title: Rho-kinase-mediated suppression of KDR current in cerebral arteries requires an intact actin cytoskeleton.
abstract: This study examined the role of the actin cytoskeleton in Rho-kinase-mediated suppression of the delayed-rectifier K(+) (K(DR)) current in cerebral arteries. Myocytes from rat cerebral arteries were enzymatically isolated, and whole cell K(DR) currents were monitored using conventional patch-clamp electrophysiology. At +40 mV, the K(DR) current averaged 19.8 +/- 1.6 pA/pF (mean +/- SE) and was potently inhibited by UTP (3 x 10(-5) M). This suppression was observed to depend on Rho signaling and was abolished by the Rho-kinase inhibitors H-1152 (3 x 10(-7) M) and Y-27632 (3 x 10(-5) M). Rho-kinase was also found to concomitantly facilitate actin polymerization in response to UTP. We therefore examined whether actin dynamics played a role in the ability of Rho-kinase to suppress K(DR) current and found that actin disruption using either cytochalasin D (1 x 10(-5) M) or latrunculin A (1 x 10(-8) M) prevented current modulation. Consistent with our electrophysiological observations, both Rho-kinase inhibition and actin disruption significantly attenuated UTP-induced depolarization and constriction of cerebral arteries. We propose that UTP initiates Rho-kinase-mediated remodeling of the actin cytoskeleton and consequently suppresses the K(DR) current, thereby facilitating the depolarization and constriction of cerebral arteries.
authors.affiliation: Department of Physiology, University of Calgary, Alberta, Canada.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Luykenaar
authors.forename: Rasha Abd
authors.initials: RA
authors.lastname: El-Rahman
authors.forename: Michael P
authors.initials: MP
authors.lastname: Walsh
authors.forename: Donald G
authors.initials: DG
authors.lastname: Welsh
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000199:Actins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002536:Cerebral Arteries / Q000166:cytology / Q000378:metabolism*; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism*; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053778:Thiazolidines / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology; D014661:Vasoconstriction / Q000502:physiology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
chemical_list: C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; D000199:Actins; D000577:Amides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D051668:Delayed Rectifier Potassium Channels; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D011725:Pyridines; D053778:Thiazolidines; C108830:Y 27632; D015638:Cytochalasin D; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C037067:latrunculin A; D014544:Uridine Triphosphate