Motilin agonist erythromycin increases human lower esophageal sphincter pressure by stimulation of cholinergic nerves

During phases II and III of the migrating motor complex, there is an increase in plasma motilin level that is synchronous with phasic and tonic contractile activity of the lower esophageal sphincter and of the stomach. The action of motilin on human lower esophageal sphincter is proposed to be mediated by cholinergic mechanisms. Recently, it has been shown that erythromycin was a motilin agonist. This study evaluated the pharmacological effects and the mechanism of action of intravenous erythromycin on esophageal motility in humans. Healthy volunteers were studied three times at seven-day intervals in a randomized, double-blind fashion. Subjects were first studied for 10 min before drug administration. Afterwards, they received blindly and randomly an intravenous injection of placebo or atropine (12 µg/kg) followed by a 20-min continuous intravenous administration of placebo or erythromycin (150 mg). The difference () between lower esophageal sphincter pressure and the duration, amplitude, and velocity of peristaltic contractions during the control period and after administration of drugs was compared. Erythromycin significantly increased (P<0.05) the lower esophageal sphincter pressure (16.8 ± 4.7 mm Hg) compared to placebo (–0.029 ± 1.4 mm Hg). Erythromycin significantly decreased peristaltic contraction velocity compared to placebo (P<0.05). The effects of erythromycin on lower esophageal sphincter pressure were completely blocked by previous administration of intravenous atropine. Erythromycin increased the number of fundic contractions compared to the placebo, but this effect was not blocked by the previous administration of atropine. Based on these observations, it is proposed that the motilin agonist erythromycin acts on the lower esophageal sphincter by stimulating cholinergic nerves but also could modify gastric motility by direct muscle stimulation.     

Motilin regulates interdigestive gastric blood flow in dogs

Background & Aims: Gastric blood flow exhibits cyclical increases in phase with the interdigestive contractions and secretion of the stomach in dogs. The aim of this study is to clarify the regulatory role of motilin in interdigestive gastric blood flow in dogs. Methods: Blood flow of the left gastric (LGA) and superior mesenteric (SMA) arteries were measured by ultrasound transit-time blood-flow meters in 5 conscious dogs. Motilin was infused intravenously with or without Phe-cyclo[Lys-Tyr(3-tBu)-βAla-] · trifluoroacetate (GM-109; motilin antagonist), granisetron (5-HT₃ antagonist), atropine, hexamethonium (C6), phenoxybenzamine, propranolol, or cimetidine. Results: Motilin (12.5, 25, 50, and 100 pmol · kg⁻¹ · h⁻¹) induced LGA blood-flow responses, consisting of a sustained increase and a rapid phasic change coupled with a contraction, without affecting the blood pressure, heart rate, and SMA blood flow. GM-109 completely abolished the LGA, motility, and secretory responses to motilin (100 pmol · kg⁻¹ · h⁻¹). Atropine abolished motilin-induced gastric contractions, secretion, and phasic changes of LGA blood flow but failed to affect the sustained flow increase. However, atropine partially inhibited the LGA responses to lower doses of motilin. The LGA flow responses to motilin were not inhibited by granisetron, C6, α-adrenergic, β-adrenergic, or H₂ blockers. Motilin induced significantly larger gastric vasodilatation than the equivalent doses of VIP. Conclusions: Motilin has a potent and selective gastric vasodilator effect, which appears to be mediated by both cholinergic and noncholinergic mechanisms. Motilin plays an important role in the regulation of interdigestive gastric blood flow in dogs.     

Effect of synthetic motilin on gastric motor activity in conscious dogs

The effect of intravenous infusion of synthetic motilin on gastric motor activity was investigated by means of chronically implanted force transducers in 4 conscious dogs. Since the gastric motor pattern consisted of two major subpatterns, digestive and interdigestive motor activity, motilin was tested for its motor stimulating activity in both states. It was found that motilin had no influence upon gastric motor activity in the digestive state. However, during the interdigestive state, intravenous infusion of motilin in doses of 0.3–2.7 g/kg/hr induced motor activity similar to the naturally occurring interdigestive contractions in a dose-related fashion. Since motilin is released by duodenal alkalinization in the dog, it may be postulated that motilin is a substance to control the interdigestive contractions in the dog, although other reports describe motilin release by duodenal acidification and inhibition of gastric emptying in man. Endogenous stimuli leading to motilin release may be different among species. The present study clearly indicates that motilin induces a contractile pattern similar to that seen during the interdigestive state in conscious dogs.This work was in part supported by a Grant for Cancer Research to Z. Itoh from the Ministry of Public Health and Welfare of Japan.     

