Previous studies with peptidic
renin inhibitors have shown that high intravenous (i.v.) doses can induce unexpectedly large decreases in blood pressure (BP) that appear to be independent of plasma
renin inhibition.
A-74273 represents a new class of potent and orally bioavailable nonpeptidic
renin inhibitors. We evaluated the BP effects of this
renin inhibitor administered orally (p.o.) or i.v. at high doses to conscious
salt-depleted dogs. Administration of
A-74273 at 30 and 60 mg/kg p.o. (n = 6 per dose) produced similar maximum reductions in BP (-40 +/- 4 vs. -46 +/- 5 mm Hg) despite the occurrence of greater plasma
drug concentrations at the higher dose. Duration of
hypotension, however, was increased (p < 0.05) from 9 h at 30 mg/kg to 18 h at 60 mg/kg. The initial depressor response to 10 and 30 mg/kg i.v. doses of
A-74273 (n = 6 per dose) was comparable, although duration and overall BP response was greater at 30 mg/kg i.v.
No BP responses to
A-74273 were noted in
salt-replete dogs (n = 5). The
hypotension produced by 30 mg/kg p.o.
A-74273 was completely reversed by
norepinephrine (NE 5 micrograms/kg/min; n = 5) or isotonic saline (4 ml/min/kg, n = 5) infusion. These studies demonstrate that high doses of
A-74273 result in predictable BP responses that are
renin-dependent and reversible. Therefore, large decreases in BP with high doses is not an attribute common to all
renin inhibitors but appears to be a function of the structural characteristics specific to a particular compound.