Functional dyspepsia (FD) is a subcategory of the functional gastrointestinal disorders according to the Rome III classification of functional gastroduodenal disorders. FD is characterized by the presence of symptoms that are believed to be associated with gastroduodenal lesions, particularly epigastric pain or burning, postprandial fullness, or early satiation, without the evidence of organic disease likely to explain the onset of these symptoms. Generally, multiple factors are considered to be involved in the onset of dyspeptic symptoms in patients with FD. Among these factors, acid is thought to be more important because proton pump inhibitors (PPIs) and histamine 2 (H2)-receptor antagonists have been proposed to be effective therapies for a subset of patients with FD. Although manometric methods, scintigraphic methods, electrogastrography and ultrasonography have been used to evaluate enterokinesis, a practical method for evaluating duodenal hypersensitivity to acid has not been reported. Recently, we attempted to evaluate duodenal hypersensitivity to acid and gastric motility by duodenal acidification using transnasal endoscopy. Using this method, we could simultaneously evaluate both dyspeptic symptoms and gastric motility in healthy volunteers. Furthermore, we evaluated duodenal hypersensitivity to acid in healthy volunteers and in patients with FD, and we reported that duodenal acidification induced dyspeptic symptoms more significantly in patients with FD than in healthy volunteers.
Objective: To measure the effects of estrogen, progesterone and polypropylene mesh on vaginal smooth muscle cell proliferation. Methods: Primary smooth muscle cell (SMC) cultures were performed from vaginal biopsies which were then incubated with estradiol (0.1 μM, 1 μM, 10 μM), progesterone (5 nM, 50 nM, 0.5 μM), or polypropylene mesh to assess cell proliferation. Results: In vitro vaginal SMC proliferation was significantly increased by estradiol but not by progesterone or by polypropylene mesh (relative cell number, mean ± SD, control vs. estrogen 0.24 ± 0.02 vs. 0.28 ± 0.02, P=0.01; control vs. progesterone 0.24 ± 0.02 vs. 0.23 ± 0.02, P=NS and control vs. mesh, 0.24 ± 0.02 vs. 0.24 ± 0.01, P=NS). In addition, estradiol increased cell proliferation in a dose responsive fashion (estradiol dose: 0.1 μM, 1 μM, 10 μM) compared to control (P=0.01). Conclusion: Vaginal SMC proliferation is significantly increased by estrogen.
The effects of various selective phosphodiesterase (PDE) inhibitors on muscle contractility and cyclic nucleotide content in the porcine coronary artery were investigated. Various selective PDE inhibitors, vinpocetine (type 1), erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, type 2), milrinone (type 3), rolipram (type 4), Ro20-1724 (type 4), and zaprinast (type 5), inhibited U46619-induced contractions in a concentration-dependent manner. The rank order of potency for the porcine coronary artery was rolipram > Ro20-1724 >milrinone > vinpocetine > zaprinast > EHNA, which was different from that of both the porcine carotid artery and aorta. Rolipram inhibited the U46619-induced muscle tension with a decreased [Ca2+]i level, but inhibited the high K+-induced contraction without a change in [Ca2+]i level. Rolipram increased cAMP but not cGMP content. Iberiotoxin restored the inhibition of muscle tension and the [Ca2+]i levels induced by rolipram. U46619 and caffeine induced a transient increase in the [Ca2+]i levels in a Ca2+-free solution, but rolipram only inhibited the U46619-induced Ca2+ transient. In conclusion, rolipram is the most potent inhibitor in the porcine coronary artery, but not in the carotid artery and aorta. Moreover it is suggested that the mechanism by which rolipram causes relaxation is due to a decrease in the [Ca2+]i levels and of the Ca2+ sensitivity of the contractile elements to cAMP.
