Na+ channels as sites of action of the cardioactive agent DPI 201-106 with agonist and antagonist enantiomers.

Romey, Georges; Quast, Ulrich; Pauron, David; Frelin, Christian; Renaud, Jean‐François; Lazdunski, Michel

doi:10.1073/pnas.84.3.896

Cited by 60 publications

(45 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DPI-enantiomers that interact with a common site in the ␣ subunit of VGSC (45) modulate differently its voltage-dependent activation (45). Only the DPI R enantiomer, which prevents the activation of VGSC (45), prevented both the depolarization- (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…6B). [␣ 32 P]GTPAA-Depolarization-induced photoaffinity labeling of G␣ o -proteins with [␣ 32 P]GTPAA was prevented by the R enantiomer of the cardiotonic and antiarrhythmic drug DPI 201-106 (10 M), which prevents activation of VGSC (45) (Fig. 7).…”

Section: Depolarization-induced Activation Of G O -Proteins Was Not Mmentioning

confidence: 99%

“…7, A and B). In contrast, the neurotoxin batrachotoxin (46) and the S-enantiomer of DPI (45), both of which prolong the activation of VGSC (45-47) although they share a common binding site with DPI R-enantiomer on the ␣subunit of VGSC (45), did not interfere with the depolarization-induced photoaffinity labeling of G␣ o -proteins or with the coupling of G-proteins to muscarinic receptors (12). These findings may suggest that voltage-induced activation of VGSC is essential for depolarization-induced activation of G o -proteins.…”

Section: Depolarization-induced Activation Of G O -Proteins Was Not Mmentioning

confidence: 99%

See 2 more Smart Citations

Activation of Go-proteins by Membrane Depolarization Traced by in Situ Photoaffinity Labeling of Gαo-proteins with [α32P]GTP-azidoanilide

Anis¹,

Nürnberg²,

Visochek³

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

GTP-binding trimeric proteins have been implicated in signal transduction from receptors in the cell membrane to intracellular effectors and ion channels in a variety of cells (1-5). The mechanism involves signal-induced G-protein activation initiated by an exchange of GDP for GTP on the ␣ subunit of the protein (5-7). Subsequent GTPase activity of the G␣ subunit converts the activated G-proteins into their inactive, GDPbound state (7). Activation of G-proteins has been induced experimentally by stimulation of G-protein-coupled receptors in the cell membrane (2,3,8,9). Evidence indicating activation of G-proteins in response to membrane depolarization were previously observed in brain stem synaptoneurosomes (10 -12).G␣ o -proteins are widely distributed in the central nervous system (15-17). Three subtypes showing marked homology but exhibiting functional differences have been identified (13,14,18). The G␣ o1 subtype appears to be involved in the coupling of muscarinic receptors to Ca ϩ2 channels, and the G␣ o2 subtype mediates inhibition of Ca ϩ2 current activated by somatostatin receptors (19). The function of the G␣ o3 subtype is not clear (14). Phospholipase C activation mediated by activation of G oproteins has been demonstrated in the cell-free system (20), and G o -protein-mediated activation of protein kinase C has been observed in Chinese hamster ovary (CHO) cells (21).In the present study, in situ photoaffinity labeling with [␣ 32 P]GTPAA 1 (22, 23) indicated a depolarization-induced accelerated exchange of GDP for [␣ 32 P]GTPAA in G␣ o1 -and G␣ o3 -proteins, implying a depolarization-induced activation of these G o -proteins. [␣ 32 P]-GTPAA was introduced into transiently permeabilized synaptoneurosomes as described before (10). Unlike the endogenously bound guanine nucleotides, [␣ 32 P]GT-PAA, covalently bound to G␣-proteins by photoaffinity labeling, was not displaced during SDS-polyacrylamide gel electrophoresis, providing a possible tool for identification of in situ activated G-proteins.In view of findings indicating a reciprocal influence of depolarization-induced activation of VGSC and uncoupling of Gproteins from muscarinic receptors (12, 24, 25), we examined the possibility that VGSC can be involved in depolarizationinduced activation of G␣ o -proteins. Our results indicated that depolarization-induced activation of G o -proteins can be prevented by preventing VGSC activation. In addition, in depolarized brain-stem and cortical synaptoneurosomes, the ␣ subunit of VGSC cross-linked most efficiently with G␣ o -proteins. In isolated synaptoneurosomal membranes, VGSC-␣ subunit cross-linked most efficiently with GDP␤S-bound rather than GTP␥S-bound G␣ o -proteins. These findings suggest repeated