Changes in plasma motilin concentration and gastrointestinal contractile activity in conscious dogs

Simultaneous measurement of plasma motilin concentration and gastrointestinal contractile activity was made in 12 healthy dogs. Plasma motilin concentration was measured by radioimmunoassay and gastrointestinal contractile activity was monitored by means of chronically implanted force transducers. During the interdigestive state, it was found that the plasma motilin concentration increased in complete accordance with the cyclical interdigestive contractions of the stomach. Furthermore, plasma motilin concentration was lowered by the ingestion of food, and it remained low as long as the gastric motor activity was in the digestive pattern. Since, as reported previously, the interdigestive contractions can be induced by the exogenous administration of motilin, we concluded that (1) motilin is released at constant intervals during the interdigestive state, and this release is suppressed by the ingestion of food; (2) motilin induces the interdigestive contractions of the stomach and duodenum; and (3) motilin is an interdigestive hormone and is the only known polypeptide hormone of the gut whose release is not induced by a meal.Parts of this work were presented at the International Symposium on GI Hormones and Pathology of the Digestive Systems in June 18–21, 1977, in Rome and at Round Table of the XXVII International Congress of Physiological Sciences in July 18–23, 1977, in Paris.     

Control of lower-esophageal-sphincter contractile activity by motilin in conscious dogs

The effect of synthetic motilin on contractile activity in the lower esophageal sphincter (LES) and the stomach has been studied in 5 healthy dogs by means of chronically implanted strain gage force transducers. Motilin produced strong contractions in the LES and the stomach simultaneously after intravenous doses ranging from 0.3 to 2.7 g/kg hr, which were similar to the naturally occurring interdigestive contractions in the LES and the stomach. However, these contractions could be induced only in the interdigestive state; infusion of motilin into dogs in the digestive state brought about no significant effect on either the LES or the stomach. Motilin-induced contractions in the LES and the stomach were instantly abolished by ingestion of food. It is considered that the contractions induced by motilin are identical with the naturally occurring interdigestive contractions in the LES and these contractions are the most orad component of the interdigestive cyclic recurring caudad-moving bands of strong contractions in the dogs.     

Beta endorphin modulation of the glucoregulatory effects of repeated epinephrine infusion in alloxan-diabetic and normal dogs

Summary When repeated epinephrine infusions are given to normal dogs as a partial stress model, there is exaggerated hyperglycaemia, associated with reduced plasma insulin levels and markedly decreased glucose clearance. In the present study, we have examined the hormonal and metabolic responses to two successive 60-min epinephrine (0.1 g-kg^–1·min^–1) infusions with or without concomitant infusion of beta endorphin (0.3 g·kg^–1·min^–1) in 6 alloxan-diabetic dogs. These studies have been compared to similar studies in 5 normal dogs.In the diabetic dogs, plasma glucose rose from 12.3±2.2 to 16.2±2.4 mmol/l (p<0.001) in response to the first epinephrine infusion and rose further to 18.1±2.5 mmol/l (p<0.001) during the second epinephrine infusion. The increases in plasma glucagon and glucose production were comparable with both infusions, but considerably greater than previously observed in normal dogs.In normal dogs, beta endorphin diminished the insulin response to the first epinephrine infusion (p<0.02), and abolished this response to the second (p<0.05). In addition beta endorphin also diminished the glucagon response to the second epinephrine infusion (p<0.01) and greatly potentiated epinephrine-induced suppression of glucose metabolic clearance during both infusions (p<0.001). However, beta endorphin did not appreciably alter the hyperglycaemic response to epinephrine due to a concomitant attenuation of the epinephrine-induced increase in hepatic glucose production.In contrast to normal dogs, beta endorphin did not modulate the effects of either the first or second epinephrine infusion on glucose kinetics in diabetic dogs. Also, beta endorphin failed to inhibit glucagon or insulin secretion in response to epinephrine in the diabetic animals. Since the alloxan-diabetic and normal dogs respond differently to the combined infusion of beta endorphin and epinephrine we conclude that the effects of beta endorphin observed in the normal dogs are dependent upon intact pancreatic endocrine function.     

