Signal transduction in endothelin-induced contraction of rabbit pulmonary vein.
The effect of porcine endothelin (endothelin 1) on rings of isolated rabbit pulmonary vein was studied using tissue bath techniques. Endothelin was found to be a potent constrictor of these vessels, producing concentration-dependent contractions with an EC50 value of 3.2 +/- 0.6 x 10(-9) M. Contractions were not significantly affected by the Ca2+ channel antagonists verapamil, nifedipine, or nicardipine. Contractions were greatly attenuated by 3 mM LaCl3 (85.8 +/- 8.0% relaxation) and were diminished in Ca(2+)-free media (51 +/- 9% of control). The protein kinase C (PKC) inhibitor H7 (20 microM) potently and reversibly inhibited endothelin-induced contractions by 82 +/- 6% when used as post-treatment. Incubation of tissues with 20 microM H7 did not significantly affect either the strength of contractions induced with endothelin or the time required for contraction to reach plateau, but these contractions were poorly sustained compared to controls. The phospholipase C (PLC) inhibitor neomycin (10 mM) inhibited endothelin-induced contractions and it also affected the rate of force development. The phospholipase A2 (PLA2) inhibitor quinacrine had no significant effect on endothelin-induced contractions. Extracellular Ca2+ appears to enter the cell via non-potential dependent channels that can be blocked by La3+. Moreover, the potent vasoconstrictor properties of endothelin on rabbit pulmonary veins involves activation of both PLC and PKC, but not PLA2. PKC is intimately associated with maintaining the tonic phase of smooth muscle contraction.
Steffan
M
M
Department of Physiology, State University of New York, Buffalo 14214.
Russell
J A
JA
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D002118:Calcium / Q000502:physiology; D016232:Endothelins / Q000494:pharmacology*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010741:Phospholipases A / Q000502:physiology; D054467:Phospholipases A2; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D011667:Pulmonary Veins / Q000187:drug effects*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D016232:Endothelins; D007546:Isoquinolines; D010879:Piperazines; D014662:Vasoconstrictor Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D014700:Verapamil; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D009543:Nifedipine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D009638:Norepinephrine