Intracellular Ca2+ silences L-type Ca2+ channels in mesenteric veins: mechanism of venous smooth muscle resistance to calcium channel blockers.
Intracellular Ca2+ silences L-type Ca2+ channels in mesenteric veins: mechanism of venous smooth muscle resistance to calcium channel blockers.
复制标题
细胞内 Ca2 沉默肠系膜静脉中的 L 型 Ca2 通道：静脉平滑肌抵抗钙通道阻滞剂的机制。
DOI：
10.1161/circresaha.109.206763
复制
发表时间：
2010
影响因子：
20.1
通讯作者：
Rusch,NancyJ
中科院分区：
文献类型：
--
作者：
Thakali,KeshariM;Kharade,SujayV;Sonkusare,SwapnilK;Rhee,SungW;Stimers,JosephR;Rusch,NancyJ
Rationale:Calcium channel blockers (CCBs) exert their antihypertensive effect by reducing cardiac afterload but not preload, suggesting that Ca2+influx through L-type Ca2+channels (LTCC) mediates arterial but not venous tone.Objective:The object of this study was to resolve the mechanism of venous resistance to CCBs.Methods and Results:We compared the sensitivity of depolarization (KCl)-induced constriction of rat small mesenteric arteries (MAs) and veins (MVs) to the dilator effect of CCBs. Initial findings confirmed that nifedipine progressively dilated depolarization-induced constrictions in MAs but not MVs. However, Western blots showed a similar expression of the α1Cpore-forming subunit of the LTCC in both vessels. Patch-clamp studies revealed a similar density of whole-cell Ca2+channel current between single smooth muscle cells (SMCs) of MAs and MVs. Based on these findings, we hypothesized that LTCCs are expressed but “silenced” by intracellular Ca2+in venous SMCs. After depletion of intracellular Ca2+stores by the SERCA pump inhibitor thapsigargin, depolarization-induced constrictions in MVs were blocked 80% by nifedipine suggesting restoration of Ca2+influx through LTCCs. Similarly, KCl-induced constrictions were sensitive to block by nifedipine after depletion of intracellular Ca2+stores by caffeine, ryanodine, or 2-aminoethoxydiphenyl borate. Cell-attached patch recordings of unitary LTCC currents confirmed rare channel openings during depolarization of venous compared to arterial SMCs, but chelating intracellular Ca2+significantly increased the open-state probability of venous LTCCs.Conclusions:We report that intracellular Ca2+inactivates LTCCs in venous SMCs to confer venous resistance to CCB-induced dilation, a fundamental drug property that was previously unexplained.