The interaction of the Bainbridge and Bezold-Jarisch reflexes in the conscious dog

Summary Experiments were undertaken to determine the efferent path of the Bainbridge reflex and to investigate the interaction of the Bainbridge reflex with the Bezold-Jarisch reflex in conscious, chronically instrumented dogs. The Bainbridge reflex was elicited by distending the left atrium by inflating a chronically implanted balloon catheter. The Bezold-Jarisch reflex was elicited using chemical stimulation of left ventricular receptors with infusions of veratridine (0.1–0.8 g/kg/min) into the left circumflex coronary artery. Heart-rate responses to left atrial balloon inflation were compared before and after either -1 antagonism with metoprolol or cholinergic antagonism with atropine, and before and during left ventricular receptor stimulation with intracoronary veratridine. Left atrial balloon inflation alone caused a significant increase in heart rate (70.1 ± 5 bpm), left atrial pressure (14 ± 3 mm Hg) and mean arterial blood pressure (10 ± 2 mm Hg). Heart-rate responses to left atrial distension were inhibited, but not abolished by either cholinergic or -1 antagonism. Left atrial distension after both cholinergic and -1 antagonism abolished the heart-rate response to balloon inflation. These results indicate that the efferent component of the Bainbridge reflex has both a vagal and a sympathetic component in conscious dogs. Left atrial distension during simultaneous left ventricular receptor stimulation resulted in a significantly decreased tachycardia than did left atrial distension alone (26 ± 3 bpm compared to 68 ± 8 bpm in the control experiments). In addition, the slope of the heart rate vs left atrial pressure relationship was significantly inhibited by left ventricular receptor stimulation (1.8 ± 0.2 bpm/mm Hg compared to 5.7 ± 0.3 bpm/mm Hg in the control experiments). There were no significant differences in either the left atrial pressure or arterial blood pressure changes between the two groups. These data suggest an interaction between these two reflexes that may be occurring in the central nervous system.Supported by funds from NIH grant HL-33359 and by a pre-doctoral fellowship from the Nebraska affiliate of the American Heart Association     

Motilin regulation of canine interdigestive intestinal motility

The objective was to determine whether motilin regulates cyclical interdigestive motility in the jejunum as well as in the duodenum. In four conscious dogs with an intact innervated duodenum, an autotransplanted (extrinsically denervated) 75-cm loop of proximal jejunum, and an autotransplanted,in situ distal jejunum, interdigestive myoelectrical complexes cycled independently in all three regions of small bowel. Plasma concentration of motilin was greater during phase III of the duodenal cycles (304±37 pg/ml) than during phase I (235±37 pg/ml) or phase II (235±39 pg/ml;P<0.05), but the concentration did not vary consistently with the phases of the cycles in the autotransplanted jejunal segments. Intravenous infusions of motilin (0.6 g/kg/min for 5 hr), begun 15–30 min after passage of phase III through the duodenum, shortened the interval between phase IIIs in the duodenum from 147±14 min before infusions to 44±3 min during the infusions (P<0.05), but did not alter consistently the interval between phase IIIs in the autotransplanted jejunal segments. Feeding decreased plasma motilin concentration. The data were consistent with motilin regulation of interdigestive motility in intact, innervated canine duodenum but not in extrinsically denervated jejunum.Supported in part by USPHS NIH grants AM18278 and AM7198 and the Mayo FoundationAn abstract of this work was presented before the American Gastroenterological Association in May 1981, and published (Gastroenterology 80:1271, 1981).     

