Role of endogenous hydrogen sulfide in nerve-evoked relaxation of pig terminal bronchioles.
Hydrogen sulfide (H2S) is a gasotransmitter employed for intra- and inter-cellular communication in almost all organ systems. This study investigates the role of endogenous H2S in nerve-evoked relaxation of pig terminal bronchioles with 260 μm medium internal lumen diameter. High expression of the H2S synthesis enzyme cystathionine γ-lyase (CSE) in the bronchiolar muscle layer and strong CSE-immunoreactivity within nerve fibers distributed along smooth muscle bundles were observed. Further, endogenous H2S generated in bronchiolar membranes was reduced by CSE inhibition. In contrast, cystathionine β-synthase expression, another H2S synthesis enzyme, however was not consistently detected in the bronchiolar smooth muscle layer. Electrical field stimulation (EFS) and the H2S donor P-(4-methoxyphenyl)-P-4-morpholinylphosphinodithioic acid (GYY4137) evoked smooth muscle relaxation. Inhibition of CSE, nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and of ATP-dependent K+, transient receptor potential A1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) channels reduced the EFS relaxation but failed to modify the GYY4137 response. Raising extracellular K+concentration inhibited the GYY4137 relaxation. Large conductance Ca2+-activated K+channel blockade reduced both EFS and GYY4137 responses. GYY4137 inhibited the contractions induced by histamine and reduced to a lesser extent the histamine-induced increases in intracellular [Ca2+]. These results suggest that relaxation induced by EFS in the pig terminal bronchioles partly involves the H2S/CSE pathway. H2S response is produced via NO/sGC-independent mechanisms involving K+channels and intracellular Ca2+desensitization-dependent pathways. Thus, based on our current results H2S donors might be useful as bronchodilator agents for the treatment of lung diseases with persistent airflow limitation, such as asthma and chronic obstructive lung disease.
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Vítor S
VS
Fernandes
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Paz
P
Recio
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Elvira
E
López-Oliva
Departamento de Anatomía y Anatomía Patológica Comparadas, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain.
María Pilar
MP
Martínez
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Ana Sofía
AS
Ribeiro
Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain.
María Victoria
MV
Barahona
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Ana Cristina
AC
Martínez
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Sara
S
Benedito
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Ángel
Á
Agis-Torres
Servicio de Cirugía Torácica, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.
Alberto
A
Cabañero
Servicio de Cirugía Torácica, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.
Gemma M
GM
Muñoz
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
Albino
A
García-Sacristán
Servicio de Neurobiología-Investigación, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.
Luis M
LM
Orensanz
Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain. Electronic address: medardo@ucm.es.
Medardo
M
Hernández
D000818:Animals; D055745:Bronchioles / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000378:metabolism*; D005260:Female; D006632:Histamine / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009126:Muscle Relaxation / Q000502:physiology; D009130:Muscle, Smooth / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase / Q000378:metabolism*; D013552:Swine
C491778:CACYBP protein, human; D002135:Calcium-Binding Proteins; C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D015221:Potassium Channels; D009569:Nitric Oxide; D006632:Histamine; D019001:Nitric Oxide Synthase; D003542:Cystathionine gamma-Lyase; D000071756:Soluble Guanylyl Cyclase; D006862:Hydrogen Sulfide
Cystathionine β-synthase; Cystathionine γ-lyase; GYY4137; Hydrogen sulfide; Nerve-evoked relaxation; Pig terminal bronchioles