Effect of chronic hypoxia on voltage-independent calcium influx activated by 5-HT in rat intrapulmonary arteries

Abstract

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.