-activated K+ channel (BK channel) in enzymatically dissociated smooth muscle cells of porcine coronary artery were studied with the cell-attached patch-clamp technique. ET-1 at concentrations between 0.1 and 10 nM potentiated the BK channel activity. This effect was maximal at 1 nM ET-1, resulting in an average of 4.2-fold increase in channel open-state probability as compared with control. ET-1 at concentrations higher than 10 nM produced an irreversible inhibition of the BK channel activity, primarily due to a marked decrease in the channel mean open-time. The activation by lower doses of ET-1, but not the inhibition by higher doses of ET-1, of the BK channel was blocked by 0.1 microM PN 200-110, a Ca2+ channel blocker. The modulation of the BK channel activity in smooth muscle cell membrane may be a possible mechanism for ET-induced vasodilator and vasoconstrictor actions.


European Journal of Pharmacology | 2002

Interaction of nateglinide with KATP channel in β-cells underlies its unique insulinotropic action

Shiling Hu

Nateglinide is a novel insulinotropic agent for the treatment of type 2 diabetes. It is a D-phenylalanine derivative, chemically distinct from repaglinide and sulphonylureas (glyburide or glimepiride). Although each agent is known to stimulate insulin release via the signaling cascade initiated by closure of ATP-dependent K+ (K(ATP)) channels in pancreatic beta-cells, the pharmacological effect of nateglinide is reportedly fast-acting, short-lasting, sensitive to ambient glucose and more resistant to metabolic inhibition. The aim of the present study was to elucidate the molecular mechanism(s) underlying the distinct properties of the insulinotropic action of nateglinide. By using the patch-clamp methods, we comparatively characterized the potency and kinetics of the effect of these agents on K(ATP) channels in rat beta-cells at normal vs. elevated glucose and under physiological condition vs. experimentally induced metabolic inhibition. Our results demonstrated that the mode of the action of nateglinide on K(ATP) current was unique in (a) glucose dependency; (b) increased potency and efficacy under ATP depletion and uncoupling of mitochondrial oxidative phosphorylation than physiological condition; (c) substantially more rapid onset and offset kinetics. The data provide mechanistic rationale for the unique in vivo and ex vivo activity profile of nateglinide and may contribute to reduced hypoglycemic potential associated with excessive insulin secretion.


Drug Development Research | 1997

Novel and potent BK channel openers: CGS 7181 and its analogs

Shiling Hu; Cynthia A. Fink; Helen S. Kim; Rodney W. Lappe

This article discloses the identification of a novel series of the opener of the large‐conductance Ca2+‐activated K+ (BK) channel, CGS 7181, and its analogs, CGS 7184, CGS 7590, and CGS 7725. The stimulatory effects of these compounds on the channels were investigated at whole‐cell and single channel levels using the patch‐clamp technique in single smooth muscle cells from vascular (coronary artery) and non‐vascular (bladder detrusor) tissues of several animal species. With a threshold of submicromolar concentration, extracellularly applied CGS 7181 and CGS 7184 (0.5–50 μM) induced a concentration‐dependent stimulation of the whole‐cell BK current (IBK) and concomitant membrane hyperpolarization in porcine coronary artery cells. The activation was prevented and reversed by TEA, but unaffected by nifedipine, suggesting that the effect was not subsequent to Ca2+ entry. CGS 7184, CGS 7590, and CGS 7725 (0.1–50 μM) produced augmentation of IBK in a similar manner in cells from bladder detrusor of guinea pig, rat, and dog. The onset and offset of the drug actions were slow compared to the known BK channel opener NS004. The effects of compounds applied intracellularly were assessed on single BK channels in inside‐out patches. With threshold concentrations ranging between 0.01 and 0.1 μM, all compounds caused a drastic and reversible increase in channel open‐state probability. The onset and washout of drug actions were considerably faster in inside‐out patches than in whole cells. It is concluded that CGS 7181 and its analogs directly open BK channels from either side of the membrane with a combination of potency and efficacy superior to any known BK channel openers, and an internal site of action best accounts for the results of our studies. Drug Dev. Res. 41:10–21, 1997.


Naunyn-schmiedebergs Archives of Pharmacology | 1995

Evidence that BKCa channel activation contributes to K+ channel opener induced relaxation of the porcine coronary artery

Joseph L. Balwierczak; Christine M. Krulan; Helen S. Kim; Dominick DelGrande; George B. Weiss; Shiling Hu

