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

Cheng-Han Lee, Damon Poburko, Paul Sahota, Jasmin Sandhu, Dietrich O. Ruehlmann and Cornelis van Breemen

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

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