The pro totypical ACEI, captopril, did not enhance the direct vasodilatory or secretory effects of topically applied vaso active intestinal polypeptide, substance P or calcitonin CT99021 gene related Inhibitors,Modulators,Libraries peptide in the nasal mucosa of 12 healthy volunteers. This is probably because ACE has a predominant plasma origin in nasal mucosa. ACEI also enhance the function of vasodila tory bradykinin B1 and B2 receptors. ACEI treat ment of rats with genetic deficiency of DPP IV leads to tachykinin mediated peri tracheal edema. Bradykinin is less likely to be involved since it is not a DPP IV substrate in rat inflam mation. DPP IV can cleave substrates such as eotaxin, regulated on activation normal T cell expressed and secreted, neuropeptide Y, substance P, chromogranin B derived peptides, and other airway peptides.

Sitagliptins Inhibitors,Modulators,Libraries inhibition of DPP IV activity may disrupt the normal functions of these polypeptides, particularly in inflamed mucosa. NEP degrades, and so regulates, the duration of action of many small neuropeptides. Like DPP IV, NEP has reduced expression in chronic rhinosinusitis. This may reduce mucosal destruction of calcitonin gene related peptide leading to increased nasal venous sinusoid engorgement and mucosal thickening, and enhance neurogenic axon responses. Substance P induced vasodilation was aug mented by DPP IV inhibition in an in vivo porcine nasal model. This potentially neurogenic effect may be Inhibitors,Modulators,Libraries tested in human nasal mucosa using hypertonic saline Inhibitors,Modulators,Libraries nasal provocations. Intranasal steroid treatment increases NEP, and potentially DPP IV, expression.

These enzymes may be biomarkers of recent mucosal injury and subsequent recovery. Neuropeptide Y is released Inhibitors,Modulators,Libraries with norepi nephrine from sympathetic neurons. NPY1 36 is an ago nist of Y1 receptors on arterioles and arteriovenous anastamoses that cause slow onset, prolonged vasocon striction and resulting in improved nasal patency. DPP IV removes the N terminal Tyr Pro dipeptide from NPY1 36 to generate NPY3 36. NPY3 36 binds to Y2 receptors that have relative antagonist properties to Y1 receptor activation. Y2 inhibitory autoreceptors on sym pathetic nerves halt the release of norepinephrine and co localized NPY. These autoreceptors are also present on parasympathetic nerves and reduce the release of acetyl choline.

Any decrease in the peptidolytic generation STI571 of NPY3 36 would decrease the activity of Y2 inhibitory autoreceptors and so augment sympathetic and parasym pathetic neurotransmitter release. The clinical conse quences are difficult to predict. Elevated parasympathetic acetylcholine release is prob ably of clinical relevance given the prevalence of rhinor rhea in our subjects. Cholinergic stimulation of M3 muscarinic receptors on submucosal glands leads to copi ous glandular secretion. This may generate the rhin orrhea reported by our subjects and the 5.