We investigated the effects of the novel gastroprokinetic agent Z-338 on the actions of excitatory and inhibitory neurotransmitters on neurons in area postrema (AP). Iontophoretic applications of acetylcholine (ACh), AMPA and NMDA increased, while GABA suppressed the firing rates of AP neurons recorded by extracellular electrodes. Z-338 (10 μM) suppressed the ACh-induced acceleratory and GABA-induced inhibitory actions without affecting the excitatory actions of AMPA and NMDA. Under voltage-clamp conditions, nicotine, NMDA, kainic acid (KA) and ATP evoked inward currents in dissociated single AP neurons recorded by whole-cell patch clamp technique, and GABA produced outward currents, at holding potentials (VH) of -60 or 0 mV. Z-338 (>3 μM) specifically suppressed the nicotine- and GABA-induced currents without affecting the currents induced by NMDA, KA and ATP. In addition, we found that Z-338 (30 μM) suppressed the spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from AP neurons in slice preparations. Experiments with microelectrode and histochemical methods revealed the presence of direct excitatory and di-synaptic inhibitory neural connections from AP to dorsal motor nucleus of the vagus (DMV). In some AP neurons, Z-338 (10 μM) enhanced the spontaneous firing rates recorded by extracellular electrode. The excitatory or inhibitory effects of Z-338 on the firing rates or actions of nicotine and GABA on AP neurons observed in the present study may explain the postmeal relaxation induced by Z-338 in patients with functional dyspepsia.
Interleukin-13 (IL-13) is believed to be a central mediator of the induction of airway hyperresponsiveness (AHR), one of the characteristic features of allergic bronchial asthma. The IL-13-mediated events are mainly generated by its binding to functional IL-13 receptor, IL13Rα1 chain. In the present study, the changes in the levels of IL-13 receptors in bronchial smooth muscles were determined in mice with AHR induced by antigen inhalation. Mice were sensitized and repeatedly challenged with ovalbumin antigen. Total RNAs of the left main bronchi were extracted, and real-time RT-PCR analyses for IL13Rα1 and IL13Rα2 chains were conducted. As a result, both the receptor chains were significantly increased in the diseased bronchial smooth muscle. The time-course analyses revealed that the peaks of IL13Rα1 and IL13Rα2 upregulations were at 6 hour and 3-12 hour after the last antigen inhalation, respectively. It is thus possible that the IL-13-mediated signaling in bronchial smooth muscle is considerably augmented by the upregulations of IL-13 itself and its functional IL13Rα1 receptor in allergic asthmatics.
RhoA has been recognized as an important protein for bronchial smooth muscle (BSM) contraction and hyperresponsiveness, and its activation is also regulated by geranylgeranyltransferase I (GGTase I). In the present study, the effects of repeated antigen exposure on the expression of GGTase I were determined in mouse BSMs. Male BALB/c mice were sensitized and repeatedly challenged with ovalbumin antigen. Animals were also treated with lovastatin (4 mg/kg/day, i.p.) once a day prior to and during the antigen inhalation period. Western blot analyses revealed that GGTase I was upregulated in BSMs of the antigen-challenged mice. The systemic treatment with lovastatin attenuated the upregulation of GGTase I induced by antigen exposure. Interestingly, lovastatin also significantly reduced the protein expression of GGTase I in BSMs of control animals. We thus concluded that an upregulation of GGTase I in BSM might be, at least in part, involved in the development of antigen-induced airway hyperresponsiveness. Lovastatin might have therapeutic potential to ameliorate airway hyperresponsiveness in allergic bronchial asthma.
The aim of the present study is to determine the chemical composition of the essential oil extracted from the flowers of Anthemis mauritiana Maire & Sennen (EOAM) and to investigate its antispasmodic effects on intestinal smooth muscle. The phytochemical composition was revealed by gas chromatography-mass spectrometer. Eighteen compounds were identified representing 90.56% of the oil. The major constituents were described as α-pinene (27.02%), sabinene (15.25%), cedrenol (14.53%) germacrene (9.61%) geraniol formate (6.82%), and caryophylene (5.38%). EOAM (10-100 μg/ml) elicited reversible relaxation of spontaneous contractions of isolated rabbit jejunal smooth muscle preparations, and similarly inhibited contractions induced by high-potassium solution ([K+]o = 76 mM) and carbachol (10-6 M) with IC50 values of 14.98 and 27.29 μg/ml, respectively. Furthermore, EOAM exhibited an inhibitory effect on the dose-response curves induced by carbachol and CaCl2 on rat jejunum preparations. These results clearly demonstrated the antispasmodic effect of EOAM which was strongly suggested to be mainly due to an inhibitory effect on Ca2+ influx through the membrane of jejunal smooth muscle cells.