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The effect of single and repeated oral doses of isosorbide dinitrate on plasma renin activity and plasma catecholamine levels in conscious dogs

Der Einfluß einzelner sowie wiederholter oraler Gabe von Isosorbiddinitrat auf die Plasma-Reninaktivität und die Plasma-Katecholaminspiegel am wachen Hund

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Summary

The effects of isosorbide dinitrate (ISDN) on plasma renin activity (PRA) and plasma catecholamines were investigated in conscious trained dogs. The following results were obtained:

  1. 1)

    A single oral application of 2 and 4 mg/kg ISDN led to increases in heart rate, decreases in central venous and arterial blood pressure and an increase in PRA over a period of 3 to 4 hours. The observed haemodynamic effects were comparable to those of clinically applied doses in men.

  2. 2)

    The repeated administration of 2, 4, 8 and 16 mg/kg ISDN given three times a day orally over a period of 5 days had no influence on the basal PRA values in the morning.

  3. 3)

    A cumulation of the increase in PRA after ISDN was observed only if the interval between the oral application of 4 mg/kg was reduced to three hours or less. Despite of the persistent increase in PRA with hourly dosage, no influence could be found on the simultaneously measured plasma catecholamine levels in this study.

The results give further evidence for the very important role of renin in the homeostasis of the circulation, especially in situations of a decreased circulatory blood volume. The effect of ISDN on the reflex increase in PRA was shown to be within the range of 3 to 4 hours, indicating a duration of action of ISDN over the same period of time. A cumulative reflectory increase in PRA does not seem to be relevant for the therapeutic use of ISDN because of the usual dosage interval above three hours during the day and the mostly drug free period during the night. However, frequent application with dose intervals shorter than three hours could lead to an unwanted counterregulation with increased PRA levels, and hence an attenuation of the therapeutic effect.

Zusammenfassung

Die Wirkung von Isosorbiddinitrat (ISDN) auf Plasma-Reninaktivität (PRA) und Plasma-Katecholaminspiegel wurde an wachen Hunden untersucht.

Einzelapplikation von 2 oder 4 mg/kg ISDN p.o. bewirkte einen Anstieg der Herzfrequenz, Abfall des zentralvenösen und arteriellen Blutdruckes und einen Anstieg der PRA über 3 bis 4 Stunden. Die hämodynamischen Wirkungen waren jenen klinisch verwendeter Dosen vergleichbar.

Wiederholte Gabe von 2, 4, 8 und 16 mg/kg ISDN 3mal täglich durch 5 Tage hindurch führte zu keinerlei Veränderung der morgens gemessenen PRA-Werte.

Eine Kumulation des PRA-Anstieges konnte bei mehrmaliger oraler Gabe von 4 mg/kg ISDN nur dann gesehen werden, wenn ein Dosisintervall von 3 Stunden oder noch kürzer eingehalten wurde. Trotz eines langanhaltenden PRA-Anstieges bei stündlicher Verabreichung von ISDN konnte keinerlei Veränderung der ebenfalls bestimmten Plasma-Katecholaminspiegel gefunden werden.

Die Untersuchungen unterstreichen die wesentliche Rolle des Renins in der Homöostase des Kreislaufes, insbesondere bei vermindertem zirkulierendem Blutvolumen. Der reflektorische Reninanstieg nach ISDN war über 3 bis 4 Stunden nachweisbar, so daß eine ebensolange Wirkdauer von ISDN anzunehmen ist. Eine Kumulation des gegenregulatorischen Reninanstiegs scheint von eher geringer therapeutischer Bedeutung zu sein, da die üblichen Dosenintervalle über 3 Stunden liegen und außerdem die Nacht meist als medikationsfreies Intervall hinzukommt. Wenn jedoch häufige Einnahme mit Intervallen unter 3 Stunden stattfindet, könnte der gegenregulatorische Anstieg der PRA zur Geltung kommen und den therapeutischen Effekt abschwächen.

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Author notes

  1. G. Raberger

    Present address: Pharmakologisches Institut der Universität Wien, Währinger Straße 13a, A-1090, Wien, Austria

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  1. Pharmakologisches Institut der Universität Wien, Währinger Straße 13a, A-1090, Wien, Austria

    Th. Benke, O. Kraupp, P. Placheta & Brigitte Stanek

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Benke, T., Kraupp, O., Placheta, P. et al. The effect of single and repeated oral doses of isosorbide dinitrate on plasma renin activity and plasma catecholamine levels in conscious dogs. Basic Res Cardiol 75, 400–409 (1980). https://doi.org/10.1007/BF01907587

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