Sensory nerves containing tachykinins and CGRP in the lower airways. Functional implications for bronchoconstriction, vasodilatation and protein extravasation.
Several tachykinins (SP, NKA and NPK) are colocalized with CGRP-LI in nerve fibres supplying bronchial smooth muscle, close to and within the lining epithelium, around blood vessels and around local tracheo-bronchial ganglion cells in animals and man. SP-IR and CGRP-IR were also present in the same cells of jugular, nodose and thoracic spinal ganglia but only in nerve fibres in local parasympathetic ganglia and the stellate ganglia, suggesting a sensory origin. After capsaicin treatment there was a selective and nearly total loss of SP- and CGRP-IR nerves in the airways in parallel with a reduction in the corresponding tissue content. Capsaicin-sensitive sensory nerves containing SP-IR in the trachea had a predominant vagal component while in the peripheral airways SP-IR nerves had a dual origin from the vagal nerves and from thoracic spinal ganglia via the stellate ganglia and sympathetic pathways. CGRP-IR, but not SP-LI, was also present in epithelial endocrine cells. A Ca2+-dependent release of tachykinin-LI and CGRP-LI was demonstrated upon perfusion of the guinea-pig lung with K+ as well as capsaicin. Other substances such as bradykinin, histamine and the nicotinic receptor agonist DMPP were also able to induce overflow, suggesting the release of both SP-LI and NKA-LI. The material released upon stimulation with capsaicin was further characterized by HPLC, and the main peak of the immunoreactivity co-eluted with ELE, a smaller peak eluted in the position of NKA, but no clear evidence for the release of material co-eluting with NPK was observed. This suggests that SP and NKA are the main tachykinins released from sensory nerves, while the nature of the ELE-LI remains to be further clarified. Upon i.v. infusion in the guinea-pig in vivo, the disappearance rate of SP-LI and NKA-LI showed half-lives of less than 2 min, while NPK-LI disappeared from the blood in a biphasic manner with two half-lives of 0.9 and 6 min, respectively. NPK given i.v. was converted into NKA-LI. In guinea-pig plasma in vitro, NKA-LI and NPK-LI were stable for 10 min, while SP-LI disappeared rapidly with a half-life of about 10 s. The long half-life of NPK-LI in vivo was also accompanied by a more long-lasting bronchoconstrictor effect of NPK compared to SP. Thus, the differences in pharmacokinetical properties makes it difficult to draw major conclusions about tachykinin receptor subtypes based on biological potencies in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D001980:Bronchi / Q000098:blood supply / Q000294:innervation*; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin / Q000493:pharmacokinetics; D002415:Cats; D006168:Guinea Pigs; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000294:innervation*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009475:Neurons, Afferent / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D014132:Trachea / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
D009479:Neuropeptides; D011506:Proteins; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin