The mechanism of phenylephrine‐mediated [Ca2+]i oscillations underlying tonic contraction in the rabbit inferior vena cava

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Abstract
We characterized the mechanisms in vascular smooth muscle cells (VSMCs) that produce asynchronous, wave-like Ca2+ oscillations in response to phenylephrine (PE). Confocal imaging was used to observe [Ca2+]i in individual VSMCs of intact inferior vena cava (IVC) from rabbits.It was found that the Ca2+ waves were initiated by Ca2+ release from the sarcoplasmic reticulum (SR) via inositol 1,4,5-trisphosphate-sensitive SR Ca2+ release channels (IP3R channels) and that refilling of the SR Ca2+ store through the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) was required for maintained generation of the repetitive Ca2+ waves.Blockade of L-type voltage-gated Ca2+ channels (L-type VGCCs) with nifedipine reduced the frequency of PE-stimulated [Ca2+]i oscillations, while additional blockade of receptor-operated channels/store-operated channels (ROCs/SOCs) with SKF96365 abolished the remaining oscillations. Parallel force measurements showed that nifedipine inhibited PE-induced tonic contraction by 27% while SKF96365 abolished it. This indicates that stimulated Ca2+ entry refills the SR to support the recurrent waves of SR Ca2+ release and that both L-type VGCCs and ROCs/SOCs contribute to this process.Application of the Na+-Ca2+ exchanger (NCX) inhibitors 2′,4′-dichlorobenzamil (forward- and reverse-mode inhibitor) and KB-R7943 (reverse-mode inhibitor) completely abolished the nifedipine-resistant component of [Ca2+]i oscillations and markedly reduced PE-induced tone.Thus, we conclude that each Ca2+ wave depends on initial SR Ca2+ release via IP3R channels followed by SR Ca2+ refilling through SERCA. Na+ entry through ROCs/SOCs facilitates Ca2+ entry through the NCX operating in the reverse mode, which refills the SR and maintains PE-induced [Ca2+]i oscillations. In addition some Ca2+ entry through L-type VGCCs and ROCs/SOCs serves to modulate the frequency of the oscillations and the magnitude of force development.