Neuromodulation mediated by the tachykinin NK3-receptor agonist [MePhe7]-neurokinin B in the isolated perfused lung of nonsensitized nonchallenged and ovalbumin-sensitized and -challenged guinea pig

Abstract

The neuromodulatory action of the tachykinin NK3-receptor agonist [MePhe7]-neurokinin B ([MePhe7]-NKB) was evaluated on vagal stimulation–induced bronchoconstriction in nonsensitized nonchallenged and ovalbumin (OVA)-sensitized and -challenged guinea pig using the isolated perfused lung preparation. Lungs were placed inside a warmed (37°C) glass chamber and suspended from a force displacement transducer (Grass FT-03) with both vagi connected to a stimulating electrode. Isolated lungs were stimulated at a constant voltage (20 V) and pulse duration (5 ms) with electrical stimulation frequencies ranging from 1 to 128 Hz. The authors demonstrated that vagal stimulation produced frequency-dependent bronchoconstriction and [MePhe7]-NKB, at a dose (0.1 μM) that does not produce bronchoconstriction by itself, potentiated the vagally induced bronchoconstriction at all frequencies in nonsensitized nonchallenged animals and to a greater extent in OVA-sensitized and -challenged guinea pigs; the potentiations were totally inhibited by the tachykinin NK3-receptor antagonist SR 142801 (1 μM). In a second set of experiments, [MePhe7]-NKB produced bronchoconstriction in a dose-dependent (1 to 300 μg/mL) manner with similar potencies and maximum responses in nonsensitized nonchallenged (EC50 = 8.6 ± 1.1 μM; EMax = 61.1 ± 3.5 mm Hg) and OVA-sensitized and -challenged (EC50 = 8.5 ± 1.3 μM; EMax = 63.5 ± 3.7 mm Hg) animals. In conclusion, these results demonstrated that [MePhe7]-NKB potentiated vagal stimulation–induced bronchoconstriction via the tachykinin NK3-receptors and OVA sensitization caused development of airway hyperresponsiveness in these potentiations. However, OVA sensitization had no effect on airway responsiveness of vagal stimulation–and [MePhe7]-NKB–induced bronchoconstrictions.