Effects of hypercapnia and hypocapnia on [Ca²⁺]_i mobilization in human pulmonary artery endothelial cells

The hydrogen ion is an important factor in the alteration of vascular tone in pulmonary circulation. Endothelial cells modulate vascular tone by producing vasoactive substances such as prostacyclin (PGI₂) through a process depending on intracellular Ca²⁺ concentration ([Ca²⁺]_i). We studied the influence of CO₂-related pH changes on [Ca²⁺]_i and PGI₂ production in human pulmonary artery endothelial cells (HPAECs). Hypercapnic acidosis appreciably increased [Ca²⁺]_i from 112 ± 24 to 157 ± 38 nmol/l. Intracellular acidification at a normal extracellular pH increased [Ca²⁺]_i comparable to that observed during hypercapnic acidosis. The hypercapnia-induced increase in [Ca²⁺]_i was unchanged by the removal of Ca²⁺ from the extracellular medium or by the depletion of thapsigargin-sensitive intracellular Ca²⁺ stores. Hypercapnic acidosis may thus release Ca²⁺ from pH-sensitive but thapsigargin-insensitive intracellular Ca²⁺ stores. Hypocapnic alkalosis caused a fivefold increase in [Ca²⁺]_i compared with hypercapnic acidosis. Intracellular alkalinization at a normal extracellular pH did not affect [Ca²⁺]_i. The hypocapnia-evoked increase in [Ca²⁺]_i was decreased from 242 ± 56 to 50 ± 32 nmol/l by the removal of extracellular Ca²⁺. The main mechanism affecting the hypocapnia-dependent [Ca²⁺]_i increase was thought to be the augmented influx of extracellular Ca²⁺ mediated by extracellular alkalosis. Hypercapnic acidosis caused little change in PGI₂ production, but hypocapnic alkalosis increased it markedly. In conclusion, both hypercapnic acidosis and hypocapnic alkalosis increase [Ca²⁺]_i in HPAECs, but the mechanisms and pathophysiological significance of these increases may differ qualitatively.