The autonomic and
antihypertensive activities of
amosulalol (YM-09538) were studied in conscious rats. Single
oral administration of
amosulalol antagonized the
phenylephrine-induced pressor and
isoproterenol-induced positive chronotropic responses with DR10 values of 11.5 and 13.6 mg/kg in pithed rats, respectively, indicating that the compound inhibits both alpha 1- and beta 1-adrenoceptors to almost the same extent in agreement with previously reported results in vitro.
Amosulalol was approximately 50 times less potent than
prazosin and 12 times more potent than
labetalol at alpha 1-adrenoceptors, and it was approximately as effective as
labetalol and 2 times more potent than
propranolol at beta 1-adrenoceptors. In spontaneously hypertensive rats (SHR), renal hypertensive rats and
DOCA/
salt hypertensive rats, a single
oral administration of
amosulalol (3-30 mg/kg) lowered acutely systolic blood pressure with a duration of over 6 hr and was found to be approximately 50 times less potent than
prazosin and 3 times more potent than
labetalol in lowering blood pressure.
Propranolol did not cause such an immediate hypotensive effect.
Amosulalol and
labetalol did not increase heart rate, whereas
prazosin induced a
tachycardia in the hypertensive rats. Repeated
oral administrations of
amosulalol and
labetalol (50 mg/kg/day, b.i.d., for 12 weeks) produced not only an
antihypertensive effect without evidence of tolerance, but also reductions in plasma
renin activity (PRA) and heart rate in SHR with established
hypertension. We conclude that alpha-
adrenoceptor blockade by
amosulalol might account for its
antihypertensive activity and that its beta-
adrenoceptor blockade might inhibit reflexogenic increases in heart rate and PRA due to the reduction in blood pressure.