Influence of TASP‐V, a novel neuropeptide Y (NPY) Y₂ agonist, on nasal and bronchial responses evoked by histamine in anaesthetized pigs and in humans

Abstract

1 In nine anaesthetized pigs we have studied the in¯uence of intranasal or intrabronchial pretreatment with TASP-V, a neuropeptide Y (NPY) Y 2 agonist formed by the attachment of NPY 21-36 to a template-assembled synthetic peptide (TASP), on the functional responses to subsequent intranasal or intrabronchial histamine challenge. 2 In a parallel study, subjective and objective nasal airway resistance (NAR) increase following intranasal histamine challenge was evaluated in 11 healthy volunteers after TASP-V or placebo pretreatment. 3 In pigs, increase in sphenopalatine blood¯ow induced by histamine dihydrochloride nasal spray (0.25 mg kg 71 in 3 ml of saline) was signi®cantly reduced by 65% (P50.05) following intranasal pretreatment with 10 mg kg 71 of TASP-V. Bronchoconstriction induced by histamine dihydrochloride nebulization (0.5 mg kg 71 in 3 ml of saline) was signi®cantly attenuated by 25 and 55% following aerosolized pretreatment with TASP-V analogue at 10 and 20 mg kg 71 , respectively. 4 In healthy volunteers, objective increase in NAR and reduction in nasal minimal cross section area (MCSA) induced by intranasal spray of histamine dihydrochloride (15 mg kg 71 in 200 ml of saline) were signi®cantly attenuated by 50% following local pretreatment with 1.275 mg kg 71 of TASP-V when compared with saline. 5 It is concluded that intranasal or intrabronchial pretreatment with TASP-V reduced nasal obstruction and bronchoconstriction evoked by histamine challenge in the pig. In healthy human volunteers, this agent attenuated NAR increase and MCSA reduction induced by intranasal application of histamine.

Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

“…Based on the concept that the structure and the biological action of a peptide and protein can be modulated by the assembly of peptide elements by means of a synthetic template (the so called TASP concept) [90], Mutter and co-workers synthesized a TASP molecule that consists of two units of the C-terminal NPY fragment 21-36 attached via chemoselective ligation to a cyclic template: this molecule, denoted as TASP-V, bound selectively to the Y 2 -receptor relative to the Y 1 -receptor and acted as an agonist of NPY by inhibiting the cAMP accumulation in vitro and by reducing the nasal and bronchial obstruction evoked by histamine in vivo [91]. Previously, Grouzmann and co-workers [92] reported a TASP molecule containing four units of the C-terminal tetrapeptide of NPY 33-36; the compound, referred to as T 4 -[NPY(33-36)] 4 , bound to the Y 2 -receptor with some affinity, but not to the Y 1 -receptor, and was reported to reduce the NPYinduced mobilization of intracellular calcium.…”

Expression of tyrosine hydroxylase and neuropeptide tyrosine in mouse sympathetic airway‐specific neurons under normal situation and allergic airway inflammation

“…This difficulty in discriminating hormonal from neuronal effects has therefore contributed to the poor understanding of the functional role of these airway nerves [30] The high expression of NPY in noradrenergic neurons and nerve fibre varicosities in many mammalian species including humans, cat, guinea‐pig and rat suggests that NPY and NA may have similar effects on airway functions [27, 31, 32] In this respect, NPY is known to be co‐localized with NA in sympathetic–adrenergic nerves and is also a potent vasoconstrictor. NPY acts on its receptors that have been cloned and identified as Y1, Y2 and Y5 receptor subtypes and that are present in human and mouse airways [33–37]…”

“…In this respect, NPY is known to be co-localized with NA in sympathetic-adrenergic nerves and is also a potent vasoconstrictor. NPY acts on its receptors that have been cloned and identified as Y1, Y2 and Y5 receptor subtypes and that are present in human and mouse airways [33][34][35][36][37]. Plasticity of the sensory airway innervation has been reported in human and guinea-pig airway diseases such as rhinitis and allergic airway inflammation [11,12,19,[38][39][40].…”

Switch-Peptides as Folding Precursors in Self-Assembling Peptides and Amyloid Fibrillogenesis

“…As a representative example, we applied the ISN-induction of conformational transitions for the onset of biological function, making use of structure-activity relationship studies on neuropeptide Y (NPY) and its shorter analogues. 47,48 As shown previously, the C-terminal peptide NPY (21-36) corresponds to the minimal chain length for retaining significant binding capacity to NPY receptor Y2, notably in a helical state as bioactive conformation. When the two peptide blocks NPY (21-31) and NPY (33)(34)(35)(36), both with n < n c , a are conformationally decoupled by insertion of switch element S (derived from Thr 32 , Figure 3a), the resulting switch peptide adopts a random-coil conformation and shows no binding to Y2 (IC 50 ) 10 lM).…”