Contributions of plasma membrane ion transporters to Ca 2+ storage and myogenic tone

We evaluated the possible interdependency of α2 Na + pumps, Na + /Ca 2+ exchanger (NCX), store‐operated channels (SOC) and L‐type voltage‐gated Ca 2+ channels (LVC) in the control of sarcoplasmic reticulum (SR) Ca 2+ release and myogenic tone (MT) in pressurized mouse mesenteric small arteries. To define the role of LVC, we used mice in which the Ca v 1.2 LVC are resistant to dihydropyridines (DHP R/R ). Nifedipine (Nif, 0.3 – 1 μM) abolished high K + ‐induced contraction and MT in wild type (WT) but not DHP R/R arteries. Thus Ca 2+ entry via Ca v 1.2 LVC is the major pathway for maintaining MT and ≤ 1 μM Nif inhibits MT only by blocking LVC. In WT arteries, after SR depletion and MT abolition, readmission of external Ca 2+ induced MT recovery. This involved activation of LVC because it was abolished by Nif pretreatment. MT recovery was partially blocked and slowed by SEA0400 (0.3 – 1 μM, a selective NCX inhibitor), and SK&F‐96365 (3–10 μM, a SOC inhibitor). This implies that the activity of DHP‐sensitive LVC depends on SOC and NCX. SR Ca 2+ stores, measured by phenylephrine (5 μM) in Ca 2+ ‐free external solution were only partially refilled upon restoration of external Ca 2+ . Increased SR Ca 2+ release was observed in both α2 Na + pump heterozygotes and NCX heterozygotes. These results suggest a model of Ca 2+ dynamics in which SR refilling and MT generation depend on SOC, NCX and LVC. LVC may be activated by depolarization produced by cation entry through SOC and by Ca 2+ influx through NCX. Furthermore, NCX and α2 Na + pumps control SR Ca 2+ content. Supported by NHLBI and Austrian Science Funds (P‐17159).