Influence of Some Antihypertensive Agents on the Genesis and Maintenance of Hypertension in the Rat

Abstract

The antihypertensive effects of α-methyldopa and clonidine have been demonstrated in conscious male Wistar rats with established DOCA-saline hypertension. The hypotensive effect of (±)-propranolol was demonstrated after administration into the lateral cerebral ventricles but not after systemic injection. The development of DOCA-saline hypertension in rats was prevented by (±)-propranolol treatment (0.02, 0.2, 2.0, 10, and 25 mg/kg/day for five weeks). At the two higher dose levels used, blood pressure remained at treatment levels when treatment with (±)-propranolol was stopped whereas with the three lowest dose levels, it rose towards hypertensive levels when treatment was withdrawn. The effect of two low doses of (±)-propranolol (0.02 and 0.2 mg/kg/day) in preventing DOCA-saline hypertension was found to be related to the treatment period. In acute experiments, (±)-propranolol (0.02 and 0.2 mg/kg) was found to produce a brief blockade of responses to β-adrenoceptor stimulation. However, when daily treatment was continued for fourteen days, the blocking action became more prolonged. Antihypertensive agents which interfere with the sympathetic nervous system (α-methyldopa, clonidine, pargyline, and guanethidine) prevented the genesis and maintenance of DOCA-saline hypertension. The implication of these findings on the genesis of this hypertension and on the possible mode of action of propranolol is discussed. In the course of this project, rats were used for experiments which developed hypertension much more rapidly and to a greater extent than those used previously in this work. This accelerated hypertension was accompanied by refractoriness to antihypertensive therapy both during the developing and sustained phases of the hypertension. Investigations into the susceptibility of rats of the same strain, obtained from different sources, to DOCA-saline hypertension showed differences both in susceptibility to hypertension and in the effectiveness of therapy. The two substrains of the Wistar rat also revealed differences in susceptibility to and level of hypertension, in the cardiovascular reactivity to pressor stimuli and in the metabolism of sodium. The significance of these findings in the routine use of DOCA-saline hypertension in rats for screening of potential antihypertensive agents is discussed.