Involvement of voltage-dependent Ca(2+) channel beta(3) subunit in the autonomic control of heart rate variability.
Noradrenaline release from sympathetic nerve terminals is dependent on Ca(2+) entry through neuronal voltage-gated N-type Ca(2+) channels. The accessory beta(3) subunits of Ca(2+) channels (Ca(V)beta(3)) are preferentially associated with the alpha(1B) subunit to form N-type Ca(2+) channels, and are therefore expected to play a functional role in the stimulation-evoked release of noradrenaline. In this study, we employed Ca(V)beta(3)-null, Ca(V)beta(3)-overexpressing (Ca(V)beta(3)-Tg), and wild-type (WT) mice to investigate the possible roles of Ca(V)beta(3) in the sympathetic regulation of heart rate in vivo. Telemetry was used to monitor the ECG and both time and frequency domain analyses were carried out to evaluate heart rate variability. In the frequency domain analysis, power spectral density of the RR interval series was computed using the fast Fourier transform algorithm. The resting heart rate was increased in Ca(V)beta(3)-Tg mice compared with both Ca(V)beta(3)-null and WT mice. Mice overexpressing Ca(V)beta(3) displayed decreased heart rate variability, which was measured by the time domain analysis of the standard deviation of RR intervals. In the frequency domain analysis, Ca(V)beta(3)-Tg mice showed decreased spectral powers compared with WT and Ca(V)beta(3)-null mice. Pharmacological blockade of beta-adrenergic receptors with metoprolol decreased the heart rate in all genotypes, but the extent of the decrease was most obvious in Ca(V)beta(3)-Tg mice. On the other hand, the spectral powers were decreased in response to parasympathetic blockade (atropine) in WT and Ca(V)beta(3)-Tg mice. These results indicate the functional roles of Ca(V)beta(3) in regulating sympathetic nerve signaling.
Department of Pharmacology, Akita University School of Medicine, Akita, Japan.
Tsai-Wen
TW
Wu
Kyoichi
K
Ono
Manabu
M
Murakami
Toshihiko
T
Iijima
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000502:physiology*; D004562:Electrocardiography; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010276:Parasympatholytics / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology*; D013565:Sympatholytics / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D020864:Calcium Channels, N-Type; D010276:Parasympatholytics; D021122:Protein Subunits; D013565:Sympatholytics; D001285:Atropine; D008790:Metoprolol; D010646:Phentolamine