Effects of hCGRP 8-37 and the NK1-receptor antagonist SR 140.333 on capsaicin-evoked vasodilation in the pig nasal mucosa in vivo.
A novel pig in vivo model was used to study vascular effects of capsaicin, substance P and calcitonin gene-related peptide (CGRP) in the nasal mucosa and skin. An acoustic rhinometer was used to measure changes in nasal cavity volume, mainly representing changes in capacitance vessels in the vascular beds. The non-peptide NK1-receptor antagonist SR 140.333 and the CGRP-receptor antagonist hCGRP 8-37 were used to investigate the role of substance P and CGRP, respectively, in capsaicin-evoked vasodilation mediated through activation of sensory C-fibre afferents. In this study we show that SR 140.333 is a potent inhibitor of substance P-induced vasodilation in the nasal mucosa whereas it has no effect on the capsaicin-evoked responses. Substance P only elicited a minor and shortlasting increase in superficial skin blood flow; this response, however, was completely blocked after administration of SR 140.333. Capsaicin-evoked vasodilation in the skin was slightly reduced by SR 140.333. CGRP-induced vasodilation in the nasal mucosa and skin was of much longer duration than the substance P-induced response, and was thus similar to the vascular effects mediated by capsaicin. hCGRP 8-37 significantly reduced both the CGRP- and capsaicin-mediated vasodilation in the nasal mucosa and the decrease of nasal cavity volume. Although the peak vasodilation in the skin in response to capsaicin, was unaltered by blockade of CGRP-receptors, the integrated response was significantly reduced by hCGRP 8-37. The present results show that vasodilatory responses to activation of afferent nerves in the pig nasal mucosa and superficial skin are mainly dependent on CGRP, while NK1-receptor mechanisms seem to be of no or minor importance.
Rinder
J
J
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Lundberg
J M
JM
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002211:Capsaicin / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009296:Nasal Cavity / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D009297:Nasal Mucosa / Q000098:blood supply* / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000494:pharmacology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D011812:Quinuclidines; C058636:calcitonin gene-related peptide (8-37); C085215:SR 140333; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin