Stimulation and Inhibition of the Na+, K+-Pump by Cardiac Glycosides

Godfraind, Théophile

doi:10.1007/978-3-642-68163-9_16

Cited by 12 publications

(8 citation statements)

References 30 publications

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“…In the rings and the layered preparations containing endothelium, the hypoxic facilitation was preceded by a transient relaxation, which can be attributed to the production of vasodilator prostanoids, as earlier work on the same preparation has shown that endothelium-dependent relaxations to hypoxia can be prevented by indomethacin (Rubanyi & Vanhoutte, 1985). Flunarizine reduces vasoconstrictor responses induced by different vasoactive agents through inhibition of the entry of Ca2 + in vascular smooth muscle (Van Nueten & Janssen, 1973;Van Nueten et al, 1978;Godfraind & Dieu, 1981). The Ca2+-antagonistic properties of flunarizine in vascular smooth muscle have a slower onset and a longer duration of action than those of other Ca2 +-antagonists, such as verapamil, diltiazem, or nifedipine (Van Nueten et al, 1978;Godfraind & Dieu, 1981;Godfraind & Miller, 1982;Wadsworth & Moss, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…Flunarizine reduces vasoconstrictor responses induced by different vasoactive agents through inhibition of the entry of Ca2 + in vascular smooth muscle (Van Nueten & Janssen, 1973;Van Nueten et al, 1978;Godfraind & Dieu, 1981). The Ca2+-antagonistic properties of flunarizine in vascular smooth muscle have a slower onset and a longer duration of action than those of other Ca2 +-antagonists, such as verapamil, diltiazem, or nifedipine (Van Nueten et al, 1978;Godfraind & Dieu, 1981;Godfraind & Miller, 1982;Wadsworth & Moss, 1982). Flunarizine was selected in the present experiments because of its long duration of action, which was evidenced by the experiments where the interval between the incubation with the drug and the exposure to hypoxia was altered.…”

Section: Discussionmentioning

confidence: 99%

“…The present experiments were designed to determine whether the inhibition of the hypoxic facilitation by these drugs is due to an action on the endothelium, on the vascular smooth muscle, or on both. To do so we used a layered preparation which allowed treatment of the endothelium and the vascular smooth muscle separately and selected flunarizine, a difluoro derivative of piperazine which inhibits Ca2 '-entry (Van Nueten & Janssen, 1973;Holmes et al, 1984;Borgers et al, 1984) and has a longer duration of action than diltiazem, nifedipine, and verapamil (Van Nueten et al, 1978;Godfraind & Dieu, 1981). This allowed us to treat the endothelium and the vascular smooth muscle separately.…”

Section: Introductionmentioning

confidence: 99%

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Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Iqbal¹,

Vanhoutte²

1988

British J Pharmacology

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1 Hypoxia augments contractile responses to several vasoactive agents in canine isolated coronary arteries with intact endothelium. Calcium antagonists inhibit the further increases in tension caused by hypoxia. The present experiments were designed to determine whether the calcium-antagonist flunarizine would inhibit hypoxic contractions in isolated blood vessels through an action on the endothelium or on the vascular smooth muscle. 2 Rings of canine coronary arteries, with or without endothelium, were suspended at optimal length for isometric tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution.3 Hypoxia (95% N2 and 5% C02) augmented contractile responses to prostaglandin F2.(2 x 106 M); removal of the endothelium abolished this hypoxic facilitation. 4 Flunarizine (5 x 10-5-5 x 10-7M) exerted a long-lasting inhibition of the hypoxic facilitation in a concentration-dependent manner. Flunarizine did not inhibit the response to prostaglandin F2,. 5 To differentiate between the response of smooth muscle and the endothelium, strips of coronary arteries without endothelium were layered with strips with or without endothelium. Hypoxia augmented contractions only in layered preparations with endothelium. Flunarizine prevented the hypoxic contractions in layered preparations in which only the smooth muscle was treated with flunarizine. In contrast, when only the endothelium was treated, no or minimal inhibition of the hypoxic contraction occurred with flunarizine (10' and 5 x 10-5M, respectively).6 These experiments indicate that the calcium antagonist flunarizine inhibits endotheliumdependent hypoxic facilitation in canine coronary arteries primarily through its action on vascular smooth muscle.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Iqbal¹,

Vanhoutte²

1988

British J Pharmacology

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“…After centuries of empiric use, a number of investigations demonstrated that the clinical benefits of digitalis glycosides were related to their positive inotropic effects [25,26] , which in turn depend on inhibition of the membrane pump sodium/potassium-adenosine triphosphatase (Na + /K + -ATPase) [27]. Therefore, to our knowledge, Na + /K + -ATPase represents the first pharmacologic target used to improve contractility in the treatment of HF.…”

Section: Characteristics Of An Ideal Inotropic Drugmentioning

confidence: 98%

Acute Heart Failure With Low Cardiac Output: Can We Develop a Short-term Inotropic Agent That Does Not Increase Adverse Events?