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Depolarization-induced Activation Of G O -Proteins Was Not Mmentioning

confidence: 99%

Section: Depolarization-induced Activation Of G O -Proteins Was Not Mmentioning

confidence: 99%

See 1 more Smart Citation

Activation of Go-proteins by Membrane Depolarization Traced by in Situ Photoaffinity Labeling of Gαo-proteins with [α32P]GTP-azidoanilide

Anis¹,

Nürnberg²,

Visochek³

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Each of the compounds used was the racemic mixture of a pair of enantiomers with opposing actions on INa (Scholtysik et al, 1986;Romey et al, 1987;Wang et al, 1990) and similar effects on ICa (see Ravens et al, 1991 for DPI 201-106 enantiomers; no data available for BDF 9148 enantiomers). Therefore, different contributions of the enantiomers in each racemic mixture to the various effects on membrane currents could also explain our observations.…”

Section: Effect Of Bdf 9148 On Sodium Currentmentioning

confidence: 99%

Characterization of the effects of the new inotropic agent BDF 9148 in isolated papillary muscles and myocytes of the guinea‐pig heart

Ravens¹,

Wettwer²,

Pfeifer³

et al. 1991

British J Pharmacology

View full text Add to dashboard Cite

1 The cardiotonic agent BDF 9148 (4-[3'-(1"-benzhydryl-azetidine-3"-oxy)-2'-hydroxypropoxy]-lHindole-2-carbonitrile) is structurally related to -(4"-benzhydryl-1"-piperazinyl)-2'-hydroxypropoxy]-1H-indole-2-carbonitrile) which is known to modify cardiac sodium channels. In guinea-pig papillary muscles, both compounds increase force of contraction with similar concentrationresponse curves. Like DPI 201-106, BDF 9148 prolongs the action potential duration in a tetrodotoxinsensitive manner. With high concentrations (>3 gM), however, the action potential duration shortens again. In order to elucidate the underlying changes in membrane currents, we have investigated the effects of BDF 9148 in isolated ventricular myocytes of the guinea-pig heart. 2 In isolated cells, a concentration of 1 M BDF 9148 prolonged the action potential duration and markedly enhanced unloaded cell shortening, indicating that the procedure of cell isolation does not abolish the effect of the drug. 3 Membrane currents were studied with the single electrode voltage clamp technique. With clamp steps from -80 mV to -40 mV, BDF 9148 (1 UM) induced a slowly decaying inward current which was suppressed by tetrodotoxin. Therefore, like DPI 201-106, BDF 9148 slows the inactivation of the sodium channels. 4 In order to quantify the effects of BDF 9148 and DPI 201-106 on sodium current inactivation, we have measured the inward current amplitude still present at 100ms after a depolarizing clamp step from -80 mV to -30 mV. Both drugs increased this current component in a concentration-dependent manner; however, BDF 9148 had a larger effect in the low concentration range. 5 The calcium current was inhibited by BDF 9148 and DPI 201-106 in a concentration-dependent manner; the pD2 values were 5.70 and 5.95, respectively. 6 The two compounds are thought to produce similar positive inotropic effects by imposing a sodium load on the muscle cells via modification of the sodium channels. The differences in action potential duration could be due to different contributions of ionic currents other than sodium or calcium currents and of pump and exchange currents. At present, there is not sufficient data to identify clearly distinct current components responsible for the differences in action potential prolongation.

show abstract

“…One strategy has been the development of Na ϩ channel enhancers that prolong the open state of Na ϩ channels, increasing net Na ϩ influx and the activity of reverse mode Na ϩ /Ca 2ϩ exchange (for review, see Steinberg et al, 1998). This leads to a decrease in net Ca 2ϩ efflux and increases in intracellular free Ca 2ϩ (Romey et al, 1987;Scholtysik, 1989). Sodium channel enhancers have been shown to elicit positive inotropic effects in isolated cardiac tissues from experimental animals and from human papillary muscles obtained from normal as well as failing hearts (Flesch et al, 1996;Schwinger et al, 1996;Mü ller-Ehmsen et al, 1997).…”

mentioning

confidence: 99%

Combined Inotropic and Bradycardic Effects of a Sodium Channel Enhancer in Conscious Dogs with Heart Failure: A Mechanism for Improved Myocardial Efficiency Compared with Dobutamine

