Reduction of mortality in Skelton-hypertensive rats by therapeutic 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 pronounced arteriosclerosis of the brain, heart and kidney. In the present study, the therapeutic effect of the antiarteriosclerotic calcium antagonist flunarizine upon the development of blood pressure and mortality was investigated in Skelton-hypertensive Long Evans rats with established generalized arteriosclerosis. In 10 non-flunarizine-treated rats subjected to the Skelton procedure, and in 10 flunarizine-treated rats (application of 300 mg flunarizine per kg food begun in the 8th week after the operation) also subjected to the Skelton procedure, as well as in 10 untreated rats (controls), the mortality and systolic blood pressure was measured weekly. The rats subjected to the Skelton procedure developed hypertension with a mean systolic blood pressure increase from 110±8 (SD) mmHg 1 week before the operation to 226±28 mmHg 7 weeks after the operation, or from 112±6 mmHg to 219±27 mmHg in the two treated groups respectively. During the experimental time course of 29 weeks with flunarizine application from the 8th week after the operation onwards, no significant reduction of the systolic blood pressure was observed in the flunarizine-treated Skelton-hypertensive rats in comparison with the nonflunarizine-treated Skelton-hypertensive rats. However, over this time period, mean survival time per rat was 9.9±11.5 (SD) weeks in the flunarizine-treated Skelton-hypertensive rats and only 5.4±7.7 weeks in the non-flunarizine-treated Skelton-hypertensive rats. The control rats remained normotensive with initial mean blood pressure values of 108±7 mmHg and final values of 127±12 mmHg. In this group mean survival time per rat was 27.2±5.3 weeks. The findings presented suggest that therapeutic application of the calcium antagonist flunarizine at the dosage used does not reduce high blood pressure in Skelton-hypertensive rats, but almost doubles survival time.

Zusammenfassung

Es gilt als gesichert, daß Arteriosklerose infolge Bluthochdruckes die Mortalität steigert [1]. Wie dazu experimentelle Untersuchungen an Skelton-hypertonen Ratten [14] zeigen, läßt sich durch prophylaktische Gabe des Kalziumantagonisten Flunarizin in hoher Dosierung die hypertoniebedingte Arteriosklerose nahezu vollständig [7, 8] und in niedrigeren Dosierungen dosisabhängig [9] hemmen sowie die Überlebenszeit der Tiere bei hoher Dosierung mehr als verdoppeln [12], ohne zugleich den Bluthochdruck zu senken. Das wirft die Frage auf, ob dieser Kalziumantagonist nicht nur prophylaktisch, sondern auch therapeutisch wirksam ist. Mit der vorliegenden Untersuchung wird geprüft, welchen Einfluß Flunarizin auf Blutdruck und Mortalität von Ratten ausübt, wenn diese aufgrund der Skelton-Hypertonie bereits eine massive bluthochdruckbedingte Arteriosklerose entwickelt haben.