Abstract
Cardioprotection in females, as observed in the setting of heart failure, has been attributed to sex differences in intracellular calcium handling and its modulation by β-adrenergic signaling. However, further studies examining sex differences in β-adrenergic responsiveness have yielded inconsistent results and have mostly been limited to studies of contractility, ion channel function, or calcium handling alone. Given the close interaction of the action potential (AP) and intracellular calcium transient (CaT) through the process of excitation-contraction coupling, the need for studies exploring the relationship between agonist-induced AP and calcium handling changes in female and male hearts is evident. Thus, the aim of this study was to use optical mapping to examine sex differences in ventricular APs and CaTs measured simultaneously from Langendorff-perfused hearts isolated from naïve adult rabbits during β-adrenergic stimulation. The non-selective β-agonist isoproterenol (Iso) decreased AP duration (APD90), CaT duration (CaD80), and the decay constant of the CaT (τ) in a dose-dependent manner (1–316.2 nM), with a plateau at doses ≥31.6 nM. The Iso-induced changes in APD90 and τ (but not CaD80) were significantly smaller in female than male hearts. These sex differences were more significant at faster (5.5 Hz) than resting rates (3 Hz). Treatment with Iso led to the development of spontaneous calcium release (SCR) with a dose threshold of 31.6 nM. While SCR occurrence was similar in female (49%) and male (53%) hearts, the associated ectopic beats had a lower frequency of occurrence (16% versus 40%) and higher threshold (100 nM versus 31.6 nM) in female than male hearts (p<0.05). In conclusion, female hearts had a decreased capacity to respond to β-adrenergic stimulation, particularly under conditions of increased demand (i.e. faster pacing rates and “maximal” levels of Iso effects), however this reduced β-adrenergic responsiveness of female hearts was associated with reduced arrhythmic activity.
Highlights
Stimulation of adrenergic receptors by catecholamines is the predominant regulatory mechanism for cardiovascular performance [1,2]
At 3 Hz, the mean calcium transient (CaT) decay constant (t) from the left ventricle (LV) base was significantly faster in female hearts than male hearts (58.563.9 ms versus 72.864.3 ms, p,0.05), while a similar trend existed for the LV apex
The main findings of this study are that: 1) at baseline there were no significant sex differences in APD90 or CaD80, and only minimal differences in t; 2) Iso reduced APD90, CaD80, t in a dose-dependent fashion with ‘‘submaximal’’ effects observed at 1– 10 nM Iso and ‘‘maximal’’ effects at $31.6 nM; 3) the Isoinduced changes in APD90 and t were significantly less in female than male hearts, and these differences were enhanced during faster pacing rates (5.5 Hz) and higher doses of Iso ($31.6 nM); 4) there were no sex differences in the frequency or dose threshold of spontaneous calcium release (SCR) (31.6 nM); 5) the frequency of EBs was lower, and the dose threshold was higher in female than male hearts
Summary
Stimulation of adrenergic receptors by catecholamines is the predominant regulatory mechanism for cardiovascular performance [1,2]. Many cardiovascular diseases involve changes in badrenergic signaling that often lead to decreased cardiac performance, cardiac arrhythmias, and sudden cardiac death [3,4]. This has made b-adrenergic receptors (b-ARs), and their signaling cascades, a significant therapeutic target in cardiovascular disease. Given the association of sympathetic stimulation with arrhythmias and mortality in cardiovascular disease, female cardioprotection and potential sex differences in b-adrenergic responsiveness are of particular interest. Despite this clear need, this important issue has been investigated by a limited number of studies. One factor that could potentially contribute to this lack of agreement is the variability in the dose(s) of b-AR agonists that were used in these studies
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