Shen

Gill²,

Jones³

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

We compared the cardiac inotropic, chronotropic, and myocardial O 2 consumption (MVO 2 ) responses to the sodium (Na ϩ ) channel enhancer, LY341311 [(S)-4-[3-[[1-(diphenylmethyl)-3-azetidinyl]oxy]-2-hydroxypropoxy]-1H-indole-2-carbonitrile monohydrate], with the ␤-receptor agonist dobutamine in conscious dogs with heart failure. Heart failure was induced in chronically instrumented dogs by right ventricular pacing at 240 beats per minute for 3 to 4 weeks. LY341311 (10 -100 g/kg/min i.v.) dose dependently increased cardiac contractile function as reflected, at the highest dose, by increases in left ventricular dP/dt max (55 Ϯ 7%), and fractional shortening (62 Ϯ 9%), accompanied by increases in cardiac stroke work (111 Ϯ 18%) and minute work (34 Ϯ 10%) and decreases in heart rate (33 Ϯ 4%). Dobutamine (2-15 g/kg/min i.v.) increased contractile responses to a similar degree but also increased heart rate (15 Ϯ 5%) at the highest dose. Complete ganglionic blockade with hexamethonium and atropine or with hexamethonium alone abolished the bradycardic effect but not the inotropic response to LY341311. At similar levels of inotropic response, dobutamine (10 g/kg/min) increased MVO 2 by 23 Ϯ 7% (P Ͻ 0.05), whereas LY341311 (100 g/kg/min) had no effect. In the presence of left atrial pacing at a constant heart rate and at matched contractile work, MVO 2 was increased by LY341311 to the same extent as dobutamine. These data indicate that autonomically mediated bradycardia produced by LY341311 contributes to a favorable net metabolic effect on myocardial O 2 utilization in the failing heart while providing inotropic support comparable to a ␤-receptor-mediated agonist.A variety of therapeutic strategies have been applied to augment the depressed left ventricular function of heart failure, particularly during periods of acute decompensation (Packer, 1988;Rahimtoola, 1989;Shipley and Hess, 1995). Current clinically available inotropic agents that act via elevation of cyclic AMP, such as dobutamine and phosphodiesterase inhibitors; are associated with tachycardia, significant changes in preload or afterload or increases in myocardial O 2 consumption (MVO 2 ), and decreases in myocardial mechanical efficiency (Katz, 1986;Simaan et al., 1988). Recently, there has been interest in agents that either increase myofibrillar Ca 2ϩ availability or directly sensitize myocardial cells to Ca 2ϩ without the participation of cAMP (Ruegg, 1986;Doggrell et al., 1994;Mathew and Katz, 1998). One strategy has been the development of Na ϩ channel enhancers that prolong the open state of Na ϩ channels, increasing net Na ϩ influx and the activity of reverse mode Na ϩ /Ca 2ϩ exchange (for review, see Steinberg et al., 1998). This leads to a decrease in net Ca 2ϩ efflux and increases in intracellular free Ca 2ϩ (Romey et al., 1987;Scholtysik, 1989). Sodium channel enhancers have been shown to elicit positive inotropic effects in isolated cardiac tissues from experimental animals and from human papillary muscles obtained from normal as well as...

show abstract

Na+ channels as sites of action of the cardioactive agent DPI 201-106 with agonist and antagonist enantiomers.

Cited by 60 publications

References 26 publications

Activation of Go-proteins by Membrane Depolarization Traced by in Situ Photoaffinity Labeling of Gαo-proteins with [α32P]GTP-azidoanilide

Activation of Go-proteins by Membrane Depolarization Traced by in Situ Photoaffinity Labeling of Gαo-proteins with [α32P]GTP-azidoanilide

Characterization of the effects of the new inotropic agent BDF 9148 in isolated papillary muscles and myocytes of the guinea‐pig heart

Combined Inotropic and Bradycardic Effects of a Sodium Channel Enhancer in Conscious Dogs with Heart Failure: A Mechanism for Improved Myocardial Efficiency Compared with Dobutamine

Contact Info

Product

Resources

About