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      Intracellular Ca2+ silences L-type Ca2+ channels in mesenteric veins: mechanism of venous smooth muscle resistance to calcium channel blockers.

      Circulation Research

      Animals, Blotting, Western, Calcium, metabolism, Calcium Channel Blockers, pharmacology, Calcium Channels, L-Type, drug effects, Chelating Agents, Dose-Response Relationship, Drug, Drug Resistance, Enzyme Inhibitors, Male, Membrane Potentials, Mesenteric Arteries, Mesenteric Veins, Muscle, Smooth, Vascular, Nifedipine, Patch-Clamp Techniques, Potassium Chloride, Rats, Rats, Sprague-Dawley, Sarcoplasmic Reticulum Calcium-Transporting ATPases, antagonists & inhibitors, Vasoconstriction, Vasoconstrictor Agents, Vasodilation, Vasodilator Agents

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          Calcium channel blockers (CCBs) exert their antihypertensive effect by reducing cardiac afterload but not preload, suggesting that Ca(2+) influx through L-type Ca(2+) channels (LTCC) mediates arterial but not venous tone. The object of this study was to resolve the mechanism of venous resistance to CCBs. 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 alpha(1C) pore-forming subunit of the LTCC in both vessels. Patch-clamp studies revealed a similar density of whole-cell Ca(2+) 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 Ca(2+) in venous SMCs. After depletion of intracellular Ca(2+) stores by the SERCA pump inhibitor thapsigargin, depolarization-induced constrictions in MVs were blocked 80% by nifedipine suggesting restoration of Ca(2+) influx through LTCCs. Similarly, KCl-induced constrictions were sensitive to block by nifedipine after depletion of intracellular Ca(2+) 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 Ca(2+) significantly increased the open-state probability of venous LTCCs. We report that intracellular Ca(2+) inactivates LTCCs in venous SMCs to confer venous resistance to CCB-induced dilation, a fundamental drug property that was previously unexplained.

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