Atrial Natriuretic Peptide Reduces the Severe Consequences of Coronary Artery Occlusion in Anaesthetized Dogs

The aim of the present study was to examine the effects of atrial natriuretic peptide (ANP) on the responses to coronary artery occlusion. In chloralose-urethane anaesthetised mongrel dogs either saline (controls) or human synthetic ANP was infused intravenously (10 g kg^–1 + 0.1 g kg^–1 min^–1), starting 30 min before and continuing 10 min during a 25 min occlusion of the left anterior descending coronary artery (LAD). ANP infusion resulted in a fall in mean arterial blood pressure (by 17 ± 2 mmHg, p < 0.05), a transient (max. at 5 min) increase in coronary blood flow (by 24 ± 5 ml min^–1, P < 0.05), and a reduction in coronary vascular resistance (by 0.27 ± 0.05 mmHg ml^–1, p < 0.05). When the LAD coronary artery was occluded, there was a less marked elevation in left ventricular end-diastolic pressure (LVEDP) in the ANP-treated dogs than in the controls (9.0 ± 0.9 versus 12.2 ± 0.8 mmHg, p < 0.05). Compared to the controls, ANP reduced the number of ventricular premature beats (VPBs, 26 ± 12 versus 416 ± 87, p < 0.05), the number of episodes of ventricular tachycardia per dogs (VT, 0.7 ± 0.3 versus 12.4 ± 4.2, p < 0.05), and the incidences of VT (45% versus 100%, p < 0.05) and ventricular fibrillation (VF 18% versus 57%, p < 0.05) during occlusion. Reperfusion of the ischaemic myocardium at the end of the occlusion period led to VF in all the control dogs (survival from the combined ischaemia-reperfusion insult was therefore 0%), but VF following reperfusion was much less in the dogs given ANP (survival 64%; p < 0.05). The severity of myocardial ischaemia, as assessed from changes in the epicardial ST-segment and the degree of inhomogeneity, was significantly less marked in dogs given ANP. We conclude that ANP protects the myocardium from the consequences of myocardial ischaemia resulting from acute coronary artery occlusion and reperfusion in anaesthetized dogs.     

Effect of erythromycin on gallbladder emptying in diabetic patients with and without autonomic neuropathy and high levels of motilin

A reduction of gallbladder emptying in response to neural or hormonal stimulation has been reported in patients with diabetes mellitus. Decreased gallbladder emptying may be a key factor in the pathogenesis of gallbladder stones. Few drugs, if any, are able to stimulate gallbladder emptying. However, in a previous study we demonstrated that erythromycin, a macrolide antibiotic, stimulates gallbladder emptying and motilin release in healthy human subjects by an atropine-sensitive pathway. Therefore, the present study was designed to evaluate the effect of erythromycin on gallbladder emptying and motilin release in diabetic patients with or without cardiac autonomic neuropathy (AN). Thirteen diabetic patients, six with AN, and 10 healthy subjects were enrolled in the study protocol. Gallbladder emptying was determined by sonography after ingestion of a standard meal and during infusion of erythromycin alone or together with 6 g/kg/hr atropine. We found that 100 mg/hr erythromycin caused a significant reduction in gallbladder volume in both healthy subjects and diabetic patients. The ejection fraction (mean ±se) of 45.3±8.2% and 37.3±5.0% was similar. The presence of AN had no influence on gallbladder emptying induced by erythromycin. Basal motilin plasma levels were 111.5±14.5 pmol/liter in diabetic patients and 63.3 ±6.0 pmol/liter in healthy subjects (P<0.01). However, patients with AN had higher (130.0 ±11.9 pmol/liter) motilin plasma levels than patients without (74.0±9.4 pmol/liter,P<0.01). Erythromycin administration caused an approximately twofold increase in plasma motilin concentrations in healthy subject and patients withou AN, but did not stimulate motilin release in neuropathic patients. A negative correlation (r=–0.75,P<0.01) was found between basal plasma levels of motilin and peak of gallbladder emptying induced by erythromycin. Atropine completely inhibited the effects of erythromycin on gallbladder emptying and motilin release (P<0.001 by ANOVA). A negative correlation (r=–0.52,P<0.05) was also found between plasma glucose concentrations and peak of gallbladder emptying. Present results demonstrate that erythromycin could be used for treating alterations of gallbladder emptying in diabetic patients with or without AN.     

