The respiratory tract can be divided into upper airway including the nasal cavities, the pharynx and larynx, and the lower airway comprising the tracheobronchial tract and the respiratory portion of the lungs. The main function of the nose includes conditioning (warming and humidifying) of inhaled air and protection (filtering, trigeminal function and olfaction) of the respiratory part of the lower airway against inhalation of exogenous particles and airborne irritants. The submucosal blood vessels, the muco-ciliary transport system and the local immune mechanisms are the main tissue components involved in these functions. The function of these elements is influenced, at least in part, by biologically active agents released from both sensory and efferent sympathetic and parasympathetic autonomic nerves. A very dense sympathetic innervation is present around both resistance and capacitance vessels of the nasal mucosa. In contrast, parasympathetic fibres are very dense around nasal mucus glands. Noradrenaline (NA) is considered as the classical transmitter released from postganglionic sympathetic nerves. Neuropeptide Y (NPY) is a 36 amino acid peptide first discovered in the porcine brain. The co-localization of NPY with NA has been observed in many peripheral sympathetic nerve fibres. In the nasal mucosa, co-existence of NA and NPY immunoreactivity was observed in sympathetic nerves present around both resistance and capacitance vessels of most species including mankind. Presence of NPY was also demonstrated in adrenergic nerves found in both lower air- way and vascular smooth muscle of the respiratory tract in several different species. Somatostatin was also observed in association with NA and NPY in nasal sympathetic nerves. Further, NPY has also been found in parasympathetic nerves in the airways in association with vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) in humans as well as in various other species.

NPY effect on airway mucus secretions

Exogenous NPY does not reduce glandular secretions in the human nasal mucus. However, a randomized double-blind, three ways, crossover placebo-controlled study has shown that pretreatment with exogenous NPY significantly reduces both nasal obstruction and mucus secretion induced by allergen challenge.

NPY receptors

The multiple biological effects of NPY are exerted through G-protein-coupled receptors. The NPY receptor family includes the Y1 receptor first characterized as a post-synaptic receptor, the Y2 receptor, known as a presynaptic receptor and the Y3 receptor considered as the NPY-preferring receptor. The Y4 receptor was characterized as a pancreatic polypeptide receptor. The Y5 is involved in feeding behavior and the Y6 receptor was recently cloned but its function remains unknown. The predominant NPY receptor type in nasal mucosa blood vessels is of the Y1 type. However, the presence of Y2 receptors is strongly suggested by in vivo studies with Y2 agonists.

Endogenous release of NPY

After SNS, NPY was detectable in the nasal venous effluent only after high frequency stimulation whereas NA was secreted already upon low frequency stimulation. Co-release of NPY and catecholamines has been demonstrated in man during intense physical exercise. Interestingly, physical exercise has been shown to induce significant reduction of subjective and objective nasal airway resistance, most likely secondary to vasoconstriction of nasal capacitance vessels, in both control and rhinitis patients. Variations of plasma NPY concentrations over time correlated better with post-exercise nasal vasoconstriction than NA levels.

Modulator effects of NPY

There is evidence suggesting that NPY released from adrenergic nerves modulates the effector response to transmitters originating from several neuronal pathways. In the lower airways, parasympathetic nerve activity can be inhibited by NPY. In anaesthetized cats, sympathetic nerve stimulation induced significant and prolonged attenuation of the vasodilator response to subsequent parasympathetic stimulation. Exogenous NPY mimicked the effect of sympathetic stimulation in attenuating subsequent parasympathetic evoked vasodilation. Similar observations were made in anaesthetized dogs. Attenuation of parasympathetic-evoked vasodilation and mucus secretion could be mimicked by the NPY analog N-acetyl (Leu²⁸, Leu³¹) NPY 24-36, a Y2-receptor agonist. In contrast, the NPY analog (Leu³¹, Pro³⁴), a potent Y1 receptor agonist did not have any effect on subsequent vasodilation and mucus secretion induced by parasympathetic stimulation. All together, these observations suggest that nasal sympathetic nerve stimulation attenuate parasympathetic vasodilation via NPY release acting on pre-junctional Y2 receptors. Observations obtained from in vitro experiments using electrical field stimulation on guinea pig tracheal smooth muscle strongly suggest that NPY modulates cholinergic neurotransmission via prejunctional mechanisms. Further studies have shown that NPY has an inhibitory action on tachykinin release such as substance P (SP) from peripheral endings of capsaicin-sensitive air- way sensory nerves.

In vitro, exogenous NPY modulates the contractile response of guinea pig tracheal smooth muscle induced by VIP, NA, SP and 5-hydroxytryptamine at both the pre- and postjunctional level. Intranasal or intrabronchial pretreatment with TASP-V, a potent NPY Y2 receptor agonist, reduces both nasal obstruction and bronchoconstriction produced by histamine challenge in the pig. In healthy human volunteers TASP-V significantly lessens the nasal airway resistance increase induced by local application of histamine. In the airways, blood flow, tracheal and bronchial smooth muscle tone, mucus and fluid production can be influenced by NPY. These functional effects can be direct or indirect via modulation of other neurotransmitters. The neuromodulatory role of NPY has been well documented on both parasympathetic activity and neurogenic inflammation, i.e., plasma extravasation elicited by sensory C-fibres stimulation. Most experiments suggest that NPY modulates neurotransmitter release by prejunctional mechanisms.

