Losartan is a
prodrug type
Angiotensin II (Ang II) AT1-receptor antagonist whose efficacy depends on the
oxidase activity of individuals. In addition,
losartan affects the normal blood pressure and can potentially cause
orthostatic hypotension. In this report, we examined effects of
TA-606 [(3-pentyloxy)carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2'(1H -
tetrazole-5-yl)
biphenyl-4-yl]methyl-4,5,6,7-tetrahydro imidazo[4,5-c]
pyridine-4-carboxylate hydrochloride], a
prodrug type AT1-receptor antagonist, on the Ang II-induced pressor response and
hypertension in a dog model, which is known to have lower
oxidase activity than other species, and
orthostatic hypotension in the rat tilting model. The results indicated that
TA-606 was immediately converted to its active form,
606A, after
oral administration, and it demonstrated potent inhibition of the Ang II-induced pressor response in conscious normotensive dogs (0.3-3 mg/kg, p.o.). It also had a potent hypotensive effect in conscious 2K,1C-renal hypertensive dogs (0.3-10 mg/kg, p.o.). These effects of
TA-606 were 32 and 30 times more potent than those of
losartan, respectively. In addition,
EXP3174 (1, 10 mg/kg, i.v.), an active metabolite of
losartan, but not
606A (1-30 mg/kg, i.v.) showed an orthostatic hypotensive effect in the rat tilting model. These results suggest that
TA-606 is an effective Ang II receptor antagonist without the drawbacks of
losartan.