Abstract

The cardiovascular effects of a new class of potent inhibitors of dopamine beta-hydroxylase (DBH) were evaluated in spontaneously hypertensive rats (SHR). SK&F 102698 [1-(3,5-difluorobenzyl)imidazole-2-thiol] is the prototype molecule of this class of substituted 1-benzylimidazole-2-thiols and is one of the most potent inhibitors of DBH yet described. After acute p.o. administration in conscious unrestrained SHR, SK&F 102698 elicited a dose-dependent decrease in mean arterial blood pressure. The antihypertensive effect was marked by a gradual onset with long duration of activity. The antihypertensive effect produced by SK&F 102698 was accompanied by bradycardia. SK&F 102698 inhibited DBH in vivo as demonstrated by its ability to increase vascular levels of dopamine (DA) while concomitantly decreasing vascular levels of norepinephrine (NE), thus increasing the overall DA/NE ratio. The chronic cardiovascular effects of SK&F 102698 were evaluated in developing SHR. SHR were administered SK&F 102698 p.o. once daily for 9 weeks beginning when animals were 4 weeks of age. SK&F 102698 (50 mg/kg) significantly attenuated the development of hypertension of these SHR. Tolerance to the chronic effects of DBH inhibition was not observed and blood pressures in drug-treated animals were still reduced significantly 20 hr after drug administration. Vascular catecholamine levels were determined in the mesenteric artery of these chronically treated animals. Vascular DA levels were increased 290%, vascular NE levels were decreased 36% and the DA/NE ratio was increased 520%, as compared to controls. Furthermore, hearts weights of SHR receiving SK&F 102698 were approximately 10% lower than controls. The present study demonstrates that in SHR SK&F 102698 is an effective antihypertensive whose effects are mediated by the novel mechanism of DBH inhibition.