Neurokinin A (porcine)

Effect of calcitonin gene-related peptide (CGRP) on motility and on the release of substance P, neurokinin A, somatostatin and gastrin in the isolated perfused porcine antrum.[Pubmed:11576394]

Neurogastroenterol Motil. 2001 Aug;13(4):353-9.

We studied the effect of porcine CGRP (pCGRP) in concentrations from 10(-10) to 10(-8) mol L(-1) on the motility and on the release of substance P, neurokinin A, somatostatin and gastrin in the antrum using the isolated perfused porcine antrum as experimental model. In addition, we studied the localization of CGRP by immunohistochemistry in the porcine antrum. CGRP-immunoreactive nerve fibres were found mainly in the submucous layer and in the external muscle coat, where they were seen in all layers, and in the ganglia of the myenteric nervous plexus. The frequency of contraction was significantly and dose-dependently increased from a basal level of 11.8 +/- 0.5 contractions per 5 min to 24.4 +/- 3.6 contractions per 5 min at pCGRP 10(-8) mol L(-1). At this dose, the release of substance P and neurokinin A was significantly increased to 470 +/- 149% and 217 +/- 26%, respectively, compared to basal release. The effect of pCGRP was unaffected by the addition of the nonpeptide antagonists for the NK-1 (CP-99994) and NK-2 receptors (SR48968), both at 10(-6) mol L(-1), whereas atropine (10(-6) mol L(-1)) completely abolished the motor effect of pCGRP. The release of somatostatin was significantly increased by 154 +/- 15% in response to CGRP at 10(-8) mol L(-1). The release of gastrin was unaffected by pCGRP. In conclusion, pCGRP increases contractile activity in the porcine antrum, an effect that involves cholinergic mechanisms but is independent of the release of substance P and neurokinin A. in addition, pCGRP increases the release of somatostatin but has no effect on gastrin release in the isolated perfused porcine antrum.

Localization of neurokinin A and chromogranin A immunoreactivity in the developing porcine adrenal medulla.[Pubmed:8045783]

Histochem J. 1994 May;26(5):431-6.

The presence of neurokinin A immunoreactivity was studied in the chromaffin cells of the porcine adrenal medulla and in the nerve fibres innervating the adrenal gland during ontogenic development. For comparison, chromogranin A immunoreactivity was used as a marker for chromaffin cells. Whereas chromogranin A was found in chromaffin cells through all steps in embryonic development, three developmental stages of neurokinin A immunoreactivity could be distinguished. In the first and second trimester of gestation, neurokinin A was observed in some groups of chromaffin cells, but no neurokinin-immunoreactive nerve fibres could be detected. In the last trimester of gestation, neurokinin A-reactive chromaffin cells and nerve fibres were both found in adrenal glands. However, in adrenal glands of neonatal piglets, neurokinin A was found only in nerve fibres and not in chromaffin cells. From these results a hypothesis is proposed that neurokinin A might act as a neurotrophic factor in the early stages of the developing porcine chromaffin cells. Biochemical studies are being performed in order to confirm these morphological results and to study the possible role of neurokinin A as a neurotrophic factor in the adrenal gland.

Trypsin induces biphasic muscle contraction and relaxation via transient receptor potential vanilloid 1 and neurokinin receptors 1/2 in porcine esophageal body.[Pubmed:28088386]

Eur J Pharmacol. 2017 Feb 15;797:65-74.

Duodenal reflux of fluids containing trypsin relates to refractory gastroesophageal reflux disease (GERD). Esophageal peristalsis and clearance are important factors in GERD pathogenesis. However, the function of trypsin in esophageal body contractility is not fully understood. In this study, effects of trypsin on circular smooth muscle (CSM) and longitudinal smooth muscle (LSM) of the porcine esophageal body were examined. Trypsin elicited a concentration dependent biphasic response, a major contraction and a subsequent relaxation only in CSM. In CSM, contraction occurred at trypsin concentrations of 100nM and relaxation at 1muM. A proteinase-activated receptor (PAR)2 activating peptide, SLIGKV-NH2 (1mM), induced a monophasic contraction. Those responses were unaffected by tetrodotoxin though abolished by the gap junction uncouplers carbenoxolone and octanol. They were also partially inhibited by a transient receptor potential vanilloid type 1 (TRPV1) antagonist and abolished by combination of neurokinin receptor 1 (NK1) and NK2 antagonists, but not by an NK3 antagonist, suggesting a PAR2-TRPV1-substance P pathway in sensory neurons. Substance P (100nM), an agonist for various NK receptors (NK1, NK2 and NK3) with differing affinities, induced significant contraction in CSM, but not in LSM. The contraction was also blocked by the combination of NK1 and NK2 antagonists, but not by the NK3 antagonist. Moreover, substance P-induced contractions were unaffected by the TRPV1 antagonist, but inhibited by a gap junction uncoupler. In conclusion, trypsin induced a biphasic response only in CSM and this was mediated by PAR2, TRPV1 and NK1/2. Gap junctions were indispensable in this tachykinin-induced response.

Ontogeny of neurokinin-1 receptors in the porcine respiratory system.[Pubmed:10612451]

Peptides. 1999 Nov;20(11):1353-60.

