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The Na+-Ca2+ exchanger contributes to beta-adrenoceptor mediated positive inotropy in mouse heart
Isao Kubota1, Hitonobu Tomoike, Xinquiang Han
1First Department of Internal Medicine, Yamagata University School of Medicine, Japan.
Abstract:
The L-type Ca2+ current (I(Ca,L)) plays an important role in the regulation of cardiac contractility. However, there is little data with regard to the significance of the I(Ca,L)-independent mechanism of beta-adrenoceptor mediated positive inotropy. The effects of isoproterenol (ISO) on I(Ca,L) and contractility in the presence of Ca2+ channel blockers (nifedipine, verapamil) were examined in adult mouse ventricular myocytes. ISO increased contractility over the level before the administration of Ca2+ channel blocker, although it had a very limited effect on I(Ca,L). The positive inotropy of ISO disappeared after administration of Ni2+, an inhibitor of the Na+-Ca2+ exchanger. The addition of ISO after nifedipine pretreatment also increased the [Ca2+]i transient over the control level and the application of Ni2+ or KB-R7943, a selective Na+-Ca2+ exchange inhibitor (reverse mode), abolished the increase in [Ca2+]i transient. Therefore, an I(Ca,L)-independent mechanism plays a significant role in beta-adrenoceptor mediated positive inotropy. The Na+-Ca2+ exchanger is necessary for the development of this action.
Insights
Beta-adrenergic stimulation enhances heart muscle contraction through an L-type calcium channel-independent pathway. The Na+-Ca2+ exchanger is crucial for this positive inotropic effect in cardiac myocytes.
Area of Science:
- Cardiology
- Molecular Physiology
- Pharmacology
Background:
- L-type Ca2+ current (I(Ca,L)) regulates cardiac contractility.
- Mechanisms of beta-adrenoceptor-mediated positive inotropy independent of I(Ca,L) are not well understood.
Purpose of the Study:
- To investigate the role of I(Ca,L)-independent mechanisms in beta-adrenoceptor mediated positive inotropy.
- To determine the involvement of the Na+-Ca2+ exchanger in this process.
Main Methods:
- Adult mouse ventricular myocytes were used.
- Effects of isoproterenol (ISO) on contractility and I(Ca,L) were assessed with and without Ca2+ channel blockers (nifedipine, verapamil) and Na+-Ca2+ exchanger inhibitors (Ni2+, KB-R7943).
Main Results:
- ISO increased contractility and intracellular Ca2+ ([Ca2+]i) transient, even with Ca2+ channel blockade.
- This ISO-induced positive inotropy and [Ca2+]i transient increase were abolished by Na+-Ca2+ exchanger inhibition.
- ISO had minimal effect on I(Ca,L) in the presence of Ca2+ channel blockers.
Conclusions:
- An I(Ca,L)-independent mechanism significantly contributes to beta-adrenoceptor mediated positive inotropy.
- The Na+-Ca2+ exchanger is essential for mediating this I(Ca,L)-independent positive inotropic effect in the heart.