Abstract:
Background: Reduced contractility is a hallmark of failing hearts, often linked to depressed Ca2+ transients, since Ca2+ is the key activator of contraction. Impaired excitation-contraction coupling has been observed in conjunction with structural alterations to the t-tubular system. However, many sub-cellular changes occur in heart failure, making it difficult to determine the contribution of disrupted t-tubules. Our aim was to quantify the impact of detubulation on Ca2+ handling and contraction in otherwise healthy ventricular tissue. Methods: Measurement of [Ca2+]i (fura-2) and stress were made in RV trabeculae from rat hearts before and after detubulation following formamide treatment (1.5 M, 5 min). The effect of detubulation on two important regulatory mechanisms was also investigated: the response to stretch, and to β-adrenergic stimulation (0.1 μM isoproterenol). Results: De-tubulation of trabeculae slowed the time course of the Ca2+ transients and twitch force: time-to-peak, maximum rate-of-rise, and relaxation were prolonged in both. The slow force response to stretch was decreased following detubulation, and the response to β-adrenergic activation blunted. Conclusions: This study enabled us to examine the effect of detubulation on Ca2+ transients and twitch force in tissue from non-failing hearts in which expression of the different Ca2+ handling proteins was not altered by any disease process. Our results demonstrate the importance of an intact t-tubular system on the kinetics of excitation-contraction coupling, as well as on mechanisms that regulate contractility in vivo: the response to stretch and β-adrenergic stimulation.
