Electrogastrograms (EGGs) were recorded at 16 locations on the thoraco-abdominal surface at rest and then both during and after the acute stress of performing the mirror drawing test (MDT). A significant linear correlation with a negative slope was found between the anxiety scores and the ratio of the power content during MDT to the power content at rest (r) (MDTr–1) of the 3 cpm component from the epigastric channel 2 recording. In contrast, significant linear correlations with positive slopes were found between the anxiety scores and MDTr–1 of the 6 cpm component of the recordings from the infraumbilical channels (channels 13, 15, and 16). The epigastric 3-cpm EGG activity reflects gastric myoelectric activity, while the infraumbilical 3- and 6-cpm activity reflects that of the colon. Therefore, these results seem to further support the previous report of the inhibition of gastric EGG by stress and the stress-mediated facilitation of colonic EGG (Homma S, J Smooth Muscle Res. 2012; 48(2–3): 47–57).
Pulmonary arterial hypertension (PAH) is defined as an intractable disease characterized by a progressive elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP), leading to right heart failure and premature death. The five-year survival rate after diagnosis is approximately 57%. Although extensive research has identified some factors associated with the cause of PAH, the etiology and pathogenesis remain unclear. In addition to Ca 2+ channel blockers (nifedipine, diltiazem), three categories of drug have been developed for the treatment of PAH based on the pathological mechanisms: prostacyclin and its analogues (epoprostenol, treprostinil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan), and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil). However, screening of novel types of drug acting on the signal pathway associated with the pathological mechanism underlying PAH is ongoing. We recently found that the extracellular Ca2+-sensing receptor (CaSR), which belongs to family C of the G protein-coupled receptor (GPCR) superfamily, is upregulated in pulmonary arterial smooth muscle cells (PASMCs) from patients with idiopathic PAH (IPAH). The upregulated CaSR is necessary for the enhanced Ca2+ signaling and the augmented cell proliferation in PASMCs from IPAH patients. Most importantly, blockage of CaSR with an antagonist, NPS2143, prevents the development of pulmonary hypertension and right ventricular hypertrophy in animal models of pulmonary hypertension. The use of calcilytics, antagonists of CaSR, may be a novel therapeutic approach for PAH patients.
Smooth muscle contraction is activated primarily by phosphorylation at Ser19 of the regulatory light chain subunits (LC20) of myosin II, catalysed by Ca2+/calmodulin-dependent myosin light chain kinase. Ca2+-independent contraction can be induced by inhibition of myosin light chain phosphatase, which correlates with diphosphorylation of LC20 at Ser19 and Thr18, catalysed by integrin-linked kinase (ILK) and zipper-interacting protein kinase (ZIPK). LC20 diphosphorylation at Ser19 and Thr18 has been detected in mammalian vascular smooth muscle tissues in response to specific contractile stimuli (e.g. endothelin-1 stimulation of rat renal afferent arterioles) and in pathophysiological situations associated with hypercontractility (e.g. cerebral vasospasm following subarachnoid hemorrhage). Comparison of the effects of LC 20 monophosphorylation at Ser19 and diphosphorylation at Ser19 and Thr18 on contraction and relaxation of Triton-skinned rat caudal arterial smooth muscle revealed that phosphorylation at Thr18 has no effect on steady-state force induced by Ser19 phosphorylation. On the other hand, the rates of dephosphorylation and relaxation are significantly slower following diphosphorylation at Thr18 and Ser19 compared to monophosphorylation at Ser19. We propose that this diphosphorylation mechanism underlies the prolonged contractile response of particular vascular smooth muscle tissues to specific stimuli, e.g. endothelin-1 stimulation of renal afferent arterioles, and the vasospastic behavior observed in pathological conditions such as cerebral vasospasm following subarachnoid hemorrhage and coronary arterial vasospasm. ILK and ZIPK may, therefore, be useful therapeutic targets for the treatment of such conditions.
Background: Diabetes induces lung dysfunction, leading to alteration in the pulmonary functions. Our aim was to investigate whether the early stage of diabetes alters the epithelium-dependent bronchial responses and whether nitric oxide (NO), KATP channels and cyclooxygenase (COX) pathways contribute in this effect. Methods: Guinea pigs were treated with a single injection of streptozotocin (180 mg/kg, ip) for induction of diabetes. Airway conductivity was assessed by inhaled histamine, using a non-invasive body plethysmography. The contractile responses of tracheal rings induced by acetylcholine (ACh) and relaxant responses of precontracted rings, induced by isoproterenol (IP) were compared in the presence and absence of the epithelium. Effects of Nω-Nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), glybenclamide (a KATP channel inhibitor) and indomethacin (a COX inhibitor) were also assessed in diabetic guinea pigs. Results: Early stage diabetes did not alter the airway conductivity. ACh-induced bronchoconstriction in epithelium intact tracheal rings was not affected by the onset of diabetes, however a reduction in the increased ACh responses due to epithelium removal, to L-NAME or to indomethacin was observed. The relaxation response to IP was impaired in trachea from guinea pigs in which diabetes had just developed. Early diabetes significantly reduced the IP response to glybenclamide and to indomethacin. Conclusion: Our results demonstrate that the early stage of diabetes, modulate the bronchial reactivity to both ACh and IP by disrupting the NO, KATP channels and COX pathways, without affecting the airway conductivity in guinea pigs.
Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD). However, little is known about the mechanisms of cigarette smoke-induced bronchial smooth muscle (BSM) hyperresponsiveness. In the present study, we investigated the effects of aqueous cigarette smoke extract (ACSE) on the BSM contraction in rats. The bronchial strips of rats were incubated with ACSE or control-extract for 24 h. The acetylcholine (ACh), high K+ depolarization and sodium fluoride (NaF)-induced BSM contraction of the ACSE-treated group was significantly augmented as compared to that of the control one. The expression levels of both myosin light-chain kinase (MLCK) and RhoA were significantly increased in the ACSE-treated BSM. These findings suggest that the water-soluble components of cigarette smoke may cause BSM hyperresponsiveness via an increase in MLCK and RhoA.
