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

¹Smooth Muscle Research Group and Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1; and ²Department of Pharmacology, Kaohsiung Medical University, Kaohsiung, Taiwan

Submitted 22 September 2003 ; accepted in final form 29 October 2003

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⁺ (K_DR) current was isolated and shown to consist of a slowly inactivating 4-aminopyridine (4-AP)-sensitive and an -insensitive component. The 4-AP-sensitive K_DR current 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 K_DR and 2) PKC inhibitors (calphostin C or bisindolylmaleimide I) could not prevent the suppression of K_DR by UTP. The Rho kinase inhibitor Y-27632 abolished the ability of UTP to inhibit the K_DR current, 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.

vasoconstrictors; membrane potential; potassium channels; protein kinase C

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