THE ANTIHYPERTENSIVE EFFECT OF THE ANGIOTENSIN-II RECEPTOR ANTAGONIST DUP-753 MAY NOT BE DUE SOLELY TO ANGIOTENSIN-II RECEPTOR ANTAGONISM

The angiotensin II (AII) receptor antagonist, DuP 753 (10 mg/kg intraduodenal), produced a sustained and long-lasting antihypertensive effect in conscious renin-dependent hypertensive rats. Blood pressures were still reduced markedly 24 to 72 hr after administration of a single dose of DuP 753. However, pressor responses elicited by either angiotensin I or AII were not blocked at these times despite the continued antihypertensive effect of DuP 753. In a model of orthostatic hypotension, DuP 753 and the selective alpha-1 adrenoceptor antagonist prazosin produced a marked orthostatic hypotension response in renin-dependent hypertensive rats as demonstrated by potentiation of the decrease in blood pressure induced by a 90-degrees tilt. The nonpeptide All receptor antagonist SK&F 108566 (10 mg/kg intraduodenal) did not produce orthostatic hypotension and the angiotensin converting enzyme inhibitor enalapril produced only a slight orthostatic response to tilting. In conscious spontaneously hypertensive rats (SHR), allowed 3 to 4 days to recover from surgery, administration of either enalapril (1 mg/kg i.v.) or SK&F 108566 (10 mg/kg i.v.) did not significantly effect blood pressure. In SHR tested within 24 hr of surgery, enalapril was effective in lowering blood pressure. In contrast, in surgically recovered SHR, DuP 753 (10 mg/kg i.v.) produced an antihypertensive effect that was slow in onset, sustained and extremely long in duration. Blood pressures did not return to predrug levels until 48 hr after administration of DuP 753. Stimulation of the thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses that were significantly potentiated by continuous infusion of a subpressor dose of AII. Captopril, Sar1-Ile8[AII] (a peptide AII receptor antagonist) and SK&F 108566, but not DuP 753, inhibited pressor responses to sympathetic nerve stimulation. The lack of effect on stimulation-induced pressor responses by DuP 753 was observed after either a 4- or 24-hr pretreatment. In conclusion, the disparent results between DuP 753 and other AII receptor antagonists and angiotensin converting enzyme inhibitors suggest additional pharmacological effects of DuP 753 beyond AII receptor blockade.