Role of Alpha-2 Adrenoceptors in Regulation of Giant Migrating Contractions and Defecation in Conscious Dogs

The aim was to investigate the effects of α₂-adrenoceptor antagonsist yohimbine on colonic motility and defecation. The effects of yohimbine (0.5, 1.0, and 3.0 mg/kg) on colonic motility and defecation were studied in neurally intact dogs (N=6), dogs with extrinsic denervation of the ileocolon (N=4), and dogs with enterically isolated ileocolnic loops (N=5) equipped with strain gauge force transducers on the ileocolon. The effects of yohimbine on colonic motility and defecation were also studied in the presence of various antagonists (atropine, hexamethonium, ondansetron, FK224, and naloxone). Yohimbine evoked giant migrating contractions and defecation in a dose-independent manner in neurally intact dogs. These stimulatory effects of yohimbine were abolished by atropine and hexamethonium. In dogs with extrinsic denervation, yohimbine induced giant migrating contractions in the colon but did not stimulate defecation. In dogs with ileocolonic loops, yohimbine induced colonic motor complexes but not giant migrating contractions in the enterically isolated colon. These results indicate that α₂-adrenoceptors in the peripheral nervous system regulate giant migrating contractions by controlling the release of acetylcholine, while those in the central nervous system must be important in the regulation of defecation. This study was presented at 19th International Symposium on Neurogastroenterology and Motility in Barcelona, Spain, in October 2003. This study was supported by a Grant-in-aid from Japan Society for the Promotion of Science (NO. 13671277).     

Role of Duodenum on Sphincter of Oddi Motility in Conscious Dogs

Our aim was to determine the role of the duodenum in controlling sphincter of Oddi motility using conscious dogs after total duodenectomy. In a control group (N = 6), a cannula was implanted into the duodenum opposite to the papilla to allow retrograde sphincter manometry. In a duodenectomy group (N = 6), the papillae were preserved at total duodenectomy and sutured to the jejunum anastomosed to the stomach (neoduodenum). The cannula was implanted opposite to the implanted papillae. Interdigestive and postprandial sphincter and duodental or neoduodenal motility were recorded by manometric and myoelectric methods. Duodenectomy disrupted sphincter cyclic motility associated with the intestinal migrating motor complex and increased sphincter activity throughout the cycle. Sphincter activity increased immediately after feeding and did not differ between the two groups. In conclusion, during the interdigestive period, the duodenum has a distinct role in regulating sphincter cyclic motility. The initiation of the fed pattern of sphincter motility does not need the duodenum.     

Diurnal Motor Activities of the Esophagus in Conscious Dogs

Diurnal motor activities of the upper, middle, and lower thirds of the thoracic esophagus, the lower esophageal sphincter, and the gastric body were recorded in six conscious dogs, using extraluminal force transducers. The motor activities of the thoracic esophagus and the lower esophageal sphincter were divided into three major motility patterns: feeding, digestive, and interdigestive. Each motility pattern was basically composed of repetitive bursts of contractions that were clearly classified into type I and II according to their contractile properties. Type I bursts were peristaltic contractions initiated at the upper thoracic esophagus and sequentially propagated distally to include the sphincter. Propagation velocity and duration of type I contractions were similar in all three motility patterns, and these contractions never were propagated into the stomach. Type II bursts were nonperistaltic simultaneous contractions of the thoracic esophagus and lower sphincter appearing synchronously with phase III of gastric interdigestive migrating contractions. Amplitude and duration of type II contractions were maximal at the sphincter, suggesting initiation at that site. In nonfeeding patterns, type I contractions would clear the esophagus of refluxed gastric contents, while type II contractions would prevent reflux.     

