Pyrimidine nucleotides suppress KDRcurrents and depolarize rat cerebral arteries by activating Rho kinase

Authors:
  • SBSuzanne E. Brett
    Suzanne E. Brett
  • BWBin Nan Wu
    Bin Nan Wu
  • WWWilliam B. Wiehler
    William B. Wiehler
  • DWDonald G. Welsh
    Donald G. Welsh
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Abstract
This study examined whether, and by what signaling and ionic mechanisms, pyrimidine nucleotides constrict rat cerebral arteries. Cannulated cerebral arteries stripped of endothelium and pressurized to 15 mmHg constricted in a dose-dependent manner to UTP. This constriction was partly dependent on the depolarization of smooth muscle cells and the activation of voltage-operated Ca2+channels. The depolarization and constriction induced by UTP were unaffected by bisindolylmaleimide I, a PKC inhibitor that abolished phorbol ester (PMA)-induced constriction in cerebral arteries. In contrast, the Rhokinase inhibitor Y-27632 attenuated the ability of UTP to both constrict and depolarize cerebral arteries. With patch-clamp electrophysiology, a voltage-dependent delayed rectifying K+(KDR) current was isolated and shown to consist of a slowly inactivating 4-aminopyridine (4-AP)-sensitive and an -insensitive component. The 4-AP-sensitive KDRcurrent was potently suppressed by UTP through a mechanism that was not dependent on PKC. This reflects observations that demonstrated that 1) a PKC activator (PMA) had no effect on KDRand 2) PKC inhibitors (calphostin C or bisindolylmaleimide I) could not prevent the suppression of KDRby UTP. The Rho kinase inhibitor Y-27632 abolished the ability of UTP to inhibit the KDRcurrent, as did inhibition of RhoA with C3 exoenzyme. Cumulatively, these observations indicate that Rho kinase signaling plays an important role in eliciting the cerebral constriction induced by pyrimidine nucleotides. Moreover, they demonstrate for the first time that Rhokinase partly mediates this constriction by altering ion channels that control membrane potential and Ca2+influx through voltage-operated Ca2+channels.

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