Campia

Nodari

Gheorghiade

2010

Curr Heart Fail Rep

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Acute heart failure represents an increasingly common cause of hospitalization, and may require the use of inotropic drugs in patients with low cardiac output and evidence of organ hypoperfusion. However, currently available therapies may have deleterious effects and increase mortality. An ideal inotropic drug should restore effective tissue perfusion by enhancing myocardial contractility without causing adverse effects. Such a drug is not available yet. New agents with different biological targets are under clinical development. In particular, istaroxime seems to dissociate the inotropic effect exerted by digitalis (inhibition of the membrane sodium/potassium adenosine triphosphatase) from the arrhythmic effect and to ameliorate diastolic dysfunction (via sarcoendoplasmic reticulum calcium adenosine triphosphatase activation). Additionally, the myosin activator omecamtiv mecarbil appears to have promising characteristics, while genetic therapy has been explored in animal studies only. Further investigations are needed to confirm and expand the effectiveness and safety of these agents in patients with acute heart failure and low cardiac output.

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“…This results in an increase in the intracellular Na'-concentration which, via the Na+ /Ca2 -exchange, is linked to an increase in the intracellular Ca2" concentration, thereby accounting for the positive inotropic effect of these drugs (for references see Schwartz et al, 1975;Akera & Brody, 1977). However, there is some evidence, that cardiac glycosides in low but positive inotropic concentrations do not inhibit Na',K'-transport in intact heart muscle preparations (Cohen et al, 1976;Noack et al, 1979;Godfraind, 1981;Brown & Erdmann, 1982, Fricke et al, 1982.…”

Section: Introductionmentioning

confidence: 99%

Erythrosin B inhibits high affinity ouabain binding in guinea‐pig heart Na⁺‐K⁺‐ATPase without influence on cardiac glyoside induced contractility

Fricke

1985

British J Pharmacology

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Binding of [3H]‐ouabain to guinea‐pig heart membranes enriched in Na+‐K+‐ATPase revealed two different cardiac glycoside binding sites. High affinity binding was obtained at a KD = 2.2 × 10−7 mol 1−1 (Bmax = 16.8 pmol ouabain mg−1 protein) whereas low affinity ouabain binding occurred at a KD > 10−6 mol 1−1. To discover whether the two ouabain binding sites are functional in guinea‐pig heart muscle, erythrosin B, an inhibitor of the high affinity ouabain binding in rat brain tissue, was tested in guinea‐pig isolated heart muscle preparations. Erythrosin B proved to be a potent inhibitor of the Mg2+(Na+)‐dependent‐, as well as Na+‐K+‐activated ATPase (ID50 = 9 × 10−6 mol 1−1). Contractility of guinea‐pig isolated papillary muscles, however, was not influenced by erythrosin B in concentrations up to 1 × 10−5 mol 1−1. Only very high concentrations (4 × 10−4 mol 1−1) resulted in a slightly negative inotropic effect (about 20%). Erythrosin B dose‐dependently inhibited [3H]‐ouabain binding to the Na+‐K+‐ATPase (KD = − 3.6 × 10−6 mol 1−1). In a concentration of 1 × 10−5 mol 1−1 the dye abolished high affinity [3H]‐ouabain binding without affecting the low affinity binding sites. In contrast, in guinea‐pig isolated atria, no functional antagonism between erythrosin B (5 × 10−5 mol 1−1) and ouabain was observed. As there is a coincidence between the high affinity binding (KD = 2.2 × 10−7 mol 1−1) and the concentration for half maximum inotropic effects of ouabain (ED50 = 1.6 × 10−7 mol 1−1), the lack of effect of erythrosin B on ouabain‐induced inotropy may be caused by an inaccessibility of the dye to the (internal) ATP‐site of the Na+‐K+‐ATPase.

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Stimulation and Inhibition of the Na+, K+-Pump by Cardiac Glycosides

Cited by 12 publications

References 30 publications

Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Acute Heart Failure With Low Cardiac Output: Can We Develop a Short-term Inotropic Agent That Does Not Increase Adverse Events?

Erythrosin B inhibits high affinity ouabain binding in guinea‐pig heart Na⁺‐K⁺‐ATPase without influence on cardiac glyoside induced contractility

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Stimulation and Inhibition of the Na+, K+-Pump by Cardiac Glycosides

Cited by 12 publications

References 30 publications

Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle

Acute Heart Failure With Low Cardiac Output: Can We Develop a Short-term Inotropic Agent That Does Not Increase Adverse Events?

Erythrosin B inhibits high affinity ouabain binding in guinea‐pig heart Na+‐K+‐ATPase without influence on cardiac glyoside induced contractility

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Erythrosin B inhibits high affinity ouabain binding in guinea‐pig heart Na⁺‐K⁺‐ATPase without influence on cardiac glyoside induced contractility