Intracellular calcium silences L‐Type Ca2+ channels in rat small mesenteric veins

Abstract

Calcium channel blockers (CCBs) exert their antihypertensive effect by reducing cardiac afterload but not preload, suggesting that L‐type Ca2+ (CaL) channels contribute to arterial tone but are silent in resistance veins. Using rat small mesenteric arteries (MA) and veins (MV) perfused at their physiological pressures, we confirmed that the CCB nifedipine prevents KCl‐induced constriction of MA but not MV. We hypothesized that MVs rely on intracellular Ca2+ ([Ca]i) rather than CaL channels for constriction and that [Ca]i silences CaL channels in MVs. Indeed, the SERCA inhibitor, thapsigargin (1 μM), constricted MV but not MA (88±2% vs 3±3% relative to 60mM KCl constriction, respectively), suggesting that SR Ca2+ may fuel MV constriction. When [Ca]i was depleted by thapsigargin and extracellular Ca2+ ([Ca]o) omitted, KCl failed to constrict MVs. After depletion of [Ca]i by thapsigargin in MV and subsequent restoration of 1.5 mM [Ca]o, KCl (60 mM) contractions were partially (61±1%) restored but these contractions were blocked (61%) by 1 μM nifedipine. These data suggest: 1) a link between SR Ca2+ and constriction in MV and 2) that depletion of [Ca]i in MV disinhibits CaL channels, restoring CaL‐mediated Ca2+ influx as a source of venoconstriction. Thus, drugs that selectively deplete venous [Ca]i may represent novel therapies for the treatment of hypertension and other diseases that exhibit elevated venous tone.