Regulation of interdigestive contractions in the denervated stomach

The effects of thiopental sodium on the regulation of interdigestive migrating contractions (IMC) in the stomach were investigated in dogs with extrinsically denervated fundic pouches. During the interdigestive state, strong phasic contractions in the pouch took place consistently in accordance with the IMC in the main stomach. The cyclic increase in plasma motilin concentration was more closely correlated with the increase in contractile activity in the pouch than the increase in the main stomach. General anesthesia by thiopental sodium promptly inhibited the IMC in the main stomach but the contractile activity in the pouch was not affected but gradually decreased in proportion to the decrease in plasma motilin concentration. In conclusion, contractile activity in the extrinsically denervated pouch, which is quite independent of the CNS, is directly controlled by a humoral factor(s), motilin. However, interdigestive motor activity in the extrinsically intact stomach appears to be regulated by the CNS as well as peripheral circulation humoral factors.     

Serum Unconjugated Bile Acids as a Test for Intestinal Bacterial Overgrowth in Dogs

Small intestinal bacterial overgrowth (SIBO) has a high incidence in dogs and, as in humans, is difficult to diagnose. The aim of this study was to determine the diagnostic significance of serum unconjugated bile acid concentrations in dogs with bacterial overgrowth. Fasting sera were obtained from 23 dogs: 10 with culture-proven SIBO, 8 with indirectly diagnosed SIBO (normal pancreatic function but small intestinal disease associated with subnormal serum cobalamin and supranormal folate concentrations), and 5 healthy controls. Unconjugated bile acids were determined using gas chromatography–mass spectrometry after isolation by liquid–solid extraction and anion-exchange chromatography. Mean serum unconjugated bile acid concentrations were significantly elevated in dogs with SIBO (mean ± sd: 0.91 ± 1.03 mol/liter), and in dogs with indirectly diagnosed SIBO (2.11 ± 2.20 mol/liter) compared to clinically healthy dogs (0.015 ± 0.015 mol/liter, P < 0.005). Cholic acid was the predominant unconjugated bile acid in the serum of dogs with SIBO. In conclusion serum unconjugated bile acid concentrations of healthy dogs are significantly lower than reported values for humans, and this fraction represents a relatively small proportion (0–2.3%; mean 0.8%) of the total bile acids in dogs. Unconjugated bile acids increased 10- to 20-fold in dogs with SIBO indicating the clinical utility of serum unconjugated bile acids for diagnosis of intestinal bacterial overgrowth in dogs.     

Inhibitory Effects of Sildenafil Citrate on the Tonus of Isolated Dog Internal Anal Sphincter

PURPOSE Although the exact pathogenesis of anal fissure is not known, hypertonicity of the internal anal sphincter might be involved in its pathogenesis as main event. To gain information about possible usefulness of the novel, smooth-muscle–relaxing drug, sildenafil, in chronic anal fissure, we investigated the effect of sildenafil citrate on acetylcholine-induced contractility of internal anal sphincter isolated from dogs.METHODS Internal anal sphincter strips were taken from German shepherd dogs and suspended in a tissue bath filled with Krebs solution at 37°C (pH 7.4) continuously bubbled with 95 percent oxygen and 5 percent carbon dioxide, and isometric contractions were recorded. Contractions were evoked by 10 μM acetylcholine, and the effects of different concentrations of sildenafil citrate (0.1, 0.3, and 1 mM) on the isometric tension of each internal anal sphincter strip were examined. The statistical significance was analyzed by one-way analysis of variance.RESULTS Pretreatment with sildenafil citrate (0.1 mM) attenuated contractile response to acetylcholine (n = 3), which were significantly weak compared with the maximum contractile response to the acetylcholine alone (610 ± 110 mg vs. 2,825.17 ± 416 mg; n = 12; P < 0.05). Sildenafil citrate also significantly inhibited the acetylcholine-induced contractions in a dose-dependent manner when applied after.CONCLUSIONS This experimental in vitro study showed that sildenafil citrate relaxes acetylcholine stimulated contractions of isolated dog internal anal sphincter. This may be of importance for raising the possibility that sildenafil cit-rate may have future potential in the treatment of chronic anal fissure. Further studies are needed for a conclusive decision on possible usefulness of sildenafil citrate in patients with chronic anal fissure.Poster presentation at the Cukurova Colo-Proctology Course and Symposium, Adana, Turkey, June 3 to 6, 2003.     

