BACKGROUND: Asthma is an inflammatory disease because there are many inflammatory changes in the asthmatic airways. Axon reflex mechanisms may be involved in the pathogenesis of asthma. Sensory neuropeptides are involved in this inflammation, which is defined as neurogenic inflammation. Substance p, neurokinin A, and neurokinin B may be main neuropeptides of neurogenic inflammation in airways. These tachykinins act on neurokinin recptors. Three types of neurokinin receptors, such as NK1, NK2, and NK3, are currently recognized, at which substance p,neurokinin A, and neurokinin B may be the most relvant natural agonist of neurogenic inflammation in airways. The receptor subtypes present in several tissues have been characterized on the basis of differential sensitivity to substance p, neurokinin A, and neurokinin B. Plasma extravasation and vasodilation are induced by substance p more potently than by neurokinin A, indicating NK1 receptors on endothelial cells mediate the response. But airway contraction is induced by neurokinin A more potently than by substance P, indicating the NK2 receptors in airway smooth muscles. These receptors are used to evaulate the pathogenesis of brochial asthma. FK224 was identified from the fermentation products of Streptomyces violaceoniger. FK224 is a dual antagonist of both NK1 and NK2 recptors. PURPOSE: For a study of pathogenesis of bronchial asthma, the effect of FK224 on plasma extravasation induced by vagal NANC electrical stimulation was evaluated in rat airway. METHOD: Male Sprague-Dawley rats weighing 180~450gm were anesthetized by i.p. injection of urethane. Plasma extravasation was induced by electrical stimulation of cervical vagus NANC nerves with 5Hz, 1mA, and 5V for 2 minutes(NANC2 group) and for sham operation without nerve stimulation(control group). To evaluate the effect of FK224 on plasma extravasation in neurogenic inflammation, FK224(lmg/kg, Fujisawa Pharmaceutical Co., dissolved in dimethylsul- phoxide; DMSO, Sigma Co.) was injected 1 min before nerve stimulation(FK224 group). To assess plasma exudation, Evans blue dye(20mg/kg,dissolved in saline) was used as a plasma marker and was injected before nerve stimulation. After removal of intravascular dye, the evans blue dye in the tissue was extracted in formamide(37degreesC, 24h) and quantified spectrophotometrically by measuring dye absorbance at 629nm wavelength. Tissue dye content was expressed as ng of dye per mg of wet weight tissue. The amount of plasma extravasation was measured on the part of airways in each groups. RESULTS: 1) Vagus nerve(NANC) stimulation significantly increased plasma leakage in trachea, main bronchus, and peripheral bronchus compared with control group, 14.1 +/-1.6 to 49.7+/-2.5, 17.5 +2.0 to 38.7 +/-2.8, and 12.7+/-2.2 to 19.1 +/-1.6ng of dye per mg of tissue(mean +/- SE), respectively(p< 0.05). But there was not significantly changed in lung parenchyma(p >0.05) 2) FK224 had significant inhibitory effect upon vagal nerve stimulation-induced airway plasma leakage in any airway tissues of rat,such as trachea, main bronchus, and peripheral bronchus compared with vagus nerve stimulation group, 49%, 58%, and 70%, respectively(p<0.05). Inhibitory effect of FK224 on airway plasma leakage in neurogenic inflammation was revealed the more significant in peripheral bronchus, but no significant in lung parenchyma. CONCLUSION: These results suggest that FK224 is a selective NK receptor antagonist which effectively inhibits airway plasma leakage induced by the endogenous neurotransmitters relased by neurogenic inflammation in rat airway. Tachykinin receptor antagonists may be useful in the treatment of brochial asthma.
Animals ; Asthma ; Axons ; Bronchi ; Dimethyl Sulfoxide ; Electric Stimulation ; Endothelial Cells ; Evans Blue ; Fermentation ; Humans ; Inflammation ; Lung ; Male ; Muscle, Smooth ; Neurogenic Inflammation* ; Neurokinin A ; Neurokinin B ; Neuropeptides ; Neurotransmitter Agents ; Plasma* ; Rats* ; Rats, Sprague-Dawley ; Receptors, Tachykinin ; Reflex ; Streptomyces ; Substance P ; Tachykinins ; Trachea ; Urethane ; Vagus Nerve Stimulation ; Vasodilation

