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Inositoltrisphosphat, ein neuer „Second Messenger“ für positiv inotrope Wirkungen am Herzen?

Inositol trisphosphate, a novel second messenger for positive inotropic effects in the heart?

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Summary

Myocardial alpha1-adrenoceptors mediate a positive inotropic effect and influence the inositol phosphate cycle. The receptor-stimulated, phospholipase C-mediated hydrolysis of phosphatidylinositol bisphosphate (PIP2) results in the generation of two novel second messengers, inositol trisphosphate (IP3) and diacylglycerol (DG). This effect is concentration-dependent and precedes the increase in force of contraction. Recently, it has been shown that the alpha1-adrenoceptor-mediated increase in IP3 and force of contraction exists in the human heart as well.

Possible mechanisms for an inositol phosphate-mediated positive inotropic effect are: (i) release of Ca2+ from the sarcoplasmic reticulum, elicited by IP3. (ii) increase in Ca2+ sensitivity of the contractile proteins, elicited by IP3, inositol tetrakisphosphate (IP4) and/or DG. (iii) increase in slow Ca2+ inward current, elicited directly by IP4 and/or indirectly by DG through a phosphorylation of the protein kinase C substrate in the sarcolemma.

In ventricular cardiac preparations muscarinic agonists have a weak positive inotropic effect, but in cardiac atrial preparations they have a negative inotropic effect. In both preparations, these different effects coincide with a concentration-dependent increase in IP3. Thus, the possible positive inotropic effect in atrial preparations is probably masked by an activation of a K+ outward current.

The relationship between the inositol phosphate cycle and the positive inotropic effect is in some points still speculative because not all of the mechanisms discussed are well settled yet. However, the stimulation of myocardial phosphoinositide breakdown resulting in an increased IP3 may be involved in the mechanism(s) whereby alpha1-adrenergic and muscarinic receptor stimulation exert an increase in myocardial force of contraction. Thus, the increase in inositol phosphates seems to be an important transmembrane signalling mechanism for alpha1-adrenergic and muscarinic receptors in the heart.

Zusammenfassung

KardialeAlpha 1-Adrenozeptoragonisten beeinflussen den Inositol-Lipid-Stoffwechsel und vermitteln einen positiv inotropen Effekt. Nach einer Agonist-vermittelten Hydrolyse von PIP2 entstehen die „second messenger“ IP3 und DG. Die Bildung von IP3 ist konzentrationsabhängig und geht dem positiv inotropen Effekt zeitlich voran. Der Inositol-Lipid-Stoffwechsel konnte kürzlich auch am menschlichen Herzen nachgewiesen werden, so daß er auch hier für den positiv inotropen Effekt eine Rolle spielen könnte. An der Vermittlung der alpha-adrenergen positiv inotropen Wirkung könnten folgende Inositol-Lipid-Stoffwechselprodukte beteiligt sein:

  1. 1.

    Eine intrazelluläre Ca2+-Freisetzung aus dem sarkoplasmatischen Retikulum, vermittelt durch IP3;

  2. 2.

    eine Steigerung der Empfindlichkeit der kontraktilen Proteine für Ca2+, vermittelt durch IP3, IP4 und/oder DG;

  3. 3.

    eine Steigerung des langsamen Ca2+-Einwärtsstromes, direkt vermittelt durch IP4 und/oder indirekt durch DG über eine Phosphorylierung der Plasmamembran und Öffnung von Ionenkanälen.

Kardialem-Cholinozeptoragonisten haben am Ventrikel einen geringen positiv inotropen Effekt, während sie am Vorhof im Gegensatz dazu negativ inotrop wirken. Am Vorhof und Ventrikel kommt es aber, ähnlich wie beim Alpha1-Adrenozeptor, zu einem IP3 Anstieg. Am Vorhof wird ein möglicherweise IP3-vermittelter positiv inotroper Effekt durch eine direkte Wirkung auf den K+-Auswärtststrom maskiert.

Der Zusammenhang zwischen dem positiv inotropen Effekt und dem Inositol-Lipid-Stoffwechsel ist in einigen Punkten noch nicht vollständig aufgeklärt. IP3 scheint jedoch ein weiterer „second messenger“ zu sein, der Rezeptoren und intrazelluläre Ca2+-Speicher verbindet. Ob Veränderungen des Inositol-Lipid-Stoffwechsels bei pathologischen Situationen wie z.B. Herzinsuffizienz, Hypertonie und Ischämie eine Rolle spielen, sollte näher untersucht werden.

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Abbreviations

IP1, IP2, IP3, IP4, IP5 und IP6 :

Inositolmono-, bis-, tris-, tetrakis-, pentakis- und hexakisphosphat

PI, PIP und PIP2 :

Phosphatidylinositol, -phosphat und -bisphosphat

DG:

Diacylglycerol

cAMP:

cyclisches Adenosin-3′,5′-monophosphat

G-Protein:

Guanin-Nukleotid-bindendes Protein

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Scholz, J. Inositoltrisphosphat, ein neuer „Second Messenger“ für positiv inotrope Wirkungen am Herzen?. Klin Wochenschr 67, 271–279 (1989). https://doi.org/10.1007/BF01892894

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