Progressive loss of myocardial contractile function despite unimpaired coronary blood flow after cardiac surgery

Objective Mild to moderate transient contractile dysfunction is frequently observed after cardiac surgery on cardiopulmonary bypass (CPB) but may also lead to low–cardiac–output (LCO) failure especially in patients with unstable angina, and is often referred to represent myocardial stunning. Whether time course of contractile dysfunction after cardiac surgery is similar to that of myocardial stunning was investigated in pigs. Methods After baseline measurements of systemic hemodynamics (micromanometry), myocardial contractile function (sonomicrometry), cardiac output and coronary flow (ultrasonic probe), CPB was instituted. Control animals (n = 7) were weaned after 3 h from CPB. In LCO animals (n = 8), global ischemia was induced for 10 min by aortic crossclamping, followed by 1 h of cardioplegic cardiac arrest. After declamping and reperfusion, CPB was terminated after a total of 3 h. Measurements were repeated at 15 min, 4 h and 8 h after CPB. Systemic TNF–plasma concentrations were measured (ELISA) and left ventricular biopsies were analyzed with respect to myocardial TNF (immunohistochemistry) and irreversible cellular damage (light/electron microscopy). Results Contractile function decreased in LCO (75 ± 12%) and control (83 ± 17%) at 15 min compared to baseline (p < 0.05). Thereafter, contractile function remained unchanged in control, but progressively decreased in LCO (52 ± 12% at 4 h; 36 ± 5% at 8 h; p < 0.05). Coronary flow remained unchanged in both groups. Cardiac output progressively decreased to 2.8 ± 0.9 l/min at 8 h in the LCO group compared to baseline (5.9 ± 1.1 l/min, p < 0.05) and control (5.7 ± 1.4 l/min, p < 0.05). There was no evidence for myocardial infarction. TNF–plasma concentrations and myocardial TNF–staining were increased at 8 h after CPB in the LCO group compared to baseline and control (p < 0.05). Conclusions The progressive pattern of myocardial dysfunction apart from ongoing ischemia after cardiac surgery suggested underlying mechanisms at least partially different from those of myocardial stunning.     

Long-term effects of brief antihypertensive treatment on systolic blood pressure and vascular reactivity in young genetically hypertensive rats

Summary Recent studies have shown that angiotensin converting enzyme (ACE) inhibitor treatment in young spontaneously hypertensive rats (SHR) reduces blood pressure into adulthood. This study explored changes in vascular reactivity in adult normotensive (WKY) rats and stroke-prone SHR (SHRSP) receiving the following treatments at 6–10 weeks of age: (a) ACE inhibitor (ramipril); (b) hydralazine/hydrochlorothiazide (hydral/HCTZ); or (c) no treatment. The hypothesis tested was that vascular changes and blood pressure would be reduced in adult SHRSP treated with ramipril during development. At 17 weeks of age, rats were anesthetized and vascular tissue was excised. Isolated experiments in the aorta included characterization of initial phasic and tonic contractions to 0.1 µM angiotensin II (AII). A phenylephrine (PE) concentration-response curve was performed on carotid arteries, and threshold values were determined. All WKY groups showed lower systolic blood pressure (131±4 mmHg) and reduced phasic AII induced contraction (7.4±4.7%) compared with SHRSP (217±4 mmHg; 37.2±4%). Antihypertensive treatment reduced blood pressure (ramipril: 168±2; hydral/HCTZ: 198±6 mmHg) but not phasic AII responses in adult SHRSP; adult WKY rats were unaffected by treatment. Threshold values for PE in carotid arteries were lower in SHRSP than in WKY, indicating increased sensitivity. However, SHRSP treated with ramipril did not demonstrate increased sensitivity to PE. These data support the hypothesis that blood pressure and sensitivity to PE but not contractile responsiveness to AII in adult SHRSP are determined by an AII-sensitive mechanism during development.     

