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Purpose: Gastric dysmotility has been reported in patients with long-standing diabetes mellitus (DM). Some patients with DM are diagnosed as diabetes gastroparesis and have several upper gastrointestinal (GI) symptoms such as appetite loss and abdominal pain. This study aimed to identify the relationship between gastric motility and upper GI symptoms in patients with long-standing DM., Method: This study was conducted among 23 patients with DM and 15 healthy controls. All the patients with DM were receiving insulin treatment and had at least one history of incidence of diabetic nephropathy, retinopathy or neuropathy. Gastric motility was evaluated using electrogastrography (EGG) and gastric emptying using the 13 C-acetic acid breath test. The most severe upper gastrointestinal symptoms were assessed in all patients., Results: Compared to healthy controls, patients with long-standing DM showed a significantly lower percentage of normogastria at the postprandial state with a lower power ratio in EGG. Gastric emptying was significantly delayed in patients with DM in the overall analysis. Sixteen patients with DM (69.6%) demonstrated abnormalities in either gastric myoelectrical activity or gastric emptying. Among patients with abnormal EGG or delayed gastric emptying, 12 had some GI symptoms, compared with 3 patients with normal gastric motility. No significant correlation was observed between the gastric emptying parameters and HbA1c values., Conclusion: Patients with long-standing DM showed gastric dysmotility, including impaired gastric myoelectrical activity and delayed gastric emptying. Gastric dysmotility appears to be closely correlated with upper GI symptoms in patients with long-standing DM.

Omeprazole, a proton pump inhibitor, is widely used for the treatment of patients with peptic ulcer, gastroesophageal reflux disease and functional dyspepsia (FD), although some studies have demonstrated that omeprazole delays gastric emptying. The purpose of this study was to investigate the efficacy of omeprazole on gastric motility including gastric myoelectrical activity and gastric emptying. This study was performed on 12 healthy volunteers. Gastric motility was evaluated with cutaneously recorded electrogastrography (EGG) and gastric emptying of semi-solid meals using the (13)C-acetic acid breath test. EGG and gastric emptying were measured before and after treatment with 20 mg omeprazole orally for 7 days. In the fasting state, the percentage of EGG normogastria increased significantly compared to the baseline. No significant changes were observed in other EGG parameters including the percentage of tachygastria and bradygastria in both fasting and postprandial states, and the power ratios between both before and after ingestion of omeprazole. In addition, administrated omeprazole did not show any significant differences in the gastric emptying parameters such as the half emptying time. We conclude that administration of omeprazole did not affect gastric motility but improved gastric myoelectrical activity. These effects of omeprazole may be one of the mechanisms involved in its efficacy in relieving dyspeptic symptoms in FD patients.

Circular smooth muscle preparations isolated from the rat proximal colon periodically generated two different amplitudes and frequencies of phasic contractions: large phasic contractions (LPC) with a frequency of about 1.5 times/min and small phasic contractions (SPC) with a frequency of about 9 times/min. Preparations with no attached longitudinal smooth muscle layer (and also myenteric layer) generated SPC alone, while those with no attached submucosal layer generated only LPC, indicating that the pacemakers of the LPC and SPC are distributed in the myenteric and submucosal layers, respectively. In intact preparations, transmural nerve stimulation (TNS) applied for 1-2 min with different frequencies (0.2-2 Hz) inhibited the phasic contractions. The amplitude of LPC was reduced at >0.25 Hz and abolished at >0.3 Hz, while the amplitude but not the frequency of SPC was reduced at >0.5 Hz (in a frequency-dependent way). The TNS-induced inhibitory responses were augmented by atropine and attenuated by N(omega)-nitro-L-arginine (L-NA). In the presence of L-NA and atropine, TNS elicited biphasic (inhibitory and following excitatory) responses. The former were not antagonized by apamin, guanethidine or suramin, while the latter were antagonized by capsaicin, suggesting an innervation by non-adrenergic non-cholinergic non-nitrergic (NANCNN) inhibitory and peptidergic excitatory nerves, respectively. In preparations with the longitudinal muscle layer removed, TNS inhibited only the amplitude of SPC, which was augmented by atropine and antagonized by L-NA. In intact preparations, muscarinic stimulation with acetylcholine increased the frequency of LPC, while nitrergic stimulation with sodium nitroprusside reduced the amplitude and frequency of LPC, and also the amplitude but not the frequency of SPC. These results indicate that the rat proximal colon has two types of pacemaker cells. Myenteric pacemaker cells which receive predominantly nitrergic, but also cholinergic, peptidergic and NANCNN innervation, and submucosal pacemaker cells that are not markedly influenced by intramural nerves.

Diabetic gastropathy is suggested to be the result of not only an autonomic neuropathy but also to disorder of the spontaneous rhythmic motility of the gastric smooth muscle. Attempts were made to investigate the alteration of the effects of endothelin-1 (ET-1), which is known to enhance the spontaneous activity of gastrointestinal smooth muscle, on gastric activity in streptozotocin (STZ)-induced diabetic rats. STZ-induced diabetic rats were prepared by the injection of Sprague-Dawley (SD) rats with STZ (i.p.). Isometric mechanical responses were recorded in isolated circular smooth muscle strips of the stomach antrum, to measure changes in the rhythmicity of the smooth muscle. ET-1 (10 nM) significantly elevated the resting tension and the frequency of spontaneous contraction, but did not alter the amplitude of the spontaneous oscillatory contractions in normal rats. In diabetic rats, ET-1 elevated the resting tension, and spontaneous contractions were increased in frequency, however they were decreased in amplitude. In normal rats, sarafotoxin S6c (S6c, 10 nM), a selective ET(B) receptor agonist, elevated the resting tension slightly and increased both the frequency and amplitude of the spontaneous contractions. However, S6c significantly elevated the resting tension alone in STZ-induced diabetic rats. Selective stimulation of endothelin type A (ET(A)) receptors with ET-1, in the presence of a selective antagonist of ET(B) receptors, produced similar responses in the gastric muscle of both normal and diabetic rats. These results indicate that ET-1 elevates the resting tension and increases the frequency of the spontaneous oscillatory contractions in both normal and STZ-induced diabetic rats, to a similar extent. However, the specific actions on ET(B) receptors were quite different between the two: the elevating actions on the resting tension were much greater in STZ-diabetic rats than in normal rats. The results suggested the facilitation of ET(B) receptor signaling in the antrum during the pathogenesis of diabetic gastropathy.