BACKGROUND: The angiotensin-converting enzyme (ACE) has a major role in the degradation of bradykinin, tachykinin, substance P which are associated with bronchial hyperresponsiveness and inflammation. The other role of ACE is the genesis of angiotensin II which causes bronchial smooth muscle contraction. The deletion polymorphism of ACE gene(DDtype) may be related to the high serum level of ACE. OBJECTIVE: We studied to evaluate an association between the insertion /deletion polymorphism of the ACE gene and asthma, and its severity. Materials and methods: Sixty asthmatic patients and 44 healthy controls were enrolled. Severity of asthma was classified by the guideline of NHLBI/WHO workshop. The ACE genotypes of all the subjects were determined by polymerase chain reaction. RESULTS: The distribution of ACE genotypes were not significantly different between healthy controls and asthma group (p)0.05). In asthmatic patients, the genetic polymorphism was similar between different severity groups (p) 0.05). Conchcsion: It is suggested that I/D polymorphism of the ACE gene may not be associated with development of asthma. The severity of asthma may not be influenced by I/D polymorphism of the ACE gene.
Angiotensin II ; Asthma* ; Bradykinin ; Education ; Genotype ; Humans ; Inflammation ; Muscle, Smooth ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Substance P ; Tachykinins

BACKGROUND AND OBJECTIVES: Angiotensin -converting enzyme (ACE) inactivates bradykinin, substance P, and neurokinin A, which are thought to play important roles in the pathogenesis of inflammatory diseases. An insertion/deletion (I/D) poly - morphism in the ACE gene was reported to be associated with atopy in a Czech population. MATERIALS AND METHODS: Using the polymerase chain reaction, we investigated the frequencies of the genotypes and alleles of the ACE gene in 137 patients with allergic rhinitis and 498 healthy control subjects. RESULTS: There was no difference in the frequencies of the genotypes in the controls and patients with allergic rhinitis (p>0.05). The D allele was more frequent in patients with allergic rhinitis, but the difference was not statistically significant (p>0.05). CONCLUSION: Our results indicate that I/D polymorphism in the ACE gene is not related to susceptibility to allergic rhinitis in the Korean population.
Alleles ; Angiotensins ; Bradykinin ; Genotype ; Humans ; Neurokinin A ; Polymerase Chain Reaction ; Rhinitis* ; Substance P

OBJECTIVE: To find out wheather the substance P takes part in the pain mediating system of uterus, and to ascertain the role of substance P in the hypersensitivity of hypogastric nerve to bradykinin during the uterine inflammation. METHODS: The uterus has two sensory innervations, which are the hypogastric nerve and the pelvic nerve. Since the hypogastric nerve is known to show increased sensitivity to bradykinin, a pain mediator, when the uterus is in inflammatory state, the hypogastric nerve recording was done for electrophysiological study of uterine pain-mediating mechanism in female SD rats (200-250 g). NK1 receptor antagonist (L-703,606) was injected through uterine artery before injecting bradykinin while uterus was under inflammation. RESULTS: The NK-1 receptor antagonist (L-703,606) decreased the spontaneous nerve impulse during inflammation, and it also decreased the hypersensitivity of the hypogastric nerve to bradykinin during the uterine inflammation. CONCLUSION: Substance P mediates the pain sense of hypogastric nerve, and it also plays a role in increased sensitivity of hypogastric nerve to bradykinin while uterus is in inflammatory state.
Action Potentials ; Animals ; Bradykinin* ; Female ; Humans ; Hypersensitivity ; Inflammation ; Mustard Plant* ; Negotiating ; Rats* ; Receptors, Neurokinin-1* ; Substance P ; Uterine Artery ; Uterus*

BACKGROUND AND OBJECTIVES: Osteoclasts are the principal cell of bone resorption playing a major role in focal bone erosion associated with cholesteatoma. This study was conducted in order to investigate direct effect of substance P (SP) on osteoclastogenesis and osteoclastic bone resorption in vitro. MATERIALS AND METHOD: SP dose response was measured in receptor activator for NF-kappaB ligand (RANKL)-induced mouse osteoclast culture and osteoclastic bone resorption assay. RT-PCR was performed for the expression of neurokinin(NK) receptor mRNAs in osteoclasts. RESULTS: Treatment with SP (100 nM and 1000 nM) significantly increased osteoclastogenesis. SP (0.1 nM and 1 nM) significantly increased resorption surface area on dentin slices by osteoclasts. Cultured osteoclasts expressed NK-2 receptor mRNA. CONCLUSION: SP has a direct upregulatory effect on osteoclastogenesis and osteoclastic bone resorption that is mediated possibly by NK-2 receptor.
Animals ; Bone Resorption* ; Cholesteatoma ; Dentin ; Mice ; NF-kappa B ; Osteoclasts* ; Receptors, Neurokinin-2 ; RNA, Messenger ; Substance P*