Clonidine Inhibits Postprandial Response of Antral Myoelectrical Activity

Clonidine, an ₂-adrenergic agonist, is known to inhibit gastric motility and delay gastric emptying in both humans and animals, but its effect on gastric myoelectric activity is unclear. The aim of this study was to investigate the effect of clonidine on postprandial gastric myoelectric activity. The experiment was performed in eight hound dogs (14.5–22.6 kg) implanted with three pairs of bipolar serosal electrodes with an interval of 4 cm and the most distal pair 2 cm above the pylorus. Each dog was studied twice on two separate days after a complete recovery from surgery. Gastric myoelectrical activity was recorded for 30 min in the fasting state and 90 min after a solid test meal of 838 kcal. Two tablets of clonidine (0.4 mg) were given with the meal in one of the sessions. The dominant frequency and power of the slow waves from the most distal pair were calculated by computerized spectral analysis. All data were expressed as mean ± se. A significant postprandial increase in the dominant power of the slow wave and an increase in the percentages of gastric slow waves with spike bursts were observed in the control session, whereas the dominant frequency of gastric slow waves showed a significant postprandial decrease after the meal. The dominant power increased 8.24 ± 0.5, 8.6 ± 0.2, and 7.5 ± 0.3 dB, respectively, in the first, and second, and third 30-min period after the meal (all P < 0.01 vs baseline). Clonidine completely abolished the postprandial increase in the dominant power of the gastric slow wave and significantly inhibited spike bursts. The dominant power only increased 2.4 ± 1.1 dB (P > 0.05 vs baseline; P < 0.01 vs the first postprandial period in the control session), 0.6 ± 1.5 dB (P > 0.05 vs baseline; P < 0.05 vs the second postprandial period in the control session) and –1.5 ± 2.2 dB (P > 0.05 vs baseline; P < 0.05 vs the third postprandial period in the control session) respectively during the first, second, and third periods after the meal and clonidine. However, it did not affect the postprandial change of the dominant frequency of gastric slow waves. No significant changes in percentage of regular slow waves were noted with the meal or with clonidine (P > 0.05). In conclusion, the postprandial response of gastric myoelectrical activity in dogs to a solid meal is featured with an increase in amplitude and spike bursts, which is inhibited by clonidine.     

Enhancement of EFS-induced contractions, by agmatine, in guinea pig gallbladder smooth muscle strips

Background Electrical field stimulation of gallbladder muscle strips produces frequency-dependent contractions by activating cholinergic nerves. The cholinergic motor function of the gallbladder and enteric system is also modulated by other mediators. The aim of this study was to investigate the role of agmatine, a ligand for alpha 2-adrenoceptors and imidazoline binding sites, in the cholinergic motor activity of guinea pig gallbladder smooth muscle.Methods Gallbladder muscle strips obtained from guinea pigs were subjected to electrical field stimulation (1–64Hz, 100V, 1-ms pulse width, and 10-s train duration). Frequency-response contractions of gallbladder muscle strips were traced before and after the addition of cumulative concentrations of agmatine (10^–5–10^–3M) to the tissue bath. The same set of experiments was repeated in the presence of different antagonists.Results Agmatine by itself did not produce any contractions in guinea pig gallbladder muscle strips, but significantly enhanced the contractile response produced by electrical field stimulation. Yohimbine (10^–6M), a selective alpha 2-adrenergic blocker, neither decreased nor increased the enhancement induced by agmatine. However, idazoxan (10^–4M), an alpha-receptor blocker and imidazoline receptor antagonist, abolished this enhanced contractile response. Pretreatment with N^W-nitro l-arginine methyl ester (l-NAME; 30µM), and indomethacin (10µM) did not inhibit the effect of agmatine.Conclusions Our findings indicate that agmatine has a modulator role in the electrical field stimulation-induced cholinergic contractions of guinea pig gallbladder smooth muscle strips, and this role could be mediated by imidazoline receptors. Receptor binding studies should be done to determine the presence of endogenous agmatine and imidazoline receptors in gallbladder smooth muscle.     

