Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle

Ishii, Kuniaki; Taira, Norio; Yanagisawa, Teruyuki

doi:10.1111/j.1476-5381.1985.tb12943.x

Cited by 26 publications

(19 citation statements)

References 10 publications

(11 reference statements)

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“…diltiazem=45:3:1. This order of potency is quite similar to that of cardiovascular inhi bitory effects, especially in the negative inotropism reported previously (2,(17)(18)(19). We have found a unique phenomenon that the KCI-induced response was converted from a contraction to a relaxation in the airway smooth muscle in the presence of Ca-an tagonists.…”

Section: Discussionsupporting

confidence: 88%

“…However, the relative potencies of Ca-an tagonists to relax the KCI-derived contraction are well consistent with those to reverse the response to KCI (Tables 1 and 2). The relative potencies of Ca-antagonists to relax airway smooth muscle are identical to those in vascular smooth muscle (17,18) and cardiac muscle (17,19). This implies that KCI induced relaxation in the presence of Ca antagonists may involve the primary calcium antagonistic effect of these compounds (18).…”

Section: Discussionmentioning

confidence: 78%

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Relaxation of airway smooth muscle induced by potassium in the presence of Ca-antagonists.

et al. 1989

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Abstract-We examined K+-induced relaxation instead of contraction in the pres ence of Ca-antagonists by measuring isometric tension in the tracheal smooth muscle isolated from guinea pigs. Cumulative administration of KCI (10-90 mM) induced a concentration-dependent contraction. When the muscle was pretreated with low concentrations of Ca-antagonists, cumulative administration of KCI caused a mild contraction, followed by a moderate relaxation. In the muscle pretreated with high concentrations of Ca-antagonists, KCI revealed a concentration-related relaxation without contraction. The potency ratios of Ca-antagonists to reverse the KCI-induced contraction to relaxation were nifedipine : verapamil : diltiazem= 94:4:1. This order of potency was quite similar to that of Ca-antagonists to relax the muscle precontracted with KCI (30 mM). Magnitudes of KCI (30 mM)-induced relaxation in the presence of Ca-antagonists were similar to those caused by Ca antagonists in the KCI (30 mM)-precontracted muscles. Thus, K+-induced relax ation in the airway smooth muscle in the presence of Ca-antagonists may be due to the voltage-dependent increase in binding of Ca-antagonists to calcium channels.It has been generally accepted that the airway smooth muscle displays a concen tration-related contraction by the adminis tration of KCI (10-2-9 x 10-2 M) in terms of a depolarization mechanism. On the other hand, it has been shown that Ca-antagonists cause a relaxation of the airway smooth muscle pre contracted with KCI due to the blocking effect of extracellular Ca" entering through voltage dependent Ca" channels (1-3). Among the various kinds of Ca-antagonists, the effects of nifedipine and verapamil on airway smooth muscle have been well-documented.In in vitro studies, verapamil has been shown to reverse the contraction of tracheal smooth muscle in guinea pigs (4, 5) and in dogs (6), while nifedipine was even more effective than verapamil in guinea pigs (7). The preventive effect of nifedipine on human bronchocons triction has been also reported in vitro (8. 9) and in vivo (10, 11). However, there is no available literature concerning the relative potencies for various kinds of Ca-antagonists, including diltiazem and nicardipine, on the airway tone. Since Ca-antagonists with dif ferent chemical structures may act on the smooth muscle through different subcellular mechanisms, we initially compared the po tencies of nifedipine, nicardipine, verapamil and diltiazem to relax the isolated tracheal smooth muscle precontracted with KCI (30 mM). We further studied the effect of KCI on these preparations pretreated with diltiazem. Interestingly, KCI-induced relaxation instead of contraction was found in the preparation pretreated with a high concentration of diltiazem. To examine whether such a relaxa tion could be seen with other Ca-antagonists, we investigated the concentration-response effects for KCI in the presence of the Ca antagonists, i.e., diltiazem, verapamil and nifedipine, at various concentrations.To ex 388 Y. Koga et al. plore...

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 78%

Relaxation of airway smooth muscle induced by potassium in the presence of Ca-antagonists.

et al. 1989

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“…Similar phenomena have been observed in porcine isolated coronary arteries and rat hearts, and taken to indicate its partial agonistic property (Grupp et al, 1984). The diminished effectiveness of Bay K 8644 in producing a positive inotropic effect at high concentrations compared to medium concentrations has also been observed in canine isolated ventricular muscle (Ishii et al, 1985). However, this has been attributed to the negative inotropic effect of the solvent used for Bay K 8644 (Ishii et al, 1985).…”

Section: Discussionsupporting

confidence: 62%

“…The diminished effectiveness of Bay K 8644 in producing a positive inotropic effect at high concentrations compared to medium concentrations has also been observed in canine isolated ventricular muscle (Ishii et al, 1985). However, this has been attributed to the negative inotropic effect of the solvent used for Bay K 8644 (Ishii et al, 1985). Therefore, a possible involvement of the solvents of Bay K 8644 in the effects of high doses of Bay K 8644 in the present experiments should be considered.…”

Section: Discussionmentioning

confidence: 49%

Similarity and dissimilarity of the vasoconstrictor effects of Bay K 8644 on coronary, femoral, mesenteric and renal circulations of dogs

