Summary
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1.
The mechanism of the positive inotropic effect of a benzimidazole-pyridazinone, UD-CG 115, was analysed in the isolated guinea-pig papillary muscle contracting isometrically at a frequency of 0.2 Hz.
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2.
UD-CG 115 produced a slowly developing and poorly reversible positive inotropic effect increasing with concentration (3–300 μmol/l). The effect amounted to 30 and 74% of the maximum inotropic effect of a standard, dihydroouabain, at 34 and 300 μmol/l, respectively. Low concentrations shortened and 300 μmol/l UD-CG 115 significantly prolonged the duration of contraction. The enhancement of the maximum rate of relaxation, S 2, was intermediate between those produced by isoprenaline and dihydroouabain, respectively.
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3.
UD-CG 115 prolonged the duration of the transmembrane action potential (90% repol.) by up to 22% at 300 μmol/l, whereas an equieffective concentration of isoprenaline did not consistently alter action potential duration. UD-CG 115 increased V max and overshoot, and prolonged the duration, of slow action potentials elicited at 24 mmol/l [K]0.
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4.
The inotropic potency of UD-CG 115 was not significantly changed by reserpine pretreatment of the guinea pig or by the presence of 1 μmol/l (−)-propranolol, 3 μmol/l phentolamine or 10 μmol/l cimetidine. Neither was it reduced by 10 μmol/l TTX. The inotropic effect of 100 μmol/l UD-CG 115 remained unchanged when [K]0 was elevated from 3.2 to 12.0 mmol/l. A sarcolemmal preparation of guinea-pig ventricular Na,K-ATPase was only slightly inhibited by the highest concentration of UD-CG 115.
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5.
Carbachol (0.1–3 μmol/l) inhibited the positive inotropic effect of UD-CG 115, and this antagonism disappeared in the presence of 1 μmol/l atropine.
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6.
In the presence of a moderately effective concentration of UD-CG 115 (10 μmol/l) the inotropic potencies (-log EC50) of isoprenaline, histamine, and IBMX were all significantly increased by 0.60±0.07, 0.36±0.06, and 0.44±0.06 log units, respectively, whereas that of dihydroouabain was not significantly affected.
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7.
UD-CG 115 increased the force of the rested-state contraction by augmenting the late component of contraction.
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8.
Cyclic AMP content determined by radioimmunoassay in individual papillary muscles was raised 1.64-fold in the presence of 10 μmol/l UD-CG 115, but did not significantly increase beyond this level when drug concentration was raised further up to 30-fold. Carbachol prevented the effect of UD-CG 115 on cyclic AMP content.
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9.
Addition of UD-CG 115 in the presence of the maximally effective concentration of isoprenaline gave a further positive inotropic and klinotropic effect, whereas the phosphodiesterase inhibitor IBMX was without effect on contraction under this condition.
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10.
These findings are consistent with the proposal that the inotropic action of UD-CG 115 depends on a moderate elevation of cyclic AMP (not involving β-adrenoceptors or histamine-H2-receptors but probably due to phosphodiesterase inhibition) combined with a prolongation of the action potential that augments the inotropic cyclic AMP effect by increasing Ca influx through Ca channels.
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Abbreviations
- F c :
-
peak force of contraction
- t 1 :
-
time to peak force
- t 2 :
-
relaxation time
- S 1 :
-
maximum rate of force development
- S 2 :
-
maximum rate of relaxation
- V max :
-
maximum rate of depolarization of action potential
- I si :
-
slow inward current
- cyclic AMP:
-
adenosine 3′,5′-cyclic monophosphate
- DMSO:
-
dimethylsulphoxide
- IBMX:
-
3-isobutyl-1-methylxanthine
- Na,K(Mg)-ATPase:
-
guinea-pig ventricular sodium-, potassium-(magnesium-) activated adenosine triphosphatase (EC 3.6.1.3)
- TTX:
-
tetrodotoxin
- UD-CG 115:
-
4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3(2H)-pyridazinone
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Part of this work is included in the thesis of Anne Heiss, Technische Universität München
Supported by the Deutsche Forschungsgemeinschaft, (Ho 705/1)
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Honerjäger, P., Heiss, A., Schäfer-Korting, M. et al. UD-CG 115 — a cardiotonic pyridazinone which elevates cyclic AMP and prolongs the action potential in guinea-pig papillary muscle. Naunyn-Schmiedeberg's Arch. Pharmacol. 325, 259–269 (1984). https://doi.org/10.1007/BF00495953
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DOI: https://doi.org/10.1007/BF00495953