Motilin: a mechanism incorporating the opossum lower esophageal sphincter into the migrating motor complex

The lower esophageal sphincter (LES) exhibits cyclical phasic contractile activity synchronous with phases II and III of the gastric migrating motor complex. Motilin has been implicated in this process, although the exact mechanism is unknown. The effect of motilin on LES pressure and on gastrointestinal myoelectric activity was examined in 8 unanesthetized opossums. Intraluminal pressure was recorded by a manometric assembly incorporating a sleeve device. Myoelectric activity was recorded from the stomach, duodenum, and jejunum via implanted electrodes. The opossum LES exhibited cyclical periods of phasic contractions synchronous with phases II and III of the gastric migrating motor complex cycle. Variations in the occurrence and magnitude of the phasic LES pressure waves paralleled the spontaneous cyclic fluctuations in the level of circulating plasma motilin. Pulse doses of exogenous motilin (25-400 ng/kg) elicited a contractile LES response that mimicked the spontaneous migrating motor complex-related phasic LES contractions. This effect was dose related with the maximal response occurring at a motilin dose of 100 ng/kg. The LES response to motilin was abolished by hexamethonium and significantly antagonized by atropine and 4-diphenylacetoxy-N-methylpiperidine methiodide, but was not affected by pirenzepine, phentolamine, or naloxone. The study findings support the hypothesis that cyclic increases in circulating endogenous motilin incorporate phasic LES as well as gastric contractile activity into the gastrointestinal migrating motor complex cycle. Motilin acts on the LES by the preganglionic stimulation of cholinergic nerves.     

The effect of prehepatic insulin administration on alanine flux rates in diabetic dogs

Summary The in vivo flux rates of glucose (6-³H-glucose) and of alanine (U-¹⁴C-alanine) were measured in insulin-dependent chronically diabetic dogs which were infused with insulin employing a bedside-type artificial B cell and either the peripheral or the portal venous route. In comparison with non-diabetic control animals the diabetic dogs had near-normal patterns of glucose metabolism and pancreatic glucagon regardless of the route of insulin administration. They also showed reduced basal portal but moderately elevated peripheral insulin levels on peripheral and near-normal peripheral values on portal insulin infusion. Both concentration and production rates of alanine were reduced on peripheral (0.142±0.016mmol/l, 4.73±0.49 mol·kg^–1·min^–1, p< 0.05) but normal on portal insulin (0.206±0.030 mmol/l, 6.33±0.63 mol·kg^–1 ·min^–1). The alanine clearance was slightly elevated or normal in the diabetic dogs, and the glucose production from alanine showed a strongly delayed response to an exogenous glucose load on either route of insulin administration. It is concluded that the peripheral hyperinsulinism during posthepatic insulin administration stimulates glucose utilisation to a normal extent, but inhibits the provision of amino groups in resting muscle. Alanine synthesis is thereby reduced, and the carbon moieties are shunted from glucose into circulating lactate. Long-term studies are needed to elucidate the role of the liver under these conditions.     

Cardiovascular actions of OPC-18790: A novel positive inotropic agent with little chronotropic action

Summary OPC-18790 [(±)-6-[3-(3,4-dimethoxy-benzylamino)- 2 - hydroxypropoxy] - 2(1H) - quinolinone], a novel positive inotropic agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and deceased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10^–6 to 10^–4 M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dosedependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive inotropic effect of OPC-18790 was not affected by -blockade. OPC-18790 (10^–5 to 10^–4 M) prolonged the duration of action potential in guinea pig papillary muscles. Na⁺, K⁺-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC₅₀ = 0.41 × 10^–6 M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.