Ishii

Sato

Taira³

1986

British J Pharmacology

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1 The effect of the dihydropyridine calcium agonist Bay K 8644 on the coronary, femoral, mesenteric and renal circulations was investigated and compared with that of noradrenaline in pentobarbitone-anaesthetized dogs.2 The left anterior descending coronary, femoral, cranial mesenteric and renal arteries were cannulated and their arterial beds perfused with autologous blood at a constant pressure slightly higher than the mean systemic arterial blood pressure. Bay K 8644 (0.1-300 nmol) and noradrenaline (0.1-300 nmol) were injected intra-arterially. 3 Bay K 8644 decreased blood flow (vasoconstriction) in all 4 arterial beds. A maximum decrease was attained at 100 nmol and a further increase.in dose did not appear to result in a further decrease in blood flow. 4 At maximum effects blood flow decreased to about 35% of the basal value in coronary, 30% in femoral, 20% in renal and 15% in mesenteric circulation.5 Normalized ED50 values (ED_% divided by basal flow) of Bay K 8644 were 0.07 ± 0.02 nmol in the femoral, 0.08 ± 0.01 nmol in the coronary, 0.16 ± 0.06 nmol in the mesenteric and 0.55 ± 0.19 nmol in the renal circulation. 6 At 100 nmol, the values for the half-duration of Bay K 8644 vasoconstrictor effects were about 196 s in the renal, 78 s in the mesenteric, 84 s in the femoral and 21 s in the coronary circulation. 7 Noradrenaline produced a dose-dependent decrease in blood flow in femoral, mesenteric and renal circulations, and was about 2 times in femoral, 4 times in mesenteric and 9 times in renal circulation more potent than Bay K 8644.8 Bay K 8644 produced slight increases in the maximum rate of rise of left ventricular pressure and intraluminal pressure of the ileum. However, the increases did not appear to impede blood flow. 9 Bay K 8644 produced slightly but significantly greater femoral vasoconstriction in normal dogs than in reserpine-pretreated dogs. 10 From these results it was concluded that differences in potency, effectiveness and duration of the vasoconstrictor effects of Bay K 8644 between the 4 arterial beds probably derive from differences in characteristics ofthe smooth muscle ofresistance vessels there. In arterial beds where x-adrenoceptors are dominant, potentiation of the vasoconstrictor effect ofendogenous catecholamines by Bay K 8644 seems to contribute to its vasoconstrictor effect.

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“…Bay K 8644 binds to the same dihydropyridine binding site as does nifedipine, in or near voltage-operated slow calcium channels (Schramm et al, 1983a,b;Thomas et al, 1984;Ishii et al, 1985). However, in contrast to nifedipine, Bay K 8644 promotes the influx of calcium ions, thus increasing heart contractility.…”

Section: Introductionmentioning

confidence: 99%

Antagonism between (–)‐N⁶‐phenylisopropyl‐adenosine and the calcium channel facilitator Bay K 8644, on guinea‐pig isolated atria

Caparrotta

Fassina

Froldi

et al. 1987

British J Pharmacology

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1 Antagonism between (-)-N6-phenylisopropyladenosine (PIA) and the dihydropyridine calcium channel facilitator Bay K 8644 was investigated in guinea-pig spontaneously beating or electrically driven isolated atria, taken from normal and from reserpine-treated animals. 2 PIA (3-100 nM) produced a dose-dependent decrease in contractile tension and frequency in spontaneously beating atria being more effective in reserpinized preparations. 3 Bay K 8644 (5-200nM) produced an increase in contractile tension in both normal and reserpinized atria. In electrically driven left atria the positive inotropic effect of Bay K 8644 was similar to that in spontaneously beating preparations. The positive chronotropic effect of Bay K 8644 was slight and variable. 4 PIA produced a rightward parallel shift of the concentration-response curves for the positive inotropic effects of Bay K 8644 in all experimental conditions. In spontaneously beating atria from normal guinea-pigs, the Schild regression plot was linear and its slope near to unity; pA2 of PIA 8.63 ± 0.05 (IC50 2.35 ± 0.25 nM). In electrically driven atria the antagonism by PIA of the effects of Bay K 8644 was apparently competitive, and the IC50 of PIA was 18.6 ± 0.4 nM. PIA antagonized the positive chronotropic effect of Bay K 8644 in spontaneously beating preparations, both from normal and from reserpine-treated animals. 5Carbachol did not modify the positive inotropic effects of Bay K 8644. 6 These data indicate that PIA may interact with Bay K 8644 at the level ofthe slow calcium channels, and may decrease the transmembrane calcium flux into the cell.

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Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle

Cited by 26 publications

References 10 publications

Relaxation of airway smooth muscle induced by potassium in the presence of Ca-antagonists.

Relaxation of airway smooth muscle induced by potassium in the presence of Ca-antagonists.

Similarity and dissimilarity of the vasoconstrictor effects of Bay K 8644 on coronary, femoral, mesenteric and renal circulations of dogs

Antagonism between (–)‐N⁶‐phenylisopropyl‐adenosine and the calcium channel facilitator Bay K 8644, on guinea‐pig isolated atria

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Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle

Cited by 26 publications

References 10 publications

Relaxation of airway smooth muscle induced by potassium in the presence of Ca-antagonists.

Relaxation of airway smooth muscle induced by potassium in the presence of Ca-antagonists.

Similarity and dissimilarity of the vasoconstrictor effects of Bay K 8644 on coronary, femoral, mesenteric and renal circulations of dogs

Antagonism between (–)‐N6‐phenylisopropyl‐adenosine and the calcium channel facilitator Bay K 8644, on guinea‐pig isolated atria

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Antagonism between (–)‐N⁶‐phenylisopropyl‐adenosine and the calcium channel facilitator Bay K 8644, on guinea‐pig isolated atria