Calphostin C-sensitive enhancements of force by lysophosphatidylinositol and diacylglycerols in mesenteric arteries from the rat.
1. A pharmacological characterization was made of the effects of lysophosphatidyl-inositol (lysoPI) and -ethanolamine (lysoPE) on the Ca(2+)-sensitivity of contraction in alpha-toxin permeabilized rat mesenteric arteries. The effect of GTP gamma S (G-protein activator), diacylglycerols (DAGs, dioctanoyl glycerol (diC8) and 1-stearoyl-2-arachidonoyl-sn-glycerol) and phorbol myristate acetate (PMA, protein kinase C (PKC) activator) on Ca(2+)-sensitivity was also assessed. 2. LysoPI increased the Ca(2+)-sensitivity, demonstrated by both an increase in tension induced by 1 microM [Ca2+]free and an increase in the Ca(2+)-sensitivity of Ca2+ concentration-tension curves. LysoPE did not enhance force or Ca(2+)-sensitivity. 3. GTP gamma S enhanced force at constant Ca2+, increased the Ca(2+)-sensitivity, and increased force under Ca(2+)-free conditions. PMA also increased force at constant Ca2+ and increased Ca(2+)-sensitivity, but caused no force development under Ca(2+)-free conditions. 4. DAGs, both diC8 and the more physiological relevant DAG, 1-stearoyl-2-arachidonoyl-sn-glycerol, enhanced force at constant Ca2+ and increased the Ca(2+)-sensitivity. DiC8, in contrast to 1-stearoyl-2-arachidonoyl-sn-glycerol, caused force development under Ca(2+)-free conditions and substantially enhanced force at maximal Ca(2+)-induced contraction. GDP-beta-S abolished the increased Ca(2+)-sensitization induced by noradrenaline, but not that by DAGs. 5. The PKC inhibitor calphostin C completely abolished Ca(2+)-sensitization induced by all of the Ca(2+)-sensitizing agents. 6. These results show that lysoPI can increase the Ca(2+)-sensitivity of smooth muscle contraction, and the Ca(2+)-sensitization induced by DAGs was not completely G-protein mediated, because it was not inhibited by GDP-beta-S. A central role for PKC in regulation of Ca(2+)-sensitization in rat mesenteric small arteries was indicated by the abolishment of Ca(2+)-sensitization by calphostin C.
Jensen
P E
PE
Institute of Pharmacology, University of Aarhus, Denmark.
D000818:Animals; D002118:Calcium / Q000494:pharmacology / Q000502:physiology; D004075:Diglycerides / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000502:physiology; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D008638:Mesenteric Arteries / Q000737:chemistry*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D010539:Permeability; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D012680:Sensitivity and Specificity; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D010738:Type C Phospholipases / Q000494:pharmacology
D004075:Diglycerides; D008246:Lysophospholipids; D009281:Naphthalenes; D013873:Thionucleotides; C025449:lysophosphatidylinositol; D006153:Guanosine Diphosphate; C023427:guanosine 5'-O-(2-thiodiphosphate); D006160:Guanosine Triphosphate; D011493:Protein Kinase C; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; C058819:calphostin C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D009638:Norepinephrine