Effect of chronic hypoxia on voltage-independent calcium influx activated by 5-HT in rat intrapulmonary arteries.
5-Hydroxytryptamine (5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose concentration increases in pulmonary hypertensive patients. Chronic hypoxia induces selective pulmonary arterial hypertension; therefore, we investigated chronic hypoxia effect on the calcium and contractile responses to 5-HT focusing on voltage-independent calcium influx in rat intrapulmonary arteries. Chronic hypoxia, induced by introducing rats in a hypobaric chamber for 3 weeks, potentiated the contraction to 5-HT and this effect was insensitive to nitrendipine. Calcium signal to 5-HT was characterized by a transient followed by a sustained phase in both normoxia and chronic hypoxia. The sustained phase was dependent on extracellular calcium and inhibited by lanthanum. RHC 80267, a specific inhibitor of diacylglycerol lipase, reduced the 5-HT-induced calcium influx in chronic hypoxia but not in normoxia. Furthermore, unlike gadolinium, RHC 80267 inhibited more the contraction to 5-HT in chronic hypoxia. Despite the apparent role of voltage-independent calcium channels in chronic hypoxia, Western blot and flow cytometry analyses demonstrated no variations in TRPC(6) expression. This study shows for the first time that the 5-HT-induced calcium and contractile signals in chronic hypoxia are more dependent on a voltage-independent, RHC 80267-sensitive calcium influx and the hyperreactivity to 5-HT may thus be explained by this influx.
Rodat
Lise
L
Université Bordeaux 2, Laboratoire de Physiologie Cellulaire Respiratoire, 146 rue Léo Saignat, F33076 Bordeaux, France.
Savineau
Jean-Pierre
JP
Marthan
Roger
R
Guibert
Christelle
C
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D003512:Cyclohexanones / Q000494:pharmacology; D004351:Drug Resistance; D004594:Electrophysiology; D005682:Gadolinium / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009568:Nitrendipine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology*; D050052:TRPC Cation Channels / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D003512:Cyclohexanones; D050052:TRPC Cation Channels; C492145:Trpc6 protein, rat; D014662:Vasoconstrictor Agents; D012701:Serotonin; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; D009568:Nitrendipine; D005682:Gadolinium; D008071:Lipoprotein Lipase; D002118:Calcium