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The effect of repeated intravenous and oral doses of molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester) on plasma renin activity and plasma catecholamine levels in conscious dogs

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Summary

The responses of plasma renin activity (PRA) and plasma catecholamine levels to molsidomine, administered both intravenously and orally, were investigated in conscious trained dogs.

Intravenous administration of molsidomine at increasing dosage up to 0.4 mg/kg with a constant dose interval of 4 hours did not lead to a sustained increase in PRA. By contrast, a significant increase in PRA was still present after 4 hours on administration of 0.4 mg/kg molsidomine by the oral route. This longer-lasting increase in PRA following oral administration is discussed in relation to the conversion of molsidomine to an active metabolite in the liver. A reduction of dose interval to 3 hours or less led to a marked cumulative increase in PRA.

It appears that substances acting via venous pooling lead to persistent activation of the renin angiotensin aldosterone system (RAA system), which counteracts its primary therapeutic effect. A slight increase in plasma noradrenaline levels was observed in response to repeated oral administration of 0.4 mg/kg molsidomine at a dose interval of 2 hours, indicating participation of the sympathetic nervous system in the counterregulatory process.

Zusammenfassung

Die Wirkung intravenöser und peroraler Gaben von Molsidomin auf die Plasmareninaktivität (PRA) und die Plasmakatecholaminspiegel wacher Hunde wurde untersucht.

Intravenöse Verabreichung von Molsidomin in einer Dosierung bis zu 0,4 mg/kg bei einem gleichbleibenden Dosisintervall von 4 Stunden führte zu keinem langanhaltenden Anstieg der PRA. Im Gegensatz dazu war nach peroraler Verabreichung von 0,4 mg/kg Molsidomin nach 4 Stunden die PRA noch deutlich erhöht. Der relativ stärkere Anstieg der PRA auf orale Gabe wird mit Bezugnahme auf den Abbau von Molsidomin zu einem aktiven Metaboliten in der Leber diskutiert. Verkürzung des Dosisintervalls auf 3 Stunden und weniger führte zu einem kumulativen PRA-Anstieg.

Es ist anzunehmen, daß Substanzen, die venöses Pooling verursachen, zu einer andauernden Aktivierung des Renin-Angiotensin-Aldosteron-Systems (RAA-System) führen, welche dem ursprünglichen therapeutischen Effekt entgegenwirkt. Der geringe Anstieg der Plasmanoradrenalinwerte, der nach peroraler Gabe von 0,4 mg/kg Molsidomin bei einem Dosisintervall von 2 Stunden beobachtet wurde, deutet die Mitbeteiligung des Sympathischen Nervensystems bei der Gegenregulation an.

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Author notes

  1. S. Bacher

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

Authors and Affiliations

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

    O. Kraupp, B. Stanek & G. Raberger

Authors
  1. S. Bacher
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  2. O. Kraupp
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  3. B. Stanek
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  4. G. Raberger
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Additional information

A preliminary report of this study has been presented at the 21st Spring Meeting of the Deutsche Pharmakologische Gesellschaft (Naunyn-Schmiedeberg's Arch. Pharmacol. 311, R 43, 1980).

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Bacher, S., Kraupp, O., Stanek, B. et al. The effect of repeated intravenous and oral doses of molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester) on plasma renin activity and plasma catecholamine levels in conscious dogs. Basic Res Cardiol 78, 193–202 (1983). https://doi.org/10.1007/BF01906672

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  • DOI: https://doi.org/10.1007/BF01906672

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