Role of Endothelial Dysfunction and Insulin Resistance in Angina Pectoris and Normal Coronary Angiogram

Abstract Angina pectoris and a normal coronary angiogram or cardiac syndrome X is a heterogeneous syndrome that probably encompasses different pathophysiological entities. Patients affected by cardiac syndrome X are often women presenting with severe, invalidating chest pain. However, there is a significant discrepancy among the severity of symptoms, the lack of hemodynamic evidence of myocardial ischemia and the relatively benign long-term prognosis. The vascular endothelium has numerous important functions, including the regulation of vascular tone, blood flow and permeability, secreting both vasorelaxing and vasoconstricting factors. It has been found that both endothelium and non-endothelium-mediated coronary blood flow are impaired in patients with cardiac syndrome X. Interestingly, it has been shown that impaired nitric oxide-dependent vasodilation could increase coronary microvessel tone and produce spasm. It has also been reported that circulating endothelin-1 levels are elevated with a direct relationship between endothelin-1 levels and impaired coronary flow reserve in these patients. In addition, patients with high endothelin-1 levels showed a time onset of chest pain during exercise significantly lower compared to patients with low endothelin-1 concentrations. Moreover, the nitric oxide/endothelin-1 ratio was found decreased in patients with cardiac syndrome X and endothelin-1 levels were also positively correlated with fasting asymmetric dimethylarginine levels. All in all, these data suggest a role of endothelial dysfunction as a cause of regional myocardial and peripheral blood flow abnormalities. Further studies are necessary to characterize the prevailing mechanisms determining alterations in nitric oxide/endothelin-1 pathway in these patients, in order to find new therapies able to improve both quality of life and prognosis.     

Role of Nitric Oxide Mechanisms in Control of Pyloric Motility and Transpyloric Flow of Liquids in Conscious Dogs

The role of nitric oxide (NO) mechanisms incontrol of pyloric function and transpyloric flow wereinvestigated in six conscious dogs. Antropyloroduodenalmotility, transpyloric flow, and gastric emptying were measured 15 min after intravenousinjection of 100 ml of either saline, L-arginine (50mg/kg), L-NNA (5 mg/kg), or L-arginine (50 mg/kg)followed by L-NNA (5 mg/kg). Infusion of L-NNA wasassociated with retardation of gastric emptying (65± 6%) in the first 30 min, in comparison to thesaline (90 ± 3%) or L-arginine (90 ± 2%).This effect was prevented by infusion of L-arginineprior to L-NNA, after which 89 ± 3% of the liquidemptied in 30 min. There was a significant reduction (P< 0.05) in the number and volume of flow pulses, andan increase in pyloric tone (P < 0.05) after L-NNA in comparison to the other three testconditions. There were no differences, however, in thenumber of antropyloric or isolated pyloric pressurewaves under the four conditions. Our findings suggestthat NO mechanisms influence gastric emptying andtranspyloric flow of nonnutrient liquids by altering thepyloric tone, thus increasing resistance toflow.     

腺苷及腺嘌呤衍生物对离体猪冠状动脉环和主动脉平滑肌细胞增殖的影响

腺苷以及ＡＭＰ、ＡＤＰ、ＡＴＰ等腺嘌呤衍生物是一类强有力的血管扩张剂。离体猪冠状动脉实验证明，ＡＴＰ，ＡＤＰ为内皮依赖性舒张作用，而腺苷本身 则为非内皮依赖性舒张效应。用噻唑蓝比色法观察到与腺苷一样，ＡＭＰ、ＡＤＰ、ＡＴＰ也能剂量依赖性抑制培养的主动脉平滑肌细胞增殖。结果表明，腺苷以及ＡＭＰ、ＡＤＰ、ＡＴＰ等腺嘌呤衍生物可能是平滑肌细胞增殖的调节因子，本文还能腺苷类药物的临床应用价值进行了讨论。     

甘油三酯与高密度脂蛋白预测冠状动脉病变的意义

７８例患者选择性冠状动脉（冠脉）造影，其中冠脉病变５１例，冠脉正常２７例。测定了其高密度脂蛋白（ＨＤＬ）及其亚组分和甘油三酯（ＴＧ）。结果表明：冠脉狭窄与ＨＤＬ２负相关（ｒ＝－０．３２，Ｐ＜０．０１）、与ＴＧ正相关（ｒ＝０．３４，Ｐ＜０．０１），认为高ＴＧ和低ＨＤＬ２对于预测冠脉病变有重要意义。     

