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1 Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
2 Department of Pharmacology, Kaohsiung Medical University, Kaohsiung, Taiwan
* To whom correspondence should be addressed. E-mail: dwelsh{at}ucalgary.ca.
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 (phorbol 12-myristate 13-acetate)-induced constriction in cerebral arteries. In contrast, the Rho-kinase inhibitor Y-27632 attenuated the ability of UTP to both constrict and depolarize cerebral arteries. Using 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 insensitive component. The 4-AP-sensitive KDR current was potently suppressed by UTP through a mechanism that was not dependent on protein kinase C (PKC). This reflects observations which demonstrated that: 1) a PKC activator (Phorbol-12-myristate-13-acetate) had no effect on KDR; and 2) PKC inhibitors (Calphostin C or Bisindolylmaleimide I) could not prevent the suppression of KDR by UTP. The Rho-kinase inhibitor, Y-27632, abolished the ability of UTP to inhibit the KDR 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 Rho-kinase partly mediates this constriction by altering ion channels which control membrane potential and Ca2+ influx through voltage-operated Ca2+ channels.
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