Differences in the distribution and characteristics of tachykinin NK1 binding sites between human and guinea pig lung.
1. The distribution and characteristics of tachykinin NK1 binding sites have been compared in human and guinea pig lung using quantitative in vitro receptor autoradiography with [125I]-Bolton Hunter-labelled substance P ([125I]-BH-SP). In addition, the effects on these sites of ovalbumin sensitization and challenge have been determined in guinea pig lung. 2. [125I]-BH-SP bound specifically and with high affinity to microvascular endothelium in both human and guinea pig lung, but to bronchial smooth muscle and pulmonary artery media in only guinea pig lung. 3. Specific binding of [125I]-BH-SP to guinea pig bronchial smooth muscle was positively correlated with airway diameter in the range 150-800 microns and was less dense in trachea than in main bronchi. 4. [125I]-BH-SP binding was inhibited by tachykinins with rank orders of affinity of SP > NKA > NKB (human microvessels) and SP > NKA = NKB (guinea pig bronchi and pulmonary arteries). NKA displayed a higher affinity for [125I]-BH-SP binding sites in human microvessels than in guinea pig tissues (P < 0.0001), indicating differences in selectivity for tachykinins between human and guinea pig NK1 receptors. 5. In both human and guinea pig lung, [125I]-BH-SP binding was inhibited by the specific tachykinin receptor antagonists FK888 (NK1 selective antagonist) and FK224 (mixed NK1/NK2 antagonist), with FK888 displaying equal affinity to SP and > 500 times higher affinity than FK224. SP, NKA, NKB and FK888 exhibited similar affinities for [125I]-BH-SP binding sites in both guinea pig arteries and bronchi. 6. Similar distributions, densities and characteristics of [I251]-BH-SP binding sites were demonstrated in oval bumin-sensitized and -challenged guinea-pig lung and in naive animals.7. Differences in the distribution and characteristics of NKI binding sites labelled with [125I]-BH-SP between guinea pig and human lung suggest limitations in the use of guinea pig models for studying roles of tachykinins in pulmonary disease. However, the similar microvascular distributions of NK,binding sites in human and guinea pig lung suggest that the selective tachykinin receptor antagonistsFK888 and FK224 may be useful in the management of airway inflammation in man.
Walsh
D A
DA
Department of Histochemistry, Royal Postgraduate Medical School, Hammersmith Hospital, London.
Salmon
M
M
Featherstone
R
R
Wharton
J
J
Church
M K
MK
Polak
J M
JM
D000818:Animals; D001345:Autoradiography; D004151:Dipeptides / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008168:Lung / Q000033:anatomy & histology / Q000378:metabolism*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010047:Ovalbumin / Q000276:immunology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011651:Pulmonary Artery / Q000033:anatomy & histology / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000503:physiopathology; D013045:Species Specificity; D013373:Substance P / Q000037:antagonists & inhibitors; D013388:Succinimides
C043194:Bolton Hunter reagent-substance P conjugate; D004151:Dipeptides; D007211:Indoles; D007457:Iodine Radioisotopes; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic; D018040:Receptors, Neurokinin-1; D013388:Succinimides; C075570:FK 224; C078949:FK 888; D013373:Substance P; D010047:Ovalbumin