The mechanism of phenylephrine-mediated [Ca(2+)](i) oscillations underlying tonic contraction in the rabbit inferior vena cava

• Published in: The Journal of physiology 2001-08, Vol.534 (Pt 3), p.641-650
• Main Authors: Lee, C H, Poburko, D, Sahota, P, Sandhu, J, Ruehlmann, D O, van Breemen, C
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium Channels - physiology; Calcium Channels, L-Type - physiology; Calcium-Transporting ATPases - metabolism; Cardiotonic Agents - pharmacology; Female; Intracellular Membranes - metabolism; Myocardial Contraction - physiology; Oscillometry; Osmolar Concentration; Phenylephrine - pharmacology; Rabbits; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Calcium Exchanger - physiology; Vena Cava, Inferior - physiology
• ISSN: 0022-3751
• DOI: 10.1111/j.1469-7793.2001.t01-1-00641.x

1. We characterized the mechanisms in vascular smooth muscle cells (VSMCs) that produce asynchronous, wave-like Ca(2+) oscillations in response to phenylephrine (PE). Confocal imaging was used to observe [Ca(2+)](i) in individual VSMCs of intact inferior vena cava (IVC) from rabbits. 2. It was found that the Ca(2+) waves were initiated by Ca(2+) release from the sarcoplasmic reticulum (SR) via inositol 1,4,5-trisphosphate-sensitive SR Ca(2+) release channels (IP(3)R channels) and that refilling of the SR Ca(2+) store through the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (SERCA) was required for maintained generation of the repetitive Ca(2+) waves. 3. Blockade of L-type voltage-gated Ca(2+) channels (L-type VGCCs) with nifedipine reduced the frequency of PE-stimulated [Ca(2+)](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 Ca(2+) entry refills the SR to support the recurrent waves of SR Ca(2+) release and that both L-type VGCCs and ROCs/SOCs contribute to this process. 4. Application of the Na(+)-Ca(2+) exchanger (NCX) inhibitors 2',4'-dichlorobenzamil (forward- and reverse-mode inhibitor) and KB-R7943 (reverse-mode inhibitor) completely abolished the nifedipine-resistant component of [Ca(2+)](i) oscillations and markedly reduced PE-induced tone. 5. Thus, we conclude that each Ca(2+) wave depends on initial SR Ca(2+) release via IP(3)R channels followed by SR Ca(2+) refilling through SERCA. Na(+) entry through ROCs/SOCs facilitates Ca(2+) entry through the NCX operating in the reverse mode, which refills the SR and maintains PE-induced [Ca(2+)](i) oscillations. In addition some Ca(2+) entry through L-type VGCCs and ROCs/SOCs serves to modulate the frequency of the oscillations and the magnitude of force development.