Sensory neuropeptides and nitric oxide in nasal vascular regulation

Abstract

The role of sensory neuropeptides and nitric oxide in vascular regulation was investigated in the pig nasal mucosa in vivo using arterial blood flow measurements and acoustic rhinometry for analysis of capacitance function. Moreover, the effects of heavy physical exercise, a-adrenoceptor agonists, nitric oxide synthase (NOS) inhibition, L-arginine, nitric oxide (NO) gas, histamine and capsaicin on nasal cavity NO levels and nasal cavity volume, were investigated in healthy subjects. The Ca2+-channel blocking agent ruthenium red preferentially attenuated the capsaicin-evoked effects in the pig nasal mucosa, compared to the nicotine-evoked vasodilatation. The NK1-receptor antagonist RP-67.580 lacked NK1-receptor blocking properties in the pig invivo. Two other NK1-receptor antagonists CP-96,345 and SR 140.333, on the other hand, significantly reduced substance P(SP)-mediated vascular effects in the pig nasal mucosa and superficial skin.

However, the capsaicin-evoked vasodilatation in the pig nasal mucosa was not attenuated after administration of the NK1-receptor antagonists whereas the CGRP-receptor antagonist CGRP 8-37 significantly reduced the capsaicin-evoked vascular effects both in the pig nasal mucosa and in superficial skin. This finding indicates that CGRP may be of primary importance for vasodilator effects observed in the nasal mucosa and skin, after sensory C-fibre activation. Capsaicin, resiniferatoxin (RTX) and lactic acid (protons) all evoked vasodilatation in the pig nasal mucosa in a similar fashion, indicating activation of sensory nerves. Furthermore, CGRP 8-37 significantly attenuated the lactic acid-evoked vasodilatation in the pig nasal mucosa, resembling the findings obtained using capsaicin before and after CGRP-receptor blockade. The vanilloid-receptor antagonist capsazepine did not inhibit the capsaicin- or lactic acid-evoked vascular effects in the pig nasal mucosa. Vanilloid receptors, as revealed by 3H-RTX binding, were identified in the pig nasal mucosa. The RTX binding to pig nasal mucosa membranes was inhibited by capsaicin and lactic acid; however, capsazepine did not inhibit RTX binding in this tissue in contrast to its effects in the pig spinal cord. Capsaicin desensitization of the human nasal mucosa attenuated the subjective pain response, as well as the reduction of the cross-sectional area in the nasal cavity, evoked by lactic acid and hypertonic saline. This finding gives further support to the hypothesis that protons may act as endogenous ligands to the vanilloid receptor also in man. Systemic administration of the NOS-inhibitor N"'-nitro-L-arginine significantly reduced basal nasal vascular conductance and increased nasal cavity volume in the pig. The effects evoked by NOS-inhibition were similar in magnitude to the effects elicited by a,- and a,-receptor activation, although of longer duration. Administration of the NOS-inhibitor did not attenuate the vasodilator effects evoked by SP and acetylcholine, suggesting that these substances may mediate their vascular effects via other mechanisms apart from the NO/cGMP pathway. Capsaicin-, vasoactive intestinal polypeptide- and nitroprusside-evoked vasodilatation was also not reduced after NOS-inhibition. Nasal cavity NO levels were significantly decreased during heavy physical exercise.

Moreover, a-adrenoceptor agonists, administered topically in the nose, also significantly reduced the nasal cavity NO levels. Since NO found in nasal cavity air seems predominantly to emanate from the paranasal sinuses. We propose that the reduction of nasal cavity NO levels evoked by heavy physical exercise and a-adrenoceptor agonists, is due to a reduced blood flow to the sinus mucosa with a subsequent shortage of substrates such as L-arginine and molecular oxygen for the paranasal sinus NO production. However, prolonged use of the a-adrenoceptor agonist oxymetazoline for 10 days, did not reduce basal nasal cavity NO levels, suggesting short term reversible effects of this agent. Topical administration of the NOS-inhibitor N'¡-nitro-L-arginine-methyl ester did not alter nasal cavity NO levels or nasal cavity volume. Nor did NO gas, administered in the nose, alter nasal cavity volume, in contrast to the well known vascular effects of NO in the lung. It must be emphasized that nasal cavity NO levels do correlate to changes in nasal cavity volume and hence that measurements of NO levels in the upper airways should be performed together with measurements of the size of the upper airway cavities.

In conclusion, the present results suggest that vanilloid receptors are present on sensory nerves in the pig nasal mucosa and that lactic acid (protons) may act as an endogenous ligand for this receptor. Sensory neuropeptides, especially CGRP, may be of importance for nasal congestion upon sensory nerve activation, whereas the involvement of SP acting on NK1-receptors is minor. Therefore, selective, non-peptide CGRP-receptor antagonists may be of potential use in nasal disorders characterized by nasal congestion. NO is of importance for basal nasal vascular regulation while the effects of various vasodilators are affected only to a minor extent by blockade of the NO/cGMP pathway. Nonetheless, the potential use of NOS-inhibitors as topical nasal decongestants needs further investigation using selective and more potent NOS-inhibitors. Heavy physical exercise and, toa lesser extent, topical administation of a-adrenoceptor agonists, reversibly reduce NO in nasal cavity air. This may influence non-specific host-defense mechanisms.