Correlation of nitrendipine and bay k 8644 binding to isolated canine heart sarcolemma with their pharmacological effects on the canine heart

Vághy, Pál L.; Grupp, Ingrid L.; Grupp, Günter; Balwierczak, Joseph L.; Williams, Judith S.; Schwartz, Arnold

doi:10.1016/0014-2999(84)90273-5

Cited by 27 publications

(7 citation statements)

References 4 publications

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“…The calcium agonistic effects of these compounds, prominent in low concentrations (10-9_10-7 mol/1), decline at higher concentrations. In isolated heart preparations there are even antagonistic effects at high concentrations characterized by negative inotropic actions (Vaghy et al 1984;Thomas et al 1984;Schramm et al 1985). Thus, potentiation of antinociceptive effects of the g-agonist fentanyl correlates strongly with the calcium-antagonistic effects of dihydropyridine derivatives, whereas their calcium agonistic effects result in an antagonism against its antinociceptive actions.…”

Section: Discussionmentioning

confidence: 96%

Calcium agonists and antagonists of the dihydropyridine type: Antinociceptive effects, interference with opiate-?-receptor agonists and neuropharmacological actions in rodents

Hoffmeister

Tettenborn

1986

Psychopharmacology

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The calcium antagonist dihydropyridine derivative nimodipine and its enantiomers BAY N 5247, BAY N 5248, as well as BAY R 4407 (calcium antagonist (+)-enantiomer of the calcium agonist dihydropyridine BAY K 8644) do not exert antinociceptive effects in the rat as measured by the vocalization test in doses up to 100 micrograms/kg IV, and in the mouse as measured by the hot plate test in oral doses up to 100 mg/kg. The calcium agonists BAY K 8644 and BAY R 5417 ((-)-enantiomer of BAY K 8644) are also ineffective in the rat vocalization test but BAY K 8644 increases reaction time in the hot plate test (mouse) dose-dependently (1-10 mg/kg PO). mu-receptor agonist (fentanyl) antinociceptive effects are potentiated by simultaneous IV administration of the calcium antagonists, the (-)-enantiomer of nimodipine BAY N 5248 being the most potent. This applies for the rat (vocalization test) and the mouse (hot plate test). The influence on fentanyl antinociception in the rat of the calcium agonist BAY K 8644 and its (-)-enantiomer BAY R 5417 is biphasic: low doses attenuate, high doses potentiate fentanyl antinociception. In the mouse (hot plate test) antinociceptive, effects of BAY K 8644 plus fentanyl are less than additive, indicating that the calcium agonist decreases fentanyl effects. The relative potency of calcium antagonists in potentiation of fentanyl antinociception correlates with their relative potency as calcium antagonists as measured by receptor binding studies, effects on vascular and cardiac muscle, and with their neuropharmacological actions (anticonvulsive effects, inhibition of balance and spontaneous motility as well as tranquilizing effects in the mouse).(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 96%

Calcium agonists and antagonists of the dihydropyridine type: Antinociceptive effects, interference with opiate-?-receptor agonists and neuropharmacological actions in rodents

Hoffmeister

Tettenborn

1986

Psychopharmacology

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“…This model does not deal with the possible contribution of a second DHP binding site with low affinity and large capacity which has been found in cardiac s.l. and other membrane preparations (Belleman et al 1981;Marsh, Loh, Lachance, Barry & Smith, 1983;Vaghy, Grupp, Grupp, Balwierczak, Williams & Schwartz, 1984). An effect on Ca channels mediated by the low affinity site has been inferred from studies on single Ca channels (Brown, Kunze & Yatani, 1984b) and cardiac contractility (Marsh et al 1983;.…”

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confidence: 99%

Dual effects of dihydropyridines on whole cell and unitary calcium currents in single ventricular cells of guinea‐pig.

Brown

Kunze

Yatani

1986

The Journal of Physiology

131

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SUMMARY1. We studied the effects of dihydropyridine Ca channel ligands (DHPs), mainly nitrendipine and Bay K8644, on whole cell and single channel Ca currents on single myocytes isolated from the adult guinea-pig ventricle.2. Nitrendipine had dual effects, stimulatory or inhibitory, depending upon the membrane potential. At low frequencies (less than 0 03 Hz) and negative holding potentials (-90 mV or more), nitrendipine increased the Ca currents in a dosedependent manner. The dose-response curve was best fitted by a Langmuir adsorption isotherm model which was the sum of two independent one-to-one drug-receptor sites with median effective doses (ED50s) of 1.0 x 10-9 M and 1-4 x 10-6 M respectively.3. When the membrane potential was held at -30 mV or less, nitrendipine inhibited the Ca currents, also in a dose-dependent manner. The dose-response curve was fitted by a single binding site model having a median inhibitor concentration (IC50) of 15 x 10-9 M. At holding potentials between -70 and -40 mV, nitrendipine produced mixed effects on Ca currents; an increase occurred initially and this was followed by a decrease.4. When rundown was excluded, Bay K8644 showed only stimulatory effects on the Ca currents between holding potentials of -120 and -30 mV. When the test potential was zero or + 10 mV the Ca currents reached peak values and the dose-response curve was best fitted by a single binding site model having an ED50 of 3 x 1o-8 M. When the effects were measured at negative test potentials of -30 to -10 mV, the curve was best fitted by a two-site model with ED50s of 3 x 10-9 and 9x 10-7M.5. At the single Ca channel level the stimulatory effect of nitrendipine was due to an increased probability that a Ca channel which had opened once would reopen, a reduction in records without activity and an increase in the mean open time. There were no changes in unit conductance. Inhibitory effects were due to a large increase in nulls. At lower concentrations the main effect of Bay K8644 was an increase in * Present address, to which reprint requests should be sent:

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“…Finally, in our experiments on the guinea-pig trachea and on the human bronchus, as in those performed on the rabbit aorta (Schramm et al, 1983a,b;Yamamoto et al, 1984), on the guinea-pig caecum (Spedding & Berg, 1984) and on the isolated heart of dog (Vaghy et al, 1984), guinea-pig (Schramm et al, 1983,b;Finet et al, 1985) or rat (Finet et al, 1985) Bay K 8644 exerted a contractile effect in a K+-enriched medium. This effect was competitively inhibited by nicardipine, a dihydropyridine derivative.…”

Section: Discussionmentioning

confidence: 54%

Effects of Bay K 8644 on contraction of the human isolated bronchus and guinea‐pig isolated trachea

Advenier¹,

Naline²,

Renier³

1986

British J Pharmacology

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1 The effects of Bay K 8644, a dihydropyridine which increases calcium flux through the potentialoperated channels were studied on the contractions induced by histamine, acetylcholine, KCl and Ca2" on human isolated bronchial strips and the results were compared to those obtained on guinea-pig isolated tracheal spirals. Subsequently the contractant effects of Bay K 8644 in K+-enriched medium and in the presence of Ca2" 0.03 mM were investigated.2 In Krebs normal calcium medium, Bay K 8644 did not significantly modify the EC50 of acetylcholine or histamine on the human bronchus, but in concentrations of 10-7-10-6M it potentiated the effects of KC1 on that preparation. It did not modify the EC50 of acetylcholine, histamine or KCl on the guinea-pig trachea. 3 In Ca2+-free Krebs medium with additional K+ (30 mM), Ca2+ concentration-response curves were displaced to the left by Bay K 8644 in the two preparations. Shifts were 0.52 ± 0.1 1 and 0.72 ± 0.16 log units respectively with Bay K 8644 10-8 and 10-7 M on human bronchus (n = 4) and 0.67 ± 0.16 and 1.06 ± 0.19 log units respectively with Bay K 8644 10-7 and 10-6 M on the guinea-pig trachea (n = 5).4 In Krebs medium with Ca2`0.03 mM and K+ 30 mM, Bay K 8644 (10-8 to 10-6 M) contracted both the human bronchus and the guinea-pig isolated trachea. This effect was competitively antagonized by nicardipine. 5These results demonstrate the presence of dihydropyridine sites of action on human bronchus and confirm the minor role played by Ca2+ influx through potential-operated channels in the contractile effects of acetylcholine or histamine. They also demonstrate the similar reactivity of human bronchus and guinea-pig isolated trachea to Bay K 8644.

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Correlation of nitrendipine and bay k 8644 binding to isolated canine heart sarcolemma with their pharmacological effects on the canine heart

Cited by 27 publications

References 4 publications

Calcium agonists and antagonists of the dihydropyridine type: Antinociceptive effects, interference with opiate-?-receptor agonists and neuropharmacological actions in rodents

Calcium agonists and antagonists of the dihydropyridine type: Antinociceptive effects, interference with opiate-?-receptor agonists and neuropharmacological actions in rodents

Dual effects of dihydropyridines on whole cell and unitary calcium currents in single ventricular cells of guinea‐pig.

Effects of Bay K 8644 on contraction of the human isolated bronchus and guinea‐pig isolated trachea

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