Garcinia buchananii Baker stem bark extract (GBB) is a traditional medication of diarrhea and dysentery in sub-Saharan Africa. It is believed that GBB causes gastrointestinal smooth muscle relaxation. The aim of this study was to determine whether GBB has spasmolytic actions and identify compounds underlying these actions. Calcium (Ca2+) imaging was used to analyze the effect of GBB on Ca2+ flashes and Ca2+ waves in guinea pig gallbladder and distal colon smooth muscle. Intracellular microelectrode recording was used to determine the effect of GBB, six fractions of GBB, M1–5 and M7, and (2R,3S,2’’ R,3’’R)-manniflavanone, a compound isolated from M3 on action potentials in gallbladder smooth muscle. The technique was also used to analyze the effect of GBB, M3, and (2R,3S,2’’ R,3’’R)-manniflavanone on action potentials in the circular muscle of mouse and guinea pig distal colons, and the effect of GBB and (2R,3S,2’’R,3’’ R)-manniflavanone on slow waves in porcine ileum. GBB inhibited Ca2+ flashes and Ca2+ waves. GBB, M3 and (2R,3 S,2’’R,3’’R)-manniflavanone inhibited action potentials. L-type Ca2+ channel activator Bay K 8644 increased the discharge of action potentials in mouse colon but did not trigger or increase action potentials in the presence of GBB and (2R,3S,2’’R,3’’ R)-manniflavanone. GBB and (2R,3S,2’’ R,3’’R)-manniflavanone inhibited action potentials in the presence of Bay K 8644. GBB and (2R,3 S,2’’R,3’’R)-manniflavanone reduced the amplitude but did not alter the frequency of slow waves in the porcine ileum. In conclusion, GBB and (2R,3S,2’’ R,3’’R)-manniflavanone relax smooth muscle by inhibiting L-type Ca2+ channels, thus have potential for use as therapies of gastrointestinal smooth muscle spasms, and arrhythmias.
“Globus sensation” is often described as the sensation of a lump in the throat associated with dry swallowing or the need for dry swallowing, which disappears completely during eating or drinking and for which no organic cause can be established. Due to the uncertain etiology of “globus sensation”, it remains difficult to establish standard treatment strategies for affected patients. Lately most attention has been focused on gastroesophageal reflux disease and several reports have indicated that there is a close relationship between esophageal acid reflux and globus sensation. Nowadays, empirical therapy with a high dose of a proton pump inhibitor (PPI) is considered to be indicated for patients with globus sensation, after excluding organic diseases such as pharyngeal cancer, Zenker’s diverticulum, or thyroid enlargement. If patients are nonresponsive to PPI therapy, evaluation of esophageal motility should be done. In our recent study, 47.9% had abnormal esophageal motility, with the most common esophageal motility abnormality being an ineffective esophageal motility in PPI-resistant patients with globus sensation. This suggests that prokinetics alone or adding prokinetics to PPI should be the treatment to be considered, although few studies have investigated the efficacy of prokinetics in the treatment of patients with globus sensation. If patients without any esophageal motility dysfunctions are nonresponsive to PPI therapy, either cognitive-behavioral therapy, anti-depressants, or gabapentin could be helpful, although further well-designed, randomized controlled large-scale studies will be necessary to determine the effectiveness of each treatment strategy on patients with globus sensation.
While the gastrocolonic reflex has been known, the cologastric relationship has not been clarified especially with regard to gastric adaptive relaxation. Therefore, in this study we have examined the correlation between gastric adaptive relaxation and colonic distension. Male Sprague-Dawley rats were used after fasting for 18 hrs. Colonic distension was performed by injecting 2.2 ml of air into a colonic balloon inserted into the colon for 5 min in conscious state. After urethane anesthesia, gastric adaptive relaxation was investigated by using a slightly modified gastric balloon introduced into the stomach through the mouth. Gastric balloon volumes increased gradually just after an increment in the gastric balloon pressure (1 to 8 mmHg), and reached a plateau within 1 min. This increased volume was defined as gastric adaptive relaxation. In control rats, gastric adaptive relaxation increased with pressure increments in a pressure dependent manner. In the colon-distended rats, gastric adaptive relaxation increased also in a pressure dependent manner, but was significantly inhibited as compared with control at 8 mmHg (P<0.05). These findings show that colonic distension inhibits the gastric adaptive relaxation and suggests the existence of a cologastric relationship in rats.
Functional studies have shown that orchidectomy increases the effects of phenylephrine on rat portal veins, but that it is completely prevented in the presence of both ETA and ETB receptor antagonists. Although it suggests the involvement of endothelin-1 (ET-1), the local production of this vasoactive peptide has not been directly quantified in portal veins. Therefore, the aim of the present study was to verify if orchidectomy increases the local expression of ET-1 as well as ETA and ETB receptors in the rat portal vein. Indeed, the genic expression of ET-1, ETA and ETB receptors in rat portal veins taken from control (CONT), orchidectomized (ORX) and ORX plus testosterone-replacement therapy (ORX + T) animals were determined by Real Time RT-PCR. The results showed that orchidectomy induced a significant increment in genic expression of ET-1 and ETB receptors in the rat portal veins, which was completely reversed by testosterone replacement treatment. In conclusion, the results suggest that orchidectomy increases the production of ET-1 in the rat portal vein and that, at least partially, it may be related to the previously reported elevation of responses to phenylephrine.