Potentiation of α‐adrenoceptor‐mediated responses following chronic β‐adrenoceptor stimulation in the rat heart

Noradrenaline and isoprenaline were infused subcutaneously in rats by use of Alzet osmotic minipumps. The effects of catecholamine infusion on ventricular α‐ and β‐adrenoceptor density and also the responses of isolated cardiac tissues were compared with saline infusion. Noradrenaline (1 mg kg⁻¹) or isoprenaline (40 μg kg⁻¹) infused for 3 days resulted in a desensitization of β‐adrenoceptor‐mediated responses of isolated left atria and papillary muscles. Concentration‐response curves to isoprenaline were shifted to the right in left atria whilst maximum responses were reduced in papillary muscles. Right atrial rate responses were not affected by infusions of catecholamines. Infusions of either noradrenaline or isoprenaline resulted in a supersensitivity of α‐adrenoceptor‐mediated responses in isolated papillary muscles with leftward displacements of concentration‐response curves to phenylephrine. The density of both ventricular [³H]‐dihydroalprenolol and [³H]‐prazosin binding sites was reduced following noradrenaline infusion. Isoprenaline infusion reduced only the density of [³H]‐dihydroal‐prenolol binding sites. Noradrenaline infusion therefore ‘down‐regulates’ both α‐ and β‐adrenoceptors in the rat heart but at the same time ventricular α‐adrenoceptor‐mediated responses are enhanced. Isoprenaline similarly enhances responses to phenylephrine and possible mechanisms for this phenomenon are discussed. 1993 British Pharmacological Society