The peripheral vascular actions of i.v. administered
ASL-7022 were investigated in anesthetized, open-chest dogs and in isolated hindlimbs of normal, acute baroreceptor-denervated and spinal dogs.
ASL-7022 decreased diastolic arterial blood pressure in open-chest dogs, an effect which was inhibited by
ganglion blockade (
hexamethonium bromide, 10 mg/kg i.v.). In hindlimbs from control animals,
ASL-7022 produced vasodilation.
Propranolol (1.0 mg/kg i.v.) reduced but did not eliminate vasodilation in these preparations but combined beta
adrenergic and
ganglion blockade converted responses to vasoconstriction.
ASL-7022 induced greater vasodilation in hindlimbs from acute baroreceptor-denervated animals than in control animals. In acute baroreceptor-denervated preparations
ganglion blockade eliminated vasodilation,
propranolol partially blocked vasodilation and combined beta
adrenergic and
ganglion blockade converted responses to vasoconstriction. In spinal dogs i.v. infusion of low doses of
ASL-7022 induced small increases in perfusion pressure; higher doses produced small decreases in perfusion pressure. The compound caused only vasoconstriction in
propranolol-pretreated hindlimbs and caused only vasodilation in
phentolamine-pretreated hindlimbs.
ASL-7022 also dose dependently inhibited
vasoconstrictor responses to electrical stimulation of the lumbar sympathetic chain and to exogenously administered
norepinephrine. The data suggest that
ASL-7022 blocks sympathetic vasoconstriction by either inhibiting the sympathetic nervous system or by inducing postsynaptic alpha
adrenoceptor blockade. The compound also produces beta
adrenoceptor-mediated vasodilation and, under appropriate pharmacological conditions, can be demonstrated to produce alpha
adrenoceptor-mediated vasoconstriction.