Subsensitivity to beta-adrenoceptor agonists in pacemakers isolated from senescent rats

1. The effects of aging on the responsiveness of the isolated pacemaker of the rat to the chronotropic effect of norepinephrine, isoproterenol and soterenol were studied. 2. Pacemakers isolated from senescent rats (22-24 months old) showed subsensitivity to norepinephrine, isoproterenol and soterenol, when compared with pacemakers isolated from young rats (3-4 months old). The maximum response to the partial agonist soterenol was reduced. 3. Determination of the pA2 value of metoprolol in pacemakers isolated from senescent and young rats showed that the chronotropic response is mediated by a homogeneous beta 1-adrenoceptor population. 4. Inhibition of extraneuronal uptake did not potentiate the chronotropic effect of isoproterenol in pacemakers isolated from senescent rats. Addition of cocaine shifted the concentration-effect curve for norepinephrine only 2.2-fold to the left in senescent rats. 5. It is concluded that, during aging, impairment of the extraneuronal and neuronal uptake mechanisms has an important role in the control of chronotropic responsiveness to catecholamines.