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

1 Using fura-2 fluorometry, the effects of FK506, an immunosuppressant, on changes in cytosolic Ca2+ concentrations ([Ca2+](i)) and tension were inves tigated in porcine coronary arterial strips. The effects of FK506 on the ac tivity of voltage-operated Ca2+ channels were examined by applying a whole cell patch clamp to the isolated smooth muscle cells of porcine coronary ar tery. 2 FK506 inhibited the sustained increases in both [Ca2+](i) and tension ind uced by 118 mM K+ depolarization and 100 nM U46619 in a concentration-depen dent manner (1-30 mu M) The extent of inhibition of the K+-induced contract ion was greater than that of the U46619-induced contraction. The increases in [Ca2+](i) and tension induced by histamine and endothelin-1 in the prese nce of extracellular Ca2+ were also inhibited by 10 mu M FK506. 3 FK506 (10 mu M) had no effect on Ca2+ release induced by caffeine or by h istamine in the Ca2+ free solution. 4 FK506 (10 mu M) had no effect on the [Ca2+](i)-tension relationships of t he contractions induced by cumulative increases of extracellular Ca2+ durin g K+ depolarization or stimulation with U46619. 5 In the patch clamp experiments, FK506 (30 mu M) partially inhibited the i nward current induced by depolarization pulse from -80 mV to 0 mV. 6 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.