Electrophysiological effects of endothelin-1 (ET-1) on circular smooth muscle of rat gastric antrum were investigated by using intracellular membrane potential recording techniques. ET-1 (10 nM) caused an initial hyperpolarization of the membrane which was followed by a sustained depolarization. ET-1 also increased the frequency but not the amplitude of slow waves. In the presence of the endothelin type A (ETA) receptor antagonist, BQ123 (1 microM), ET-1 (10 nM) depolarized the membrane and increased the frequency of slow waves, but without the initial hyperpolarization. The selective endothelin type B (ETB) receptor agonist, sarafotoxin S6c (10 nM), also depolarized the membrane and increased the frequency of slow waves. In the presence of the ETB receptor antagonist, BQ788 (1 microM), ET-1 (10 nM) hyperpolarized the membrane. However, in the presence of BQ788, ET-1 caused neither the depolarization nor the increase in the frequency of the slow waves. The ET-1-induced hyperpolarization was completely abolished by apamin (0.1 microM). In the presence of apamin, ET-1 depolarized the membrane and increased the frequency of slow waves. The ET-1-induced depolarization was significantly attenuated by 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS, 0.3 mM). The increase of the frequency by ET-1 was observed both in the presence and absence of DIDS. These results suggest that, ET-1 hyperpolarizes the membrane by the activation of Ca2+-activated K+ channels via ETA receptors, and depolarizes the membrane by the activation of Ca2+-activated Cl- channels via ETB receptors. ET-1 also appears to increase the frequency of slow waves via ETB receptors, however this mechanism would seem to be independent of membrane depolarization.

The electrophysiological properties of smooth muscle in the murine lower oesophageal sphincter (LOS) were investigated by intracellular microelectrode recording. Inhibitory junction potentials (IJPs) evoked by trains of field stimulation (30 V, 0.2-0.3 ms, 10 stimuli at 1-50 Hz) were observed in the murine LOS in the presence of atropine (1 microM) and nifedipine (1 microM). The IJP consists of two components, which we termed fast IJP and slow IJP. The fast IJP was partly sensitive to guanethidine (5 microM), pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 30 microM) and apamin (0.1 microM), suggesting that the fast IJP was produced partly through the activation of apamin-sensitive Ca2+-activated K+ channels and of P2-purinoceptors. The other part of the fast IJP was sensitive to N(omega)-nitro-L-arginine (L-NNA, 100 microM) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 1 microM), but insensitive to apamin (0.1 microM), iberiotoxin (50 nM) and charybdotoxin (30 nM). Slow IJP was sensitive to L-NNA (100 microM), ODQ (10 microM) and glibenclamide (10 microM), but insensitive to apamin (0.1 microM), iberiotoxin (50 nM) and charybdotoxin (30 nM). KT5823, a protein kinase G (PKG) inhibitor, had no effect on the fast and slow IJP in this tissue. It was suggested that, in the mouse LOS, adenosine trisphosphate (ATP) partly mediated the fast UP through apamin-sensitive Ca2+-activated K+ channels, and nitric oxide mediated the remained part of the fast IJP and the slow IJP through cGMP, but not PKG. ATP-sensitive K+ channels were suggested to be partly involved in the production of slow IJP, but the responsible channel(s) for the nitrergic fast IJP remained unclarified.

Electrical properties of colonic smooth muscle were investigated in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model animal for spontaneous non-insulin-dependent diabetes mellitus (NIDDM), and the results were compared with those obtained from the Long-Evans Tokushima Otsuka (LETO) rat, a control of OLETF rat. At experiments (aged 60-80 weeks), blood glucose level was about 171 mg/dl in LETO rats and 370 mg/dl in OLETF rats. Feces in the colon were restricted to the proximal region in LETO rats and distributed widely in the whole colon in OLETF rats. In both LETO and OLETF rats, the circular smooth muscle strips of the isolated distal colon revealed two types of spontaneous electrical response, slow wave and transient hyperpolarization. The resting membrane potential was smaller in OLETF rats than in LETO rats by about 3 mV, but it was not positively related with the blood glucose level. The amplitude of hyperpolarization produced by noradrenaline (NA) was smaller in OLETF rats than in LETO rats. Transmural nerve stimulation evoked a non-adrenergic, non-cholinergic (NANC) inhibitory junction potential (i.j.p.) in both LETO and OLETF rats; the amplitude of the i.j.p. was smaller in OLETF rats than in LETO rats, while the latency of the i.j.p. was longer in OLETF rats than in LETO rats. Thus, in the distal colon, NIDDM may cause a depolarization of the membrane, an attenuation of NANC inhibitory transmission and a reduction in reactivity of adrenoceptors to NA. These results suggest that the constipation appearing with diabetes mellitus involves dysfunction of both the enteric autonomic nerves and the smooth muscles in the colon.