Penile corpus cavernosum can be seen as a special kind of vascular structure. The cause of erectile dysfunction (ED) is often related to the changes of penile vasoactive mediators which modulate the functional conditions of penile erectile tissues. The penile vasoactive mediators including angiotensin and kinins, prostaglandins, endothelins, endothelium-derived hyperpolarizing factors (EDHF), NOS and NO, RhoA/Rho-kinases, etc., may play an important role in the development of ED. Further researches on these mediators can furnish some theoretical evidence for the clinical treatment of ED.
Angiotensins ; physiology ; Animals ; Dogs ; Endothelins ; physiology ; Erectile Dysfunction ; physiopathology ; Humans ; Kinins ; physiology ; Male ; Nitric Oxide ; physiology ; Nitric Oxide Synthase ; physiology ; Penis ; blood supply ; Prostaglandins ; physiology ; Rats

The involvement of plasma kallikrein-kinin system in some pathological states such as bronchial asthma and coughing induced by captopril has been suggested, LTC, and LTD, have been well reported to have a potent activity of bronchoconstriction and mucous secretion. The author tried to confirm whether leukotrienes increase glandular kallikrein activity in bronchial wash or not, and if it is true, to investigate the possible mechanism of leukotrienes-induced increase of glandular kallikrein activity. Bronchial wash was collected from excised lungs of guinea pig, and incubated with synthetic substrate (Pro-Phe-Arg-MCA), and released amount of AMC was measured by fluorescence spectrophotometer as the amidase activity (glandular kallikrein activity). In order to confirm that glandular kallikrein can release kinin, bronchial wash was also incubated with purified LMW- kininogen in the presence of kininase inhibitor (o-phenanthroline), and the amount of kinin was measured by enzyme immunoassay as the kinin releasing activity of glandular kallikrein. The results were as follows: 1) The glandular kallikrein activity (control: 2.98 x 10(-11) mole/min/ml wash) was increased by pilocarpine (12-120 umole/kg, i.v.), and the increased glandular kallikrein activity by pilocarpine (41 nmole/kg, i.v.) was inhibited by atropine (4-43 nmole/kg, i.v.). 2) LTC(4) (1-10 nmole/kg, i.v.) or LTD(4) (1-10 nmole/kg, i.v.) increased the glandular kallikrein activity, but the potency of LTD, was about 1/3 of that of LTC,. The increased glandular kallikrein activity by LTC, (3 nmole/kg, i.v.) was inhibited by ONO-1078 (20-203 nmole/kg, i.p.). 3) The increased glandular kallikrein activity by LTC, (3nmole/kg, i.v.) was inhibited by in- domethacin (8-83 nmole/kg, i.p.), OKY-046 (11-113 nmole/kg, i.v.), atropine (4-43 nmole/kg, i.v.), scopolamine (9-88 umole/kg, i.v.) and Thi-D-Phe-BK (100-1000 nmole/kg, i.v.). 4) STA, (6-60pmole/kg, i.v.) increased the glandular kallikrein activity, and the increased glandular kallikrein activity by STA, (20 pmole/kg, i.v.) was inhibited by atropine (14 umole/kg, i.v.) (p < 0. 001). 5) The increased glandular kallikrein activity by pilocarpine (41 urnole/kg, i.v.) was not inhibited by indomethacin (83 umole/kg, i.p.), but it was inhibited by Thi-D-Phe-BK (300 nmole/kg, i.v.) (p< 0. 001). 6) Bradykinin (3-30 nmole/kg, i.v.) increased the glandular kallikrein activity, and the increased glandular kallikrein activity by bradykinin (30 nmole/kg, i.v.) was inhibited by indomethacin (83 umole/kg, i.p.) or atropine (14 umole/kg, i.v.) (p<0.001). 7) The kinin releasing activity by glandular kallikrein in bronchial wash was 24 x 10 " mole/min/ ml wash in control group, and it was markedly increased in pilocarpine-pretreated group (124 x 10 mole/min/ml wash) (p<0.05), and in LTC4-pretreated group (164x10 mole/min/ml wash) (p<0. 01). The increased kinin releasing activity by LTC, (3 nmole/kg, i.v.) was completely inhibited by aprotinin (5000IU/ml, i.v.). I could conclude that i ) LTC, and LTD, increased glandular kallikrein activity in bronchial wash of guinea pig, ii) the most possible mechanism of LTC,-induced increase of glandular kallikrein activity in bronchial wash may be as follows; LTC,TXA,aeetyleholineinerease of glandular kallikrein acitivity, and iii) kinin released by glandular kallikrein may enhance the action of TXA, or acetylcholine to increase the glandular kallikrein activity.
Acetylcholine ; Animals ; Aprotinin ; Asthma ; Atropine ; Bradykinin ; Bronchoconstriction ; Captopril ; Cough ; Fluorescence ; Guinea Pigs* ; Guinea* ; Immunoenzyme Techniques ; Indomethacin ; Kallikrein-Kinin System ; Kallikreins ; Kininogens ; Leukotriene C4* ; Leukotrienes ; Lung ; Pilocarpine ; Plasma ; Scopolamine Hydrobromide ; Tissue Kallikreins*