甘油三酯与高密度脂蛋白预测冠状动脉病变的意义

腺苷以及ＡＭＰ、ＡＤＰ、ＡＴＰ等腺嘌呤衍生物是一类强有力的血管扩张剂。离体猪冠状动脉实验证明，ＡＴＰ、ＡＤＰ为内皮依赖性舒张作用，而腺苷本身则为非内皮依赖性舒张效应。用噻唑蓝比色法观察到与腺苷一样，ＡＭＰ、ＡＤＰ、ＡＴＰ也能剂量依赖性抑制培养的主动脉平滑肌细胞增殖。结果表明，腺苷以及ＡＭＰ、ＡＤＰ、ＡＴＰ等腺嘌呤衍生物可能是平滑肌细胞增殖的调节因子。本文还对腺苷类药物的临床应用价值进行了讨论。     

Two Challenging Translocation Procedures for Intramural Coronary Arteries in the Setting of Transposition of Great Arteries

Translocation of the coronary arteries remains a technical challenge in anatomic correction of transposition of great arteries. Myocardial ischemia related to the difficulties with coronary relocation is an important factor in perioperative and postoperative morbidity and mortality, particularly in the patients with complex coronary artery anatomy. Intramural coronary artery is a rare anatomic variety which may complicate the arterial switch operation in 2% to 4.6% of the reported cases. Even in the hands of experts, the mortality rate may be in twofold in this subset of patients compared with simple transposition of great artery procedures. In this report, 2 successful translocation techniques for intramural coronary arteries in the setting of arterial switch operation are described.     

Effect of Motilin on Endogenous Release of Insulin in Conscious Dogs in the Fed State

The aim was to investigate the insulin-releasing activity of motilin during and after feeding. A single intravenous bolus injection of motilin (0.01-0.3 microg/kg) dose-dependently stimulated endogenous release of insulin in the postprandial state. The insulin-releasing activity of motilin in the fed state was completely abolished by pretreatment with atropine or hexamethonium and was partly inhibited by ondansetron. Truncal vagotomy also greatly suppressed the motilin-induced insulin release. While phentolamine significantly enhanced insulin release in response to motilin, propranolol significantly inhibited this response in both states. The motilin-induced insulin release in the fed states was not accompanied by any changes in glucose concentrations. In conclusion, while the physiological significance remains unclear, these results indicate that physiological doses of motilin stimulate endogenous release of insulin via a vagally cholinergic muscarinic pathway, and that adrenergic and 5-hydroxytryptamine3 receptors are also involved in this response, in the dog.     

切应力对内皮细胞组织因子表达上调的影响及其作用机制

研究切应力对内皮细胞组织因子表达的影响及其作用机制。利用原位杂交和免疫组织化学观察组织因子基因、Sp1和Egr 1的mRNA转录及蛋白表达。切应力作用采用平行板流动腔系统给予。结果发现 ,在静置培养内皮细胞中 ,组织因子基因mRNA及蛋白表达极低 ,促凝活性也低。Sp1蛋白表达在胞核较高 ,Sp1mRNA表达在胞浆较高。Egr 1在胞核和胞浆均无表达或表达极低。在切应力 (1.2、2 .4及 4 .8Pa)作用后 ,内皮细胞胞浆组织因子基因mRNA转录和蛋白合成及组织因子促凝活性升高 ,与对照组比较均有显著性差异 (P <0 .0 5 )。Sp1和Egr 1基因mRNA转录和蛋白合成均有增加 (P <0 .0 5 ) ,但以Egr 1增加更显著 (P <0 .0 5 ) ,其变化趋势与组织因子基因mRNA转录、组织因子基因蛋白合成、组织因子促凝活性的变化趋势相同。结果提示 ,切应力是内皮细胞组织因子基因表达上调的触发因素之一 ,其触发机制与转录因子Egr 1和Sp1介导有关。     

Nisoldipine Selectively Induces Coronary Vasodilation and Improves Mild Myocardial Ischemia in Dogs: A Potential Role of Cellular Acidosis