We characterized the ontogeny of NK-1 receptor agonist affinity (Kd) and density (Bmax) in membranes from tracheal epithelium, smooth muscle, and lung of pigs aged 1-7 days, 8-21 days, and adult in comparison to contractile responses in vitro. Affinity of [125I] Bolton-Hunter substance P ([125I]BH-SP) in epithelium and smooth muscle was three- to fourfold lower in young piglets than in adults. The Bmax of NK-1 sites in epithelium was elevated by more than twofold at 8-21 days relative to 1-7 days piglets and adults. In the lung, NK-1 density as well as affinity was lower than in trachea, regardless of age. In all three groups, [125I]BH-SP binding was potently inhibited by Gpp(NH)p, in both trachea and lung, implying coupling to G-proteins. Inhibition by Gpp(NH)p was most potent in the adult relative to younger animals, in both tracheal epithelium and smooth muscle. Functional sensitivity to the NK-1 agonists substance P and septide was reduced in neonates, as shown by the higher concentration of agonist required to elicit contractile responses. We conclude that the reduced sensitivity of newborn piglet airways to substance P reflects immaturity of G-protein coupling to NK-1, independent of receptor density.

Neurokinin A-induced vasoconstriction and muscular contraction in the rat isolated stomach: mediation by distinct and unusual neurokinin2 receptors.[Pubmed:9190865]

J Pharmacol Exp Ther. 1997 Jun;281(3):1294-302.

This study examined the pharmacological identity of the tachykinin receptors which in the rat stomach mediate vasoconstriction and muscular contraction. The vasculature of the rat isolated stomach was perfused with oxygenated Krebs buffer containing 3% dextran. Vasoconstrictor responses were recorded as increases in the vascular perfusion pressure and gastric contractions were measured as increases in the intraluminal pressure. By examining the effects of selective agonists and antagonists for tachykinin neurokinin (NK)1, NK2 and NK3 receptors it was found that the vasculature contained only NK2 receptors that were activated by the NK2 receptor agonist [betaAla8]-NKA-(4-10) and inhibited by the NK2 receptor antagonists MEN-10,627 and GR-94,800. However, the vasoconstrictor action of NKA was blocked only when the preparations were exposed to a combination of NK1, NK2 and NK3 receptor antagonists (SR-140,333, MEN-10,627, PD-161,182). In contrast, the NKA-evoked contraction of the gastric musculature was suppressed by NK2 receptor antagonists but little affected by NK1 or NK3 receptor antagonists. This observation was consistent with the predominance of NK2 receptors on the muscle as revealed by the effects of receptor-selective NK1, NK2 and NK3 agonists and antagonists. These results demonstrate that the major tachykinin receptor type present on the gastric vasculature and musculature is a NK2 receptor that is sensitive to receptor-selective agonists and antagonists. The NKA-evoked gastric contraction is also primarily due to NK2 receptor activation, whereas the NKA-induced vasoconstriction is mediated by a distinct and unusual type of NK2-like receptor that is blocked by a combination of NK1, NK2 and NK3 receptor antagonists only.

Bronchoconstrictor and respiratory effects of neurokinin A in dogs.[Pubmed:9353399]

J Pharmacol Exp Ther. 1997 Nov;283(2):788-93.

Neurokinin A (NKA) is the primary bronchoconstrictor tachykinin in the lungs of several species, including humans and has been implicated as an important mediator of inflammatory lung disorders, such as asthma. In this study, we investigated the effect of NKA on airway mechanics (lung resistance, dynamic lung compliance) and respiration (tidal volume, respiratory rate) in anesthetized, spontaneously breathing, male beagle dogs. The dogs were challenged with aerosolized NKA that was delivered from a jet nebulizer to the airways through an endotracheal tube. The challenge consisted of five separate inflations of 600 ml of air/inflation over a 1-min period. Challenge with aerosolized NKA (0.1-1%) produced a dose-dependent increase in lung resistance and a decrease in dynamic lung compliance. The bronchoconstriction induced by 1% NKA peaked at 0.5 min after challenge and had a duration of approximately 5 min. Challenge with 1% NKA also reduced tidal volume and increased respiratory rate. Pretreatment of dogs with the NK-2 receptor antagonist, SR 48968 dose-dependently (1-10 mg/kg, p.o.) blocked the bronchoconstriction and respiratory responses to NKA challenge. Pretreatment with the NK1-receptor antagonist, CP 99994 (1 mg/kg, i. v.) had no effect on the increase in lung resistance and the decrease in dynamic lung compliance due to NKA challenge, but blunted the respiratory response to NKA. Pretreatment of dogs with inhaled ipratropium bromide (0.01%) slightly, but significantly reduced the increase in lung resistance due to NKA challenge but had no effect on the decrease of dynamic lung compliance or on the respiratory responses to NKA. As expected, the bronchoconstrictor response to inhaled methacholine was completely blocked by inhaled ipratropium bromide (0.01%). In conclusion, we have identified an NK2-receptor mediated bronchoconstrictor effect of NKA in dogs. Cholinergic reflexes play a small, but significant role in this response. Furthermore, both NK1 and NK2-receptors appear to be involved with the development of the rapid, shallow breathing response to NKA challenge. These results demonstrate an effect of tachykinins on airway mechanics and ventilatory reflexes in dogs.

Nucleotide sequences of cloned cDNAs for two types of bovine brain substance P precursor.[Pubmed:6195531]

Nature. 1983 Nov 3-9;306(5938):32-6.

The primary structures of two types of bovine brain substance P precursors have been determined. One precursor contains a sequence homologous to that of the amphibian peptide kassinin. This new tachykinin sequence is bounded by paired basic amino acids Lys-Arg, which suggests that, like substance P, it can be liberated from the precursor and may serve as an endogenous hormone or neuromediator in mammalian organisms.