Interaction of the Cardiotonic Agent DPI 201-106 with Cardiac Ca2+ Channels

Holck, Mark; Osterrieder, Wolfgang

doi:10.1097/00005344-198804000-00015

Cited by 21 publications

(16 citation statements)

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“…(Trautwein, 1973). This point needs to be addressed in a further carefully designed study, because there is some evidence from the literature, that DPI 201-106 does indeed decrease IK1 (Holck & Osterrieder, 1988 In addition, the increased intracellular Na' concentration may modify physiological pump and exchanger currents which also affect the action potential duration. With BDF 9148, the (Na', K+)-ATPase could contribute more outwardly directed pump current and therefore shorten the APD.…”

Section: Effect Of Bdf 9148 On Sodium Currentmentioning

confidence: 96%

“…also inhibits the calcium current (ICa) as shown by its effects on slow action potentials in partially depolarized papillary muscles (Buggisch et al, 1985;Scholtysik et al, 1985) and by voltage clamp experiments in guinea-pig cardiomyocytes (Holck & Osterrieder, 1988;Pfeifer et al, 1989). The concentration which blocks calcium channels is one order of magnitude higher than that required for the positive inotropic effect .…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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Section: Effect Of Bdf 9148 On Sodium Currentmentioning

confidence: 96%

Section: Introductionmentioning

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

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“…Thus, the Na + channel activator veratridine (VII) interacts at 1,4-dihydropyridine-sensitive Ca2+ channel^'^^,"^ and the Na + channel-activating, cardiotonic agent DPI 201-106 (VIII) interacts with Ca2+ channels. 120 Additionally, 1,Cdihydropyridines interact stereoselectively with Na + channels121J22; of particular interest, ( -) Bay K 8644, the L-type Ca2+ channel activator, is also an activator of Na+ channels.…”

Section: <--Coohmentioning

confidence: 99%

Ca²⁺ channel ligands: Structure‐function relationships of the 1,4‐dihydropyridines

Triggle

Langs

Janis

1989

Medicinal Research Reviews

267

131

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“…Ca2"-channel blocking activity (Hof & Hof, 1985;Takahashi et al, 1987;Siegl et al, 1988;Holck & Osterrieder, 1988). Direct evidence for inhibition of reconstituted Ca2+-channels in Drosophila brain membranes by DPI 201-106 is missing.…”

Section: Photoaffinity Labelling Experimentsmentioning

confidence: 99%

Very high affinity interaction of DPI 201‐106 and BDF 8784 enantiomers with the phenylalkylamine‐sensitive Ca²⁺‐channel in Drosophila head membranes

Glossmann

Zech

Striessnig

et al. 1991

British J Pharmacology

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1 Piperazinylindoles BDF 8784), drugs known to act on voltage-dependent Na+-channels, bind with very high affinity to a Ca2+-channel-associated phenylalkylamine receptor in Drosophila melanogaster head membranes. These compounds and (+)-tetrandrine, a naturally occurring Ca2 +-antagonist, were the most selective inhibitors for phenylalkylamine-labelled Drosophila Ca2 +-channels compared to mammalian L-type Ca2 +-channels. 2 Replacement of the cyano group by a methyl group in ( + )-DPI 201-106 ((+)-BDF 8784) increases the IC50 value for inhibition of phenylalkylamine labelling of Drosophila Ca2+-channels from 0.29 to 2.1 nm but decreases the IC50 value for inhibition of phenylalkylamine labelling of mammalian skeletal muscle Ca2 +-channels from 3480 to 49 nm. 3 DPI 201-106 enantiomers completely block (at 0.1 M) phenylalkylamine photolabelling of a 136 K polypeptide in Drosophila head membranes whereas 10pM aconitine or lidocaine are without effect.4 Assessment of the Ca2+-antagonist effects of the substituted DPI 201-106 enantiomers in K+-depolarized taenia strips from guinea-pig caecum yielded pA2 values of 6.33 + 0.07 for (-)-BDF 8784 and 6.99 + 0.17 for (+)-BDF 8784, respectively. 5 Piperazinylindoles, previously believed to act nonspecifically on voltage-dependent mammalian L-type Ca2+-channels, therefore have stereoselectivity for a novel binding site and chemical selectivity unrelated to local anaesthetic activity. 6 It is proposed that a very high affinity piperazinylindole-selective site is coupled to the phenylalkylamine receptor of Drosophila Ca2+-channels. These sites are still present on mammalian L-type Ca2+-channels but have lower affinity and/or are less tightly coupled to phenylalkylamine receptors on the cl-subunit.

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Interaction of the Cardiotonic Agent DPI 201-106 with Cardiac Ca2+ Channels

Cited by 21 publications

References 0 publications

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

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

Ca²⁺ channel ligands: Structure‐function relationships of the 1,4‐dihydropyridines

Very high affinity interaction of DPI 201‐106 and BDF 8784 enantiomers with the phenylalkylamine‐sensitive Ca²⁺‐channel in Drosophila head membranes

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Interaction of the Cardiotonic Agent DPI 201-106 with Cardiac Ca2+ Channels

Cited by 21 publications

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

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

Ca2+ channel ligands: Structure‐function relationships of the 1,4‐dihydropyridines

Very high affinity interaction of DPI 201‐106 and BDF 8784 enantiomers with the phenylalkylamine‐sensitive Ca2+‐channel in Drosophila head membranes

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Ca²⁺ channel ligands: Structure‐function relationships of the 1,4‐dihydropyridines

Very high affinity interaction of DPI 201‐106 and BDF 8784 enantiomers with the phenylalkylamine‐sensitive Ca²⁺‐channel in Drosophila head membranes