Kisspeptin has recently emerged as a key regulator of the mammalian reproductive axis. It is known that kisspeptin, acting centrally via the kisspeptin receptor, stimulates secretion of gonadotrophin releasing hormone (GnRH). Loss of kisspeptin signaling causes hypogonadotrophic hypogonadism in humans and other mammals. Kisspeptin interacts with other neuropeptides such as neurokinin B and dynorphin, to regulate GnRH pulse generation. In addition, a growing body of evidence suggests that kisspeptin signaling be regulated by nutritional status and stress. Kisspeptin may also represent a novel potential therapeutic target in the treatment of fertility disorders. Early human studies suggest that peripheral exogenous kisspeptin administration stimulates gonadotrophin release in healthy adults and in patients with certain forms of infertility. This review aims to concisely summarize what is known about kisspeptin as a regulator of reproductive function, and provide an update on recent advances within this field.
Adult ; Dynorphins ; Fertility ; Gonadotropin-Releasing Hormone ; Humans ; Hypogonadism ; Hypothalamus ; Infertility ; Kisspeptins ; Mammals ; Neurokinin B ; Neuropeptides ; Nutritional Status ; Axis, Cervical Vertebra

Immune responses of periodontal tissue may be regulated by products of sensory afferent nerve endings such as neuropeptides. Substance P(SP), a tachykinin neuropeptide, has been previously reported to stimulate the activities of T lymphocyte. Therefore, I examined the role of SP in IL-2 production and cell proliferation by using a homogeneous line of T lymphocytes(Jurkat and HuT78). Cell proliferation rate was determined by [3H]-thymidine incorporation test, and IL-2 was quantitated by the growth rate of CD4+ IL-2-dependent T lymphocyte line CTLL-2. SP stimulated cell proliferation of T lymphocytes at the concentration of 10(-12) and 10(-8)M in a biphasic bell-shape dose-dependent manner. However, SP alone did not induce IL-2 release at the concentration range of 10(-6) to 10(-14)M. The upregulation of IL-2 release was observed when 10(-12)M SP was applied together with mitogens such as Con A or PHA+PMA on T cell lines, especially on Jurkat. Con A or PHA+PMA demonstrated to increase the rate of cell proliferation of Jurkat, which had shown to produce much amount of IL-2 indicating that mitogen-induced cell proliferation might be partially influenced by released IL-2. It was concluded that regulatory effects of SP on the immune/inflammatory response could be mediated through the costimulatory upregulation of IL-2 production and increase of cell proliferation of T lymphocyte.
Cell Line ; Cell Proliferation* ; Interleukin-2* ; Lymphocytes* ; Mitogens ; Nerve Endings ; Neuropeptides ; Substance P* ; T-Lymphocytes ; Tachykinins ; Up-Regulation

<p><b>OBJECTIVEb>To investigate the effects of substance P on cultured rat osteoclasts.p><p><b>METHODSb>Neurokinin-1 (NK1) receptor expression in osteoclasts was examined by immunohitochemical method, and changes of bone resorption activity caused by substance P and NK1 receptor antagonists were detected by pit formation assay.p><p><b>RESULTSb>Immunoreactivity for NK1 receptor was distributed in the cytoplasm of osteoclasts. The average of pit formation areas significantly increased with addition of substance P (10(-7)-10(-4) mol/L) (P < 0.05), but the number of pitformations did not change (P > 0.05). NK1 receptor antagonists inhibited the enhancement of the bone resorption by substance P addition.p><p><b>CONCLUSIONb>The findings suggested that substance P may stimulate osteoclasts and result in bone resorption by the mediation of NK1 receptor.p>
Animals ; Osteoclasts ; Rats ; Receptors, Neurokinin-1 ; Substance P