Reduction of mortality in Skelton-hypertensive rats by prophylactic application of the calcium antagonist Flunarizine without suppression of the high blood pressure

Abstract

Following Skelton’s procedure with unilateral adrenonephrectomy, contralateral adrenal enucleation and application of 1% NaCI with the drinking fluid, rats develop severe hypertension resulting in increased mortality due to high blood pressure and generalized arteriosclerosis. In the present study, the effect of the antiarteriosclerotic calcium antagonist flunarizine upon the development of blood pressure and mortality was investigated in normal male Long Evans rats previously subjected to the Skelton procedure. In 10 non flunarizine treated rats subjected to the Skelton procedure, and in 10 flunarizine treated rats (application of 300 mg flunarizine per kg rat pellets over the whole experimental time course, begun 1 week before the operation) also subjected to the Skelton procedure, as well as in 10 untreated rats (controls), the mortality and systolic blood pressure were measured weekly. In the non-flunarizine-treated Skelton rats, mean systolic blood pressure increased from preoperative mean values of 106 mmHg to maximal mean values of 243 mmHg and mean survival time was 9±3 weeks per rat measured over the experimental time period of 27 weeks after the operation. In the flunarizine treated Skelton rats, a comparable increase in blood pressure from 110 mgHg to 235 mmHg was observed, but in contrast to the non-flunarizine-treated Skelton rats mean survival time was 19 ±7 weeks per rat. The control rats remained normotensive and mean survival time was 24± 8 weeks per rat. The findings presented show that prophylactic application of the calcium antagonist flunarizine at the dosage used does not suppress Skelton-hypertension in rats, but more than doubles survival time.

Zusammenfassung

Mit Hilfe von Tierexperimenten konnte nachgewiesen werden, daß Flunarizin (Janssen, Neuss) an Arterien endothelprotektiv wirkt [2] und eine elektrisch erzeugte Arteriopathie hemmen kann [1]. Wie dazu neuere Untersuchungen zeigten, supprimiert dieser Kalziumantagonist in hoher Dosierung bei Skeltonhypertonen Ratten [15, 16] die innerhalb von sieben Wochen entstehende Arteriosklerose an Gehirn, Herz und Niere nahezu vollständig [9, 10] sowie bei niedrigeren Dosierungen an der Niere dosisabhängig [11], ohne dabei zugleich den Bluthochdruck zu senken. Da die hypertoniebedingte Arteriosklerose die Lebenszeit bei Mensch und Tier verkürzt [3], lag es nahe zu prüfen, welchen Einfluß Flunarizin auf Blutdruck und Mortalität von Ratten ausübt, wenn diese zum Erzeugen einer Hypertonie zuvor nach Skelton behandelt wurden.