Effects of histamine H(2)-receptor antagonists on human plasma levels of calcitonin gene-related peptide,substance P and vasoactive intestinal peptide

The effects of the histamine H(2)-receptor antagonists (H(2)-antagonists), ranitidine, nizatidine, cimetidine and famotidine, on plasma levels of gastrointestinal peptides, calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP) was investigated with respect to regulation of gastric mucosal blood flow, in healthy volunteers. H(2)-Antagonists or placebo was orally administered to five healthy male volunteers. Venous blood samples were taken before and after drug administration. The levels of plasma gastrointestinal peptides were determined by enzyme immunoassay. The administration of ranitidine and nizatidine caused significant increases in plasma CGRP and SP levels at 30 to 120 min compared with the placebo group. Peak plasma CGRP levels (39.8+/-3.1 and 40.6+/-3.6 pg mL(-1)) were achieved 60 min after administration of ranitidine and nizatidine, respectively. Maximum plasma SP levels (21.3+/-5.2 and 22.8+/-4.2 pg mL(-1)) were reached 60 min after administration of ranitidine and nizatidine, respectively. However, all H(2)-antagonists did not alter the levels of VIP. The released CGRP and SP by ranitidine and nizatidine administration may produce a gastroprotective effect, increase mucosal blood flow, and inhibit acid secretion in the gastrointestinal tract.     

藿香正气液对大鼠血管活性肠肽的影响

目的：观察藿香正气液对大鼠血管活性肠肽（VIP）的影响。方法：80只Wistar大鼠随机分为藿香正气液组和时照组，分别给大鼠灌服藿香正气液或生理盐水1，6h后：①观察大鼠胃肠动力的变化；②运用放射免疫分析法测定血浆、胃窦和空肠组织匀浆中VIP含量的变化；③运用免疫组化法显示胃窦、空肠组织中VIP阳性产物的分布情况。结果：①应用藿香正气液后1，6h，大鼠胃肠动力显著增强，以用药后1h更为明显。②藿香正气液明显降低血浆、胃窦及空肠组织匀浆中VIP的含量，减少胃窦和空肠组织中VIP的阳性产物。结论：藿香正气液促胃肠动力作用可能与其对VIP的影响有关。     

Effect of terfenadine on the plasma concentrations of substance P and vasoactive intestinal polypeptide in volunteers.

The effect of terfenadine on the plasma concentrations of substance P and vasoactive intestinal polypeptide (VIP) was studied in 7 healthy subjects and 8 subjects with the common cold. Before terfenadine administration, the mean plasma substance P concentration of the subjects with the common cold was significantly higher than that of the healthy subjects. The increased mean plasma substance P concentration of the subjects with the common cold was decreased after terfenadine administration. In the healthy subjects, the mean plasma substance P concentration was unchanged by terfenadine administration. The mean plasma VIP concentration of the subjects with common cold was slightly higher than that of the healthy subjects before and after terfenadine administration, with no significant difference.     

盐酸戊乙奎醚对小鼠血浆血管活性肠肽的影响

目的观察盐酸戊乙奎醚对小鼠胃肠动力及血浆血管活性肠肽的影响。方法健康昆明小鼠30只,体重18～24g,雌雄不限,随机分为对照组、阿托品组和盐酸戊乙奎醚组,每组10只。阿托品组腹腔注射阿托品0.3mg/kg,盐酸戊乙奎醚组腹腔注射盐酸戊乙奎醚0.3mg/kg,对照组给予等容量0.9%氯化钠溶液。3组给药15min后以营养性半固体糊0.8ml/只灌胃,30min后处死小鼠,采用放免法测定血管活性肠肽水平,计算胃内残留率。结果与对照组比较,阿托品组血管活性肠肽水平升高(P<0.05),盐酸戊乙奎醚组血管活性肠肽水平差异无统计学意义(P>0.05);与阿托品组比较,盐酸戊乙奎醚组血管活性肠肽水平下降(P<0.05)。与对照组比较,阿托品组胃内残留率升高,盐酸戊乙奎醚组胃内残留率差异无统计学意义(P>0.05);与阿托品组比较,盐酸戊乙奎醚组胃内残留率降低(P<0.05)。结论与阿托品比较,盐酸戊乙奎醚不抑制胃肠运动,其对血管活性肠肽的分泌无影响。     

Calcium-dependent stimulation of acetylcholine release by substance P and vasoactive intestinal polypeptide

In the guinea-pig myenteric plexus-longitudinal muscle preparation from the small intestine, the release of acetylcholine evoked by substance P and vasoactive intestinal polypeptide was examined in vitro. Both neuropeptides stimulated efflux of [3H]acetylcholine from myenteric neurons in a calcium-dependent manner. This observation is consistent with the view that neurotransmitter release elicited by neuropeptides requires the presence of extracellular calcium ions.     

