Vasorelaxation and inhibition of the voltage-operated Ca2+ channels by FK506 in the porcine coronary artery

摘要

class="enumerated" style="list-style-type:decimal">Using fura-2 fluorometry, the effects of FK506, an immunosuppressant, on changes in cytosolic Ca²⁺ concentrations ([Ca²⁺]i) and tension were investigated in porcine coronary arterial strips. The effects of FK506 on the activity of voltage-operated Ca²⁺ channels were examined by applying a whole cell patch clamp to the isolated smooth muscle cells of porcine coronary artery.FK506 inhibited the sustained increases in both [Ca²⁺]i and tension induced by 118 mM K⁺ depolarization and 100 nM U46619 in a concentration-dependent manner (1–30 μM). The extent of inhibition of the K⁺-induced contraction was greater than that of the U46619-induced contraction. The increases in [Ca²⁺]i and tension induced by histamine and endothelin-1 in the presence of extracellular Ca²⁺ were also inhibited by 10 μM FK506.FK506 (10 μM) had no effect on Ca²⁺ release induced by caffeine or by histamine in the Ca²⁺-free solution.FK506 (10 μM) had no effect on the [Ca²⁺]i-tension relationships of the contractions induced by cumulative increases of extracellular Ca²⁺ during K⁺ depolarization or stimulation with U46619.In the patch clamp experiments, FK506 (30 μM) partially inhibited the inward current induced by depolarization pulse from −80 mV to 0 mV.In conclusion, FK506 induces arterial relaxation by decreasing [Ca²⁺]i mainly due to the inhibition of the L-type Ca²⁺ channels, with no effect on the Ca²⁺ sensitivity of the contractile apparatus.