Pharmacology of AH 5158; a drug which blocks both α‐ and β‐adrenoceptors

Abstract

1 AH 5158 differs from conventional adrenoceptor blocking drugs in producing competitive blockade of both α- and β-adrenoceptors. 2 AH 5158 is 5–18 times less potent than propranolol in blocking β-adrenoceptors. It resembles propranolol in its non-selective blockade of β₁-cardiac and β₂-vascular and tracheal adrenoceptors and in its lack of intrinsic sympathomimetic activity. 3 AH 5158 is 2–7 times less potent than phentolamine in blocking α-adrenoceptors. AH 5158 itself is more active on β- than α-adrenoceptors. 4 Blockade of noradrenaline vasopressor responses by AH 5158 in anaesthetized dogs was dose-dependent up to 1 mg/kg but no further blockade was obtained with larger doses of AH 5158. ‘Self-limiting’ blockade was not observed in dogs pretreated with cocaine, or in untreated dogs if the vasopressor agent was oxymetazoline instead of noradrenaline. A possible cause of ‘self-limiting’ blockade is discussed. 5 In doses higher than those required for either α- or β-adrenoceptor blockade, AH 5158 produced effects on cardiac muscle that are attributable to membrane-stabilizing activity. This was manifested as a negative inotropic action in spinal dogs and in guinea-pig left atrial strips, as a negative chronotropic action in syrosingopine pre-treated dogs, and as an increase in the effective refractory period of guinea-pig left atrial strips. AH 5158 was 3–11 times less potent than propranolol in these tests. 6 In open chest dogs AH 5158 resembled propranolol in reducing cardiac output, rate and contractility, effects which are attributable to β-adrenoceptor blockade. The drug differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger decreases in arterial blood pressure at equipotent β-adrenoceptor blocking doses. These differences are attributable to the α-adrenoceptor blocking actions of AH 5158. 7 In anaesthetized dogs, intravenously administered AH 5158 antagonized both catecholamine and ouabain-induced arrhythmias. Orally administered AH 5158 lowered systolic arterial pressure in conscious renal hypertensive dogs. 8 These results show AH 5158 to possess a novel profile of activity. Possible uses of the drug in cardiovascular disorders such as hypertension, angina pectoris and cardiac arrhythmias are discussed.