Effects of penehyclidine hydrochloride on vasoactive intestinal peptide content in mice

目的 观察盐酸戊乙奎醚对小鼠胃肠动力及血浆血管活性肠肽的影响.方法 健康昆明小鼠30只,体重18 ～24 g,雌雄不限,随机分为对照组、阿托品组和盐酸戊乙奎醚组,每组10只.阿托品组腹腔注射阿托品0.3 mg/kg,盐酸戊乙奎醚组腹腔注射盐酸戊乙奎醚0.3 mg/kg,对照组给予等容量0.9％氯化钠溶液.3组给药15 min后以营养性半固体糊0.8 ml/只灌胃,30 min后处死小鼠,采用放免法测定血管活性肠肽水平,计算胃内残留率.结果 与对照组比较,阿托品组血管活性肠肽水平升高(P＜0.05),盐酸戊乙奎醚组血管活性肠肽水平差异无统计学意义(P＞0.05);与阿托品组比较,盐酸戊乙奎醚组血管活性肠肤水平下降(P＜0.05).与对照组比较,阿托品组胃内残留率升高,盐酸戊乙奎醚组胃内残留率差异无统计学意义(P＞0.05);与阿托品组比较,盐酸戊乙奎醚组胃内残留率降低(P＜0.05).结论 与阿托品比较,盐酸戊乙奎醚不抑制胃肠运动,其对血管活性肠肽的分泌无影响.     

Effect of substance P on dopamine-beta-hydroxylase and phenethanolamine-N-methyltransferase in the adrenal glands of rats

Resulting from literature data concerning interactions between catecholamines and Substance P (SP) the influence of SP on the activity of dopamine-beta-hydroxylase (DBH) and phenylethanolamine-N-methyltransferase (PNMT) was studied in rat adrenals. Intraperitoneal application of SP (500 micrograms/kg) to male Wistar rats 15 minutes before decapitation induced a decrease of PNMT activity in the adrenals, while DBH activity remained unchanged. After incubation of adrenals with SP (10(-6) mol/l) a decrease of activity of both PNMT and DBH was observed. The experimental results are discussed in connection with a normalizing function of SP during stress induced disorders.     

Effects of vasoactive intestinal peptide and its homologues on the substance P-mediated secretion of fluid and protein from the rat submandibular gland

1. Vasoactive intestinal peptide (VIP) and secretin elicited slight secretion of saliva but peptide histidine isoleucine (PHI) and gastric inhibitory peptide (GIP) failed to elicit secretion of saliva from rat submandibular glands.2. Substance P (SP)-mediated secretion of fluid and protein were enhanced by VIP and secretin but not by PHI or GIP.3. These results suggest that the effects of VIP, PHI, secretin and GIP on the secretion of fluid from rat submandibular glands and the synergistic effects of VIP and its homologues on the SP-mediated secretion of fluid and protein do not correspond to the extent of the structural homology of each analogue to VIP.     

Effects of vasoactive intestinal peptide on phenotypic and functional maturation of dendritic cells

The present study was designed to investigate the effects of vasoactive intestinal peptide (VIP) on differentiation, maturation of dendritic cells (DCs) in vitro. DCs were derived from the murine bone marrow hemopoietic progenitor cells by culturing in RPMI 1640 complete medium supplemented with GM-CSF and IL-4 in the presence or absence of various concentrations of vasoactive intestinal peptide (VIP) and lipopolysaccharide (LPS). The phenotype of DCs was analyzed by flow cytometry. Mixed leukocyte reaction (MLR) was employed to measure the capacity of DC to stimulate the allogeneic T cells. IL-12p70 secretion by DC was examined by ELISA. In the absence of LPS, VIP, in a dose dependent manner, up-regulated the expression of CD80, CD86, CD54 and CD40, but down-regulated the expression of MHC class II molecule (Ia(b)). In the presence of LPS, VIP also dose dependently up-regulated the expression of CD80, CD86, CD54 and CD40, and down-regulated the expression of Ia(b). The capacity to stimulate alloreactive T cells and the production of IL-12p70 by DC were significantly augmented by VIP when compared with VIP-untreated DCs. These data suggest that VIP could promote the phenotypic and functional maturation of DCs, hereby regulating the type and outcome of the conducting immune response.     