NPY metabolism

Some proteases have been shown to be involved in the metabolism of biologically active peptides in various tissues. The enzymes neutral endopeptidase (NEP) and dipeptidylpeptidase IV (DPPIV) are involved in NPY degradation. The activity of NEP can be inhibited by phosphoramidon. The inhibitory effect of NPY on the contraction of human bronchial segments in vitro could be enhanced in the presence of phosphoramidon. This observation suggests that NEP modulates the effect of NPY in the human airway by an inactivation mechanism. Similar observations were made regarding DPPIV. In patients suffering from chronic rhinosinusitis or bronchitis, the activity of both NEP and DPPIV is significantly reduced. This suggests that the catabolism of NPY and other neuropeptides could also be involved in upper airway homeostasis. Neutral endopeptidase activity and concentration of sensory neuropeptides in the human nasal mucosa varies proportionally to patient symptoms. These observations could explain the significant increase of NPY as well as SP and VIP in airway diseases.

Reference:

Zukowska, Z., & Feuerstein, G. Z. (Eds.). (2006). The NPY Family of Peptides in Immune Disorders, Inflammation, Angiogenesis, and Cancer. Springer Science & Business Media.

NPY Distribution

NPY has been found in every organ in the body; though, it is most abundant in the mammalian central and peripheral nervous system and the heart. In the central nervous system, in addition to the cerebral cortex and spinal cord, NPY immunoreactivity (NPY-ir) is particularly rich in the hypothalamic nuclei, namely: paraventricular, arcuate, suprachiasmatic, dorsal nucleus of vagus, and median eminence. In the sympathetic nervous system, NPY is co-localized with noradrenalin, and in the adrenal medulla, with epinephrine. Moreover, NPY has also been found in the respiratory tract, the biliary tract, the genitourinary system, the thyroid gland, immune, endothelial, and vascular smooth muscle cells, a subpopulation of parasympathetic neurons, and some species in platelets and megakaryocytes.

NPY’s Functions

Numerous physiological and pathological functions have been attributed to NPY. The most well known NPY actions are control of feeding behavior and energy metabolism. NPY is one of the most potent orexigenic peptides known. Its administration intracerebroventricularly causes a robust increase in carbohydrate-rich food intake in several species. Also via central actions, NPY has marked effect on peripheral metabolism, such as decrease of brown adipose tissue, thermogenesis, and increase of lipoprotein lipase activity that promotes white fat lipid storage. These observations suggest an important role of NPY in the pathophysiology of disorders such as obesity, anorexia nervosa, and diabetes. The role of NPY in reproduction, pregnancy, and onset of menarche, via modulating secretion of luteinizing hormone, has also been suggested. Acting centrally, NPY has been implicated in many neuro-physiological systems including but not limited to: facilitating learning and memory, shifting the circadian rhythm and the sleep-wake mechanisms, alteration of cardiorespiratory parameters, anxiolytic and anticonvulsive effects, neuronal growth and development, and decreasing alcohol intake. Recently, altered levels of NPY have been found in schizophrenia and Parkinson’s disease. Peripherally, NPY modulates immune

functions, gut motility and digestion, cirrhosis and ascites; and, exhibits important cardiovascular and angiogenic activities.

In the cardiovascular system, NPY has long been known as a vasoconstrictor of small arteries, leading to a stress-induced rise in blood pressure, either directly or indirectly, by enhancing the effect of catecholamines and other vasoconstrictors. Reciprocally, catecholamines have been shown to sensitize resistant vessels to NPY and augment NPY’s vasoconstrictive activity, A number of studies supported NPY’s role in stress-induced increase in blood pressure, including those that showed restoration of blood pressure during endotoxic and hemorrhagic shock, and exercise-induced rise in blood pressure in male human patients with angina pectoris. However, most recently, NPY has been shown to play a role in the regulation of basal vascular tone indirectly via modulation of the sympathetic system activity. In the latest study by Michalkiewicz et al., over-expressive rats had marked decrease, rather than increase, in both basal and stress-induced blood pressure, as well as lower levels of plasma catecholamines. In this case, NPY’s sympatholytic activity, through stimulation of the a 2-adrenergic receptors was postulated as the mechanism. Consequently, NPY has been implicated in both physiological and pathophysiological regulation of blood pressure, mechanisms of which, however, require further investigation.

Reference:

Movafagh, S. (2005). Neuropeptide Y receptor subtype (s) mediating migration, proliferation, and differentiation of endothelial cells in vitro, and angiogenesis in vivo.