Tacrolimus inhibits vasoconstriction by increasing Ca²⁺ sparks in rat aorta

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 BK_Ca currents by increasing Ca²⁺ sparks released from ryanodine receptors, which inhibited the NE- or KCl-induced contraction in rat aorta.

Keywords

tacrolimus / Ca²⁺ sparks / large-conductance Ca²⁺-activated K⁺ channels / vasoconstriction

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