The rank order of potency of a series of benzopyran and cyanoguanidine K+ channel openers (KCOs) for causing relaxation of the PGF2α-precontracted porcine coronary artery was determined. Glyburide, an inhibitor of KATP channels, showed an apparent competitive inhibition of the vasorelaxant activity of the KCOs. The pA2 values of glyburide when cromakalim and CGP 14877 (P1060) were used as vasorelaxants were 7.66 and 7.83, respectively. Charybdotoxin (40 nM), an inhibitor of BKCa channels, also caused a significant inhibition of the cromakalim mediated relaxation of the porcine coronary artery. In order to clarify the site of action of these KCOs, we identified a K+ channel current in single porcine coronary arterial cells and measured channel activity in the presence of these compounds. The prominent K+ ion current in these cells had characteristics typical of the conventional large Ca2+-activated K+ channel BKCa present in other smooth muscle cells. Using symmetrical K+ concentrations, the channel had a conductance of 214 pS and was found to be sensitive to [Ca2+]i and membrane potential. The KCOs were found to reversibly increase the open probability (Po) of the channel without changing channel conductance. The potency of the KCOs to increase K+ channel opening was similar to the potency of these compounds to cause coronary artery relaxation. These results indicate that the porcine coronary artery contains the BKCa channel and that this channel, along with other types of K+ channels (KATP), mediate the vasorelaxant effects of K+ channel openers.


Neurochemistry International | 1991

A comparison of the binding of endothelin to various tissues from spontaneously hypertensive and Wistar-Kyoto rats.

Arco Y. Jeng; Paula Savage; Shiling Hu

The binding affinities for endothelin-1 and endothelin-3 to membrane preparations of various tissues of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats were compared by competition binding of the peptides with [(125)I]endothelin-1. Endothelin-1 binding data obtained using membrane preparations from brain, heart, kidney, liver, lung and spleen of both strains were better fit with a one-site model. The brain tissue demonstrated the highest affinity for endothelin-1 in both strains with the same IC(50) of 0.11 nM, while the kidney and lung tissues showed the lowest affinities in both strains with IC(50) values ranged between 1.4 and 4.1 nM. Only the kidney tissues of these two strains showed a statistically significant difference in binding affinities for endothelin-1; the IC(50) values were 1.4 +/- 0.1 nM (mean +/- SE, n = 3) and 3.2 +/- 0.4 nM (n = 4) for the spontaneously hypertensive and normotensive rats, respectively. Endothelin-3 binding data obtained using membrane preparations from brain, kidney and lung of both strains were also better fit with a one-site model. In contrast, a two-site model was more suitable for analyzing endothelin-3 binding results obtained using membrane preparations from heart, liver and spleen of both strains. Again, only the kidney tissues of the two strains showed a statistically significant difference in binding affinities for endothelin-3. The ratio of IC(50) value of the major endothelin-3 binding site to that of endothelin-1 in each tissue varied from approx. 1.5 in brain, kidney and liver to greater than 500 in heart and spleen of both strains. Scatchard analysis of saturation binding data showed that [(125)I]endothelin-1 bound to a single class of binding sites in brain, heart, liver and spleen of both rat strains and in kidney of the spontaneously hypertensive rats. Specific binding to the kidney membrane preparation of the normotensive rats was not saturable at radioligand concentrations up to about 2 nM. These results suggest that the tissues of both strains investigated have different affinities as well as different selectivities for endothelin-1 and endothelin-3. Furthermore, kidney is the only tissue examined which showed higher binding affinity in the spontaneously hypertensive rats than that of the normotensive ones.


European Journal of Pharmacology | 2001

Effect of insulinotropic agent nateglinide on Kv and Ca2+ channels in pancreatic β-cell

Shiling Hu; Shuya Wang

Abstract Novel insulinotropic agent nateglinide stimulates insulin via binding to sulfonylurea receptor and closing the ATP-dependent K + (K ATP ) channels in pancreatic β-cells, leading to an increase in [Ca 2+ ] i for exocytosis. The voltage-dependent Ca 2+ channel and the delayed rectifier K + (Kv) channels are also present in β-cells and their activities determine the configuration of action potential and hence contribute to the regulation of [Ca 2+ ] i and insulin secretion. This study, by using the patch-clamp method in whole cell configuration, comparatively characterized the direct effects of sulfonylurea receptor ligands including nateglinide, glyburide, and repaglinide on Kv and Ca 2+ channels. Each agent inhibited Kv currents in a concentration-dependent manner with effective concentration range two to three orders higher than that for blocking K ATP channels. A marginal stimulation of Ca 2+ current was observed with all drugs, while repaglinide at concentration greater than 300 nM inhibited Ca 2+ current. The direct effects of these antidiabetic agents on Kv and Ca 2+ channels may act concertedly with their primary action on K ATP channels in regulating [Ca 2+ ] i and the stimulus–secretion coupling.


European Journal of Pharmacology | 1996

On the mechanism of the differential effects of NS004 and NS1608 in smooth muscle cells from guinea pig bladder.

Shiling Hu; Helen S. Kim


Journal of Pharmacology and Experimental Therapeutics | 1997

Modulation of ATP-Sensitive and Large-Conductance Ca++-Activated K+ Channels by Zeneca ZD6169 in Guinea Pig Bladder Smooth Muscle Cells

Shiling Hu; Helen S. Kim


European Journal of Pharmacology | 1997

Activation of BKCa channel via endothelin ETA receptors in porcine coronary artery smooth muscle cells

Shiling Hu; Helen S. Kim; Paula Savage; Arco Y. Jeng

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