Mechanisms of coronary artery depolarization by uridine triphosphate

We sought to define the basic mechanisms by which pyrimidine nucleotides constrict rat coronary resistance arteries. Uridine triphosphate (UTP) caused a dose-dependent constriction in coronary arteries stripped of endothelium. UTP also depolarized and increased cytosolic Ca2+in coronary smooth muscle cells. Nisoldipine, an antagonist of voltage-operated Ca2+channels, blocked the rise in cytosolic Ca2+and reduced UTP-induced vasoconstriction by ∼75% which suggests a prominent role for depolarization in this constrictor response. The ionic basis of UTP-induced depolarization was subsequently explored in coronary smooth muscle cells using whole-cell patch-clamp electrophysiology. In the absence of K+and with CsCl in the pipette, UTP (40 μM) activated a sustained inwardly rectifying current (−0.66 ± 0.10 pA/pF at −60 mV). A 100 mM reduction in bath Na+shifted the reversal potential of this current (from −2 ± 1 to −28 ± 4 mV) and reduced the magnitude (from −2.26 ± 0.61 to −0.51 ± 0.11 pA/pF). In addition to activating a depolarizing cation current, UTP inhibited hyperpolarizing outward currents. Specifically, UTP inhibited ATP-sensitive and voltage-dependent K+currents yet had no effect on inwardly rectifying and Ca2+-activated K+channels. This study indicates that electromechanical coupling is integral to pyrimidine-induced constriction in coronary resistance arteries.