Reduced Excitability and Ca2+ Current Density in Sinoatrial Myocytes from Aged Mice

Abstract

Cardiac pacemaking results from the generation of spontaneous action potentials (APs) by specialized myocytes in the sinoatrial node (sinoatrial myocytes, SAMs). These APs are produced by the coordinated activity of a number of different ion channels, including hyperpolarization-activated cyclic nucleotide-sensitive (HCN) channels and voltage-gated Ca2+ channels. Across all mammalian species, the maximum heart rate that can be elicited by stress or exercise decreases with age. However, little is known about age-related changes in the intrinsic excitability of SAMs. In this study, we examined differences in heart rate in young (<3 mo) versus old (>32 mo) mice, and the corresponding differences in spontaneous AP firing rate and ionic currents in isolated SAMs from young versus old animals. ECG measurements in vivo confirmed previous observations of age-related reductions in maximum heart rate and intrinsic heart rate (i.e., in the absence of autonomic input). Current clamp recordings from acutely isolated SAMs revealed age-related deficits in spontaneous AP firing rate that mirrored the age-related changes in heart rate; the basal AP firing rate was significantly slower in SAMs from elderly animals, and maximal stimulation with 1 μM isoproterenol (Iso, a β adrenergic agonist) resulted in a slower average maximum firing rate in SAMs from old mice. To explore the mechanistic bases of these age-related deficiencies in sinoatrial AP generation, we have recently begun voltage-clamp recordings of hyperpolarization-activated currents and voltage-gated calcium currents from isolated SAMs from young and old mice. To date, we have found significant reductions in Ca2+ current density in cells from older animals. These studies may provide mechanistic information about fundamental processes that limit the physical capability of the elderly.