Controlled β-Receptor Blockade with Flestolol: A Novel Ultrashort-Acting β-Blocker

The pharmacological properties of an ultrashort- acting β-receptor blocking agent, flestolol, were evaluated in rabbits. Infusion of graded doses (1–100 µg/kg/min, i.v.) into conscious rabbits produced dose-dependent bradycardia without any significant effect on mean arterial pressure. A desired level of heart rate could be obtained by either increasing or decreasing the dose infused. Such titration could be done by changing the dose of flestolol at 20-min intervals. Infusion of 31 µg/kg/ min of flestolol into reserpinized, conscious rabbits had no effect on mean arterial pressure or heart rate but produced significant inhibition of isoproterenol-induced hypotension and tachycardia. This dose had no effect on the chronotropic and vascular effects of norepinephrine (NE), angiotensin II, adenosine, or acetylcholine. In these rabbits, flestolol was >10-fold as active as esmolol, another ultrashort-acting β-blocking agent, in inhibiting the responses to isoproterenol. In rabbits under pentobarbital anesthesia, infusion of flestolol (3.1, 10, and 31 (µg/kg/min) produced dose-dependent β-receptor blockade. On termination of a 70-min infusion, recovery of the responses to isoproterenol occurred within 30 min. In a separate series of experiments, the effects of infusion of flestolol (10 µg/kg/min) into the portal vein were compared with the effects of infusion of the same dose of flestolol into the femoral vein of anesthetized rabbits. Infusion into the femoral vein produced bradycardia and inhibited the hypotensive as well as cardioaccelerator effects of isoproterenol. Infusion into the portal vein was devoid of either effect, suggesting extensive inactivation by the liver. The results of this study show that flestolol is a specific β-receptor blocking agent with a very short duration of action. Such properties permit rapid titration of the dose to achieve desired level of β-receptor blockade.