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

1972; Wiley; Volume: 45; Issue: 4 Linguagem: Inglês

10.1111/j.1476-5381.1972.tb08125.x

1476-5381

J B Farmer, I. Kennedy, Gerhard Levy, Richard Marshall,

Analytical Methods in Pharmaceuticals

Summary AH 5158 differs from conventional adrenoceptor blocking drugs in producing competitive blockade of both α‐ and β‐adrenoceptors. AH 5158 is 5–18 times less potent than propranolol in blocking β‐adrenoceptors. It resembles propranolol in its non‐selective blockade of β 1 ‐cardiac and β 2 ‐vascular and tracheal adrenoceptors and in its lack of intrinsic sympathomimetic activity. 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. 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. 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. 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. 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. 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.