Effects of the vasoactive intestinal peptide on stress-induced mucosal ulcers and modulation of methylation of histamine in gastric tissue of the rats

Vasoactive intestinal peptide (VIP) prevents stress-induced gastric ulcers, inhibits mast cell degranulation and protects gastric tissue from lipid peroxidation. Histamine has an important role in the development of gastric ulcers and mast cell derived histamine might be essential in this process.     

Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats

The aim of this work was to study in rats the nasal route for the brain delivery of the vasoactive intestinal peptide (VIP) neuropeptide. After evaluating VIP stability in solutions obtained from nasal washes, the effect of formulation parameters (pH 4-9, 0-1% (w/v) lauroylcarnitine (LC), hypo- or isoosmolality) on the brain uptake of intranasally administered VIP (10(-8)M)/125I-VIP (300,000 cpm/ml) was studied, using an in situ perfusion technique. Brain radioactivity distribution was assessed by quantitative autoradiographic analysis. Results were compared to intravenously administered VIP. With a hypotonic formulation at pH 4 containing 0.1% LC and 1% bovine serum albumin, VIP stability was satisfactory and loss by adsorption was minimal. Using this formulation, around 0.11% of initial radioactivity was found in the brain after 30 min perfusion and was located in the olfactory bulbs, the midbrain and the cerebellum. HPLC analysis of brain and blood extracts demonstrated the presence of intact VIP in brain and its complete degradation in the blood compartment. By intravenous administration, no intact VIP was found either in brain or in blood. In conclusion, intact VIP could be delivered successfully to the brain using the intranasal route for administration.     

清胰汤治疗大鼠重症急性胰腺炎后结肠黏膜下神经节血管活性肠肽神经元的变化

目的 探讨中药清胰汤治疗大鼠重症急性胰腺炎(SAP)后结肠黏膜下神经节血管活性肠肽免疫反应(VIP-IR)阳性神经元的变化.方法 30只SD大鼠随机均分为假手术组(A组)、SAP模型组(B组)和清胰汤组(C组).24 h后应用双重免疫荧光染色法观察结肠黏膜下神经节的VIP-IR神经元的变化,并与结肠蠕动频率进行相关性分析.结果 与A组相比,B组胰腺病理评分及结肠黏膜下神经节的VIP-IR神经元表达率增加,结肠蠕动频率降低(P＜0.05);而C组的上述指标均较B组明显改善(P＜0.05).结肠蠕动频率与VIP-IR神经元表达呈负相关(P＜0.05).结论 清胰汤抑制SAP大鼠结肠黏膜下神经节VIP-IR神经元的过表达.     

Antidipsogenic action of vasoactive intestinal peptide in the rat

The effect of vasoactive intestinal peptide (VIP) on the intake of water was studied in the rat. Intracerebroventricular administration of vasoactive intestinal peptide strongly inhibited drinking in rats deprived of water, but peripheral administration had no effect, indicating that the site of action was central. Drinking induced by angiotensin II was also markedly blocked by simultaneous administration of vasoactive intestinal peptide. The results indicate that in the rat, vasoactive intestinal peptide may play a role in the control of intake of water as a neuropeptide thirst inhibitor.     

Effects of neuropeptide Y and vasoactive intestinal peptide on human venous smooth muscle in vivo

The direct and noradrenaline-modulating effects of neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) on venous smooth muscle were studied in healthy volunteers employing the dorsal hand vein compliance technique. Local infusions of NPY had no measurable effect on venous tone, but coinfusion of a constant high dose of NPY (242 pmol/min) with noradrenaline caused a 2.9-fold increase in the mean ED₅₀ for noradrenaline. The dilating effect of VIP on preconstricted hand veins was weak, maximal venodilation could not be achieved, because systemic side effects occurred at submaximally venodilating doses. Coinfusion of noradrenaline with a weakly venodilating, constant dose of VIP (93.2 pmol/min) caused a 0.5-fold decrease in the sensitivity for noradrenaline. Although functional interactions between NPY or VIP and noradrenaline could be demonstrated, the dosages of the peptides required were high. Thus our results indicate that neither NPY nor VIP exert a major direct or noradrenaline-modulating effect on human veins. Correspondence to: H. G. Eichler at the above address     

Effects of avian pancreatic peptide on smooth muscle relaxations by vasoactive intestinal peptide and inhibitory nerve stimulation