We examined whether nisoldipine, a calcium (Ca) channel blocker, increases coronary blood flow (CBF) without decreasing aortic blood pressure (AoP) with ischemic and nonischemic hearts, and whether the presence of cellular acidosis in ischemic myocardium contributes to the augmentation of coronary vasodilation due to nisoldipine. In 42 dogs, coronary perfusion pressure (CPP) was reduced so that CBF decreased to 60% of the baseline, and CPP was maintained constant thereafter. First, we administered nisoldipine into a systemic vein in the ischemic and nonischemic hearts. Second, nisoldipine was administered into the canine coronary artery of the ischemic myocardium with and without administration of either sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), or amiloride. Nisoldipine (0.25–4.0 mg/kg, IV) increased CBF by 59% in the ischemic myocardium more than the nonischemic myocardium (by 34%) without reducing AoP. The infusion of nisoldipine (40 ng/kg/min, IC) increased CBF markedly by about 55% in the ischemic myocardium with increases in fractional shortening (FS; 11 ± 2% to 21 ± 2%) and lactate extraction ratio (LER; –19 ± 4% to 15 ± 2%). Increases in CBF, FS, and LER were markedly attenuated during administration of nisoldipine with concomitant administration of either NaHCO3 or NaOH. Furthermore, the extent of increases in CBF (54 ± 2 mL/100 g/min), FS (13 ± 2%), and LER (–17 ± 4%) were also markedly attenuated due to the concomitant treatment with amiloride. We conclude that myocardial cellular acidosis plays an important role in mediating coronary vasodilation affected by nisoldipine in the ischemic myocardium. H+ may modulate the property of voltage-dependent Ca channels via Na+–H+ exchange.     

The Role of the Membrane Potential of Endothelial and Smooth Muscle Cells in the Regulation of Coronary Blood Flow

Membrane Potential of Coronary Endothelial and Smooth Muscle Cells. In the mammalian heart the supply of oxygen and energy-rich substrates through the coronary arterioles is continuously adapted to the variations of cardiac work. The coronary resistance arteries and the surrounding myocardium form a functional unit with multiple interactions between coronary endothelial cells, smooth muscle cells, perivascular nerves, and cardiac muscle cells. We describe the mechanisms underlying the electrical and chemical communication between the different cell types, the ionic channels contributing to the resting potential of endothelial and smooth muscle cells, and the mechanisms responsible for modulation of the resting potential. The main conclusion of our analysis is that the membrane potential of coronary endothelial and smooth muscle cells is one of the major determinants of coronary blood flow, and that modulation of the membrane potential provides a way to dilate or constrict coronary resistance arteries. It is proposed that the membrane potential of the myo-endothelial regulatory unit, i.e., of the endothelial cells and the underlying smooth muscle cells in the terminal arterioles, may function as an integrator of the numerous local and global vasodilator and constrictor signals that provide for the adaptation of coronary blood flow to the metabolic demands of the heart.     

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.     

长期应用氯吡格雷对冠心病患者血管内皮功能的影响

目的探讨长期应用氯吡格雷对冠心病患者血管内皮功能的保护作用。方法将166例经冠状动脉造影确诊为冠心病的患者(均予裸支架植入治疗)随机分为试验组和对照组,治疗的前6个月两组均应用氯吡格雷和阿司匹林6个月,6个月后对照组只应用阿司匹林,试验组继续应用氯吡格雷和阿司匹林6个月(其他冠心病基础用药一致)。分别于治疗6个月、12个月采用肱动脉超声和上臂反应性充血试验的方法观察并比较两组肱动脉舒张期内径、平均血流速度、血流量、动脉扩张性、血流阻力和肱动脉中膜厚度等反映患者血管内皮功能的指标。结果试验组肱动脉管径、血流速度、血流量和扩张性增加,血流阻力和肱动脉内膜中膜厚度降低;其应用12个月比6个月效果更明显。治疗12个月后试验组比对照组血管内皮功能指标改善更明显(P<0.05)。在反应性充血状态下,试验组肱动脉管径、血流速度、血流量增加,血流阻力降低;而对照组血流速度、血流量、血流阻力、肱动脉管径等指标治疗12个月与治疗6个月差异无统计学意义(P>0.05)。结论长期应用氯吡格雷对冠心病患者血管内皮功能可能有保护作用。