Inhibition of thrombin-induced contractile responses by protein kinase inhibitors in porcine pulmonary arteries.
The clotting enzyme thrombin is known to cause receptor-mediated contractile effects in isolated blood vessels. In the present studies the influence of protein kinase inhibitors on the contractile response of porcine pulmonary arteries to thrombin (3 U/ml) was investigated. Endothelium-denuded rings (2-3 mm) from small arteries were placed in organ baths for isometric tension recording. The vessels were preincubated for 30 min with the inhibitors before inducing contractions. In the presence of the protein kinase C (PKC)-inhibitors staurosporine, BIM I (bisindolyl-maleimide I), chelerythrine and Ro 31-8220 (1 microM each), the contractile responses to the PKC activator phorbol 12,13-dibutyrate (PDBu; 50 nM) were diminished by 70-100%. However, for inhibition of thrombin-induced contractions generally higher concentrations of the inhibitors were required. Only staurosporine at 1 microM inhibited the thrombin effect by about 75%. The tyrosine kinase inhibitor erbstatin (30 microM) did not significantly alter the thrombin effect, whereas genistein at 10 microM caused a significant inhibition of contractile responses to both thrombin and PGF2alpha. At 100 microM genistein also inhibited the contractile effects of PdBu and KCl. These studies suggest that activation of both PKC and non-receptor tyrosine kinases seems to be involved in the signal transduction pathways of thrombin-induced contractile effects in isolated vessels.
University of Jena, Center for Vascular Biology and Medicine, Erfurt, Germany.
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Kutz
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Paintz
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Glusa
D000818:Animals; D002417:Cattle; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011651:Pulmonary Artery / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013552:Swine; D013917:Thrombin / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D015240:Phorbol 12,13-Dibutyrate; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D013917:Thrombin