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Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

¹ INSERM, U885, Laboratoire de Physiologie Cellulaire Respiratoire, ² Université Bordeaux 2, Bordeaux, France. ³ Le Bilarium, Université de Sherbrooke, Sherbrooke, QC, Canada.

CORRESPONDENCE: C. Guibert, INSERM U 885, Laboratoire de Physiologie Cellulaire Respiratoire, 146, rue Léo Saignat, F33076 Bordeaux, France. E-mail: christelle.guibert{at}u-bordeaux2.fr

Keywords: Calcium, contraction, human pulmonary artery, myofilament calcium sensitivity, 5-HT

Received: September 19, 2008
Accepted May 23, 2009

Serotonin (5-hydroxytryptamine; 5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose plasma level is increased in pulmonary hypertensive patients. Thus, we explored the signalling pathways involved in the contractile response to 5-HT in human pulmonary arteries (HPAs).

Intact and β-escin permeabilised rings from HPAs mounted in an organ bath system were used to assess both tension and myofilament Ca²⁺-sensitisation. Microspectrofluorimetry was used for intracellular Ca²⁺ recordings in cultured HPA smooth muscle cells.

Voltage-operated Ca²⁺ channel blockers (nitrendipine and nifedipine) partially reduced the contraction to 5-HT. Thapsigargin or cyclopiazonic acid (CPA), known to deplete sarcoplasmic reticulum Ca²⁺ stores, also partially inhibited the contraction, whereas removal of extracellular Ca²⁺ under these conditions further inhibited the contraction. Changing from Ca²⁺-free to Ca²⁺ containing solution, in the presence of nitrendipine and CPA, a protocol known to stimulate store-operated Ca²⁺ channels, induced HPA contractions that were blocked by nickel. Nickel or gadolinium also reduced the contraction to 5-HT. Finally, 5-HT increased intracellular Ca²⁺ responses in cultured HPA smooth muscle cells and myofilament Ca²⁺-sensitisation in HPA rings.

Collectively, these results indicate that voltage-operated and voltage-independent Ca²⁺ channels, as well as Ca²⁺ release and myofilament Ca²⁺-sensitisation, participate in 5-HT-induced contraction in HPAs.