title: Mechanisms of agonist-induced constriction in isolated human pulmonary arteries.
abstract: We determined the calcium signalling pathways involved in the mechanisms of contraction of the vasoconstrictive agonists KCl, U46619 and PDBu in isolated human pulmonary arteries. The influence of gender, vessel diameter and age of the patients was also investigated. Human pulmonary arteries (n = 86) were loaded in a wire myograph and maintained at a tension equivalent to the in vivo pressure of 17.5 mm Hg, bubbled with 95%O2/5%CO2 to maintain pH 7.4 in physiological saline solution (PSS). Cumulative concentration-response curves were obtained to KCl (100 microM-100 mM), U46619 (1 nM-1 microM) or PDBu (1 nM-1 microM), before or after a 30 min incubation with either the voltage-gated calcium channel (VGCC) blocker nifedipine (10 microM), the store-operated calcium channel (SOCC) blocker SK&F96365 (50 microM) or in calcium-free PSS (-Ca2+PSS). The KCl response was partially blocked in -Ca2+PSS and with nifedipine. The U46619 response was partially blocked in -Ca2+PSS and with nifedipine and SK&F96365. Incubation in -Ca2+PSS had no effect on the response to PDBu. Endothelial intact arteries responded significantly higher to U46619 than endothelial denuded arteries. This study demonstrates that KCl induces pulmonary vasoconstriction via activation of extracellular calcium entry through VGCCs, U46619 induces pulmonary vasoconstriction predominantly via activation of VGCCs and PDBu induces pulmonary vasoconstriction via a calcium-independent pathway.
authors.affiliation: Hormone and Vascular Biology Group, Academic Unit of Endocrinology, Division of Genomic Medicine, F-Floor, University of Sheffield Medical School, Beech Hill Road, Sheffield S102RX, UK. j.o.hall@leeds.ac.uk
authors.forename: Joanne
authors.initials: J
authors.lastname: Hall
authors.forename: T Hugh
authors.initials: TH
authors.lastname: Jones
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Channer
authors.forename: Richard D
authors.initials: RD
authors.lastname: Jones
mesh_terms: D000368:Aged; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D014662:Vasoconstrictor Agents