Experiments were carried out to investigate whether avian pancreatic peptide (APP) antagonized relaxations of vascular and gastrointestinal smooth muscles induced by vasoactive intestinal peptide (VIP) and non-adrenergic, non-cholinergic inhibitory nerve stimulation using the cat submandibular gland, cat colon and dog stomach in vivo and several isolated smooth muscles in vitro. APP caused a dose-dependent inhibition of an atropine-resistant vasodilatation induced by chorda-lingual and pelvic nerve stimulation and by VIP. APP did not reduce VIP output induced by pelvic nerve stimulation. APP shifted the dose-response curve for VIP and the frequency-response curve for pelvic nerve stimulation to the right. The vasodilatation induced by isoproterenol or bradykinin was inhibited by somewhat higher doses of APP. APP failed to inhibit the vago-vagal reflex relaxation of the dog stomach. In guinea pig and rat fundic strips and in isolated chick rectum, APP did not exert any significant effects on relaxation caused by VIP or transmural stimulation in the presence of atropine and guanethidine. The result indicates that APP inhibits VIP-mediated relaxation of the vascular smooth muscle, but not that of the gastrointestinal smooth muscle. The inhibitory effect of APP on VIP-mediated vasodilatation is suggested to be due to the physiological competition.     

Role of vasoactive intestinal peptide in inflammation and autoimmunity

Vasoactive intestinal peptide (VIP), a peptide produced by immune cells, exerts a wide spectrum of immunological functions that control the homeostasis of the immune system. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, both in innate and adaptive immunity. In innate immunity, this peptide inhibits the production of inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP reduces the expression of co-stimulatory molecules on antigen-presenting cells, and therefore reduces stimulation of antigen-specific CD4 T-cells. In terms of adaptive immunity, VIP promotes T-helper (Th)2-type responses, and reduces inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors are known. Therefore, VIP and its analogs have been proposed as promising alternative candidates to existing therapies for the treatment of acute and chronic inflammatory and autoimmune diseases. The aim of this review is to update knowledge of the cellular and molecular events that are relevant to VIP function in the immune system. The central functions that VIP plays in cellular processes is being recognized and attention is being focused on this important peptide with regard to exciting new candidates for therapeutic intervention and drug development.     

Effects of vasoactive intestinal peptide (VIP) on contractile responses of smooth muscle in rat stomach.

1. The effects of vasoactive intestinal peptide (VIP) on contractile responses to carbachol (CCh), KCl and caffeine of the circular smooth muscle in rat stomach were examined by the isometric tension recording method and by measurement of the intracellular Ca level, [Ca]i, with fura 2. 2. Removal of extracellular Ca or nifedipine (0.1 microM) inhibited contractions induced by KCl (40 mM) and a low concentration (1 microM) of CCh but not that induced by caffeine (3 mM). After these treatments, the contraction induced by a high concentration of CCh (100 microM) changed to a phasic response. 3. VIP dose-dependently inhibited the contraction induced by 1 microM CCh, but not those caused by 40 mM KCl or 3 mM caffeine. 4. In Ca-free solution containing 2 mM EGTA, VIP inhibited the phasic contraction induced by 100 microM CCh, but not that induced by 30 mM caffeine. 5. CCh caused dose-dependent tension development concomitant with the increase in [Ca]i. VIP reduced both responses and thus did not affect the [Ca]i-force relation for CCh. In the chemically skinned muscle fibres, VIP had no effect on the pCa-tension relation. 6. It is suggested that the inhibitory effects of VIP on CCh-induced contractions are due to the inhibition of the processes of signal transduction from muscarinic receptors to voltage-dependent Ca channels and to intracellular Ca stores.     

Antagonistic effect of a vasoactive intestinal peptide fragment, vasoactive intestinal peptide(1-11), on guinea pig trachea smooth muscle relaxation.

The conformation of various regions of vasoactive intestinal peptide (VIP) has been analyzed by semiempirical methods, CD, and NMR spectroscopy, indicating that residues 11-21 are most likely to be helical, whereas the amino-terminal portion VIP(1-11) could exhibit two beta-turn structures. VIP(1-11) inhibits 125I-VIP binding to intact guinea pig tracheal epithelial cells and the VIP-induced smooth muscle response. However, the endecapeptide exhibits no effect on the muscle tone. All these data suggest that VIP(1-11) may be a useful tool in studying VIP receptor recognition, its regulation, and cellular functions.