Tacrolimus Inhibits Vasoconstriction by Increasing Ca²⁺ Sparks in Rat Aorta

【摘要】 The present study attempted to test a novel hypothesis that Ca²⁺ sparks play an important role in arterial relaxation induced by tacrolimus. Recorded with confocal laser scanning microscopy, tacrolimus（10 μmol/L） increased the frequency of Ca²⁺ sparks, which could be reversed by ryanodine（10 μmol/L）. Electrophysiological experiments revealed that tacrolimus（10 μmol/L） increased the large-conductance Ca²⁺-activated K+ currents（BKCa） in rat aortic vascular smooth muscle cells（AVSMCs）, which could be blocked by ryanodine（10 μmol/L）. Furthermore, tacrolimus（10 and 50 μmol/L） reduced the contractile force induced by norepinephrine（NE） or KCl in aortic vascular smooth muscle in a concentration-dependent manner, which could be also significantly attenuated by iberiotoxin（100 nmol/L） and ryanodine（10 μmol/L） respectively. In conclusion, tacrolimus could indirectly activate BKCa currents by increasing Ca²⁺ sparks released from ryanodine receptors, which inhibited the NE- or KCl-induced contraction in rat aorta.更多还原

【Abstract】 The present study attempted to test a novel hypothesis that Ca²⁺ sparks play an important role in arterial relaxation induced by tacrolimus. Recorded with confocal laser scanning microscopy, tacrolimus（10 μmol/L） increased the frequency of Ca²⁺ sparks, which could be reversed by ryanodine（10 μmol/L）. Electrophysiological experiments revealed that tacrolimus（10 μmol/L） increased the large-conductance Ca²⁺-activated K+ currents(BK_Ca) in rat aortic vascular smooth muscle cells（AVSMCs）, which could be blocked by ryanodine（10 μmol/L）. Furthermore, tacrolimus（10 and 50 μmol/L） reduced the contractile force induced by norepinephrine（NE） or KCl in aortic vascular smooth muscle in a concentration-dependent manner, which could be also significantly attenuated by iberiotoxin（100 nmol/L） and ryanodine（10 μmol/L） respectively. In conclusion, tacrolimus could indirectly activate BKCa currents by increasing Ca²⁺ sparks released from ryanodine receptors, which inhibited the NE- or KCl-induced contraction in rat aorta.更多还原