Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery.
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 beta-escin permeabilised rings from HPAs mounted in an organ bath system were used to assess both tension and myofilament Ca(2+)-sensitisation. Microspectrofluorimetry was used for intracellular Ca(2+) recordings in cultured HPA smooth muscle cells. Voltage-operated Ca(2+) channel blockers (nitrendipine and nifedipine) partially reduced the contraction to 5-HT. Thapsigargin or cyclopiazonic acid (CPA), known to deplete sarcoplasmic reticulum Ca(2+) stores, also partially inhibited the contraction, whereas removal of extracellular Ca(2+) under these conditions further inhibited the contraction. Changing from Ca(2+)-free to Ca(2+) containing solution, in the presence of nitrendipine and CPA, a protocol known to stimulate store-operated Ca(2+) channels, induced HPA contractions that were blocked by nickel. Nickel or gadolinium also reduced the contraction to 5-HT. Finally, 5-HT increased intracellular Ca(2+) responses in cultured HPA smooth muscle cells and myofilament Ca(2+)-sensitisation in HPA rings. Collectively, these results indicate that voltage-operated and voltage-independent Ca(2+) channels, as well as Ca(2+) release and myofilament Ca(2+)-sensitisation, participate in 5-HT-induced contraction in HPAs.
Rodat-Despoix
L
L
INSERM U 885, Laboratoire de Physiologie Cellulaire Respiratoire, Bordeaux, France.
Aires
V
V
Ducret
T
T
Marthan
R
R
Savineau
J-P
JP
Rousseau
E
E
Guibert
C
C
D000368:Aged; D002118:Calcium / Q000378:metabolism; D004928:Escin / Q000378:metabolism; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D009200:Myocardial Contraction; D009543:Nifedipine / Q000494:pharmacology; D009568:Nitrendipine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000503:physiopathology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology*; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence / Q000379:methods
D012701:Serotonin; D004928:Escin; D009568:Nitrendipine; D009543:Nifedipine; D002118:Calcium