Modulation of noradrenaline-induced microvascular constriction by protein kinase inhibitors.
We have tested the role of various protein kinases in noradrenaline-induced, alpha1A-adrenoceptor-mediated constriction of mesenteric and intrarenal rat microvessels. The protein kinase C inhibitors, H7 and staurosporine, inhibited constriction in both vessel types in concentrations which also inhibit myosin light chain kinase. The more selective protein kinase C inhibitors, bisindolylmaleimide I and Gö 6976, did not inhibit microvessel constriction in concentrations selective for protein kinase C. Moreover, the protein kinase C-activating phorbol ester, phorbol-12-myristate-13-acetate, did not cause constriction. The tyrosine kinase inhibitors, genistein and tyrphostin 23, inhibited constriction in concentrations compatible with tyrosine kinase inhibition. An inhibitor of the extracellular signal-regulated kinase cascade, PD 98059, also caused concentration-dependent inhibition. While chelation of extracellular Ca2+ abolished noradrenaline-induced constrictions, the Ca2+-ATPase inhibitor, thapsigargin, had no effects. We conclude that tyrosine kinases and extracellular signal-regulated kinase (but not protein kinase C) may be involved in noradrenaline-induced rat mesenteric and intrarenal microvessel constriction but this appears to occur independently of an effect on sarcoplasmic Ca2+ storage.
Fetscher
C
C
Department of Medicine, University of Essen, Germany.
Chen
H
H
Schäfers
R F
RF
Wambach
G
G
Heusch
G
G
Michel
M C
MC
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002227:Carbazoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008643:Mesentery / Q000098:blood supply; D009638:Norepinephrine / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D002227:Carbazoles; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D020032:Tyrphostins; C081021:Go 6976; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019311:Staurosporine; C070515:bisindolylmaleimide I; C060641:tyrphostin A23; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D009638:Norepinephrine