Selectivity of the Intrinsic Sympathomimetic Activity of the β-Adrenergic Blocking Drug Bucindolol

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Abstract
The comparative effects of .beta.-adrenergic blockade with propranolol (PROP) and bucindolol (BUC), a .beta.-adrenergic agonist having both .alpha.-adrenergic blocking properties and intrinsic sympathomimetic activity (ISA) on airway and cardiovascular responses, were studied in 38 mongrel dogs in situ. I.v. infusion of 0.6 mg/kg + 6 .mu.g/kg per min BUC and 2.0 mg/kg + 20 .mu.g/kg per min PROP caused identical shifts in the isoproterenol (ISO) EC50 for chronotropic and hypotensive arterial blood pressure responses. After PROP administration, resting heart rate (HR) decreased from 188 .+-. 15 to 142 .+-. 12 beats/min (P < 0.02); BUC caused no decrease in HR. The BUC and PROP effects on mean arterial blood pressure response to ISO were similar. No change in bronchomotor tone was observed after bolus injection of BUC or PROP. .beta.-Adrenrergic relaxation to ISO and .alpha.-adrenergic contraction to norepinephrine (NE) were studied simultaneously in tracheal and bronchial airways using chronotropically equivalent .beta.-adrenoceptor blocking doses of PROP and BUC. Comparable inhibition of ISO-induced airway relaxation after contraction with 120 .mu.g/kg per min i.v. serotonin was demonstrated in PROP (n = 15) and BUC (n = 5) groups (P < 0.01 for doses > 5 .times. 10-11 mol/kg). Both BUC (n = 5) and PROP (n = 5) blocked .beta.-adrenergic relaxation and caused identical .alpha.-adrenergic airway contraction to i.v. NE. Apparently, the ISA of the .beta.-adrenergic blocking drug BUC can be demonstrated on the spontaneous HR but not on bronchial smooth muscle activity. BUC neither augments ISO-induced relaxation nor inhibits NE-induced contraction of airways after effective chronotropic blockade.