Study of the mechanism underlying the prokinetic action of erythromycin on lower esophageal sphincter pressure in dogs

Erythromycin [EM] and a number of its derivatives exhibit prokinetic properties. In particular, the drug increases the contractile activity of smooth muscles of esophagus and promotes gastric emptying in both health and disease. The drug enhances esophageal and gastric motility by acting as a motilin agonist. The aim of the study was to evaluate the effect of low dose of EM, as a prokinetic agent, on the lower esophageal sphincter pressure [LESP] and to study the receptors involved in the mediation of the prokinetic action of EM. The study was carried out on 30 adult healthy dogs [10-15 kg] divided into five groups, each group consisted of 6 dogs. The studied groups were: I: a control group [placebo treated], II: an erythromycin treated group [EM gp] [7 mg/kg b.w. by i.v.i], and three groups III, IV, V that were treated with EM [7 mg/kg b.w. i.v.L preceded by either atropine [a muscarinic blocker] in a dose of 40 micro ag/kg b.w. i.v.i., ondansetrone [5 HT3 antagonist] in a dose of 0.1 mg/kg b.w. i.v.i or metoclopramide [dopamine receptor type 2 antagonist] in a dose of 150 micro g/kg b.w. i.v.i. respectively. After an over night fasting, basal recording of LESP was carried out in each group by an esophageal manometer connected to a pressure transducer. LESP was recorded for all animals in all groups fifteen minutes after the end of the predescribed treatments. Data obtained showed that EM significantly increased the resting LESP. Pretreatment with either atropine or ondansetrone totally prevented the increase in LESP induced by EM. However, pretreatment with metoclopramide failed to prevent the increase in LESP induced by EM. The findings suggest that EM in a low, subantimicrobial dose has a prokinetic action on the lower esophageal sphincter. It was found that this prokinetic action is exerted most probably by stimulating cholinergic pathway and strongly suggested that 5 HT3 receptors are involved in this process. Meanwhile, the dopaminergic receptors seem to have no role in the mediation of this prokinetic action of EM. It is hoped that this prokinetic action of EM could be of a particular benefit in the improvement of GIT motility disorders. However this warrants further investigation to help more understanding of cellular mechanisms regarding that effect of EM

Serum leptin elevation in obese women with polycystic ovary syndrome: a continuing controversy

The full pathogenesis of the polycystic ovary syndrome is not yet known. Heterogeneity is a confounding factor and several links between the diverse abnormalities seen in these cases are still missing. Obesity was one of the triad mentioned in the original description, and is an important differentiating factor between the two phenotypes of the syndrome namely obese and non-obese. Leptin is suggested to contribute to the pathogenesis of PCOS in obese subjects. In this study leptin levels were significantly different between obese and non-obese subjects, and were significantly different between insulin resistant and non-insulin resistant PCOS suggesting that body mass index and insulin resistance were the two main factors governing serum leptin levels

Evaluation of some haemostatic markers in normal pregnancies and pregnancies complicated by preeclampsia or eclampsia

To establish the plasma evolution of P-selectin, plateletfactor4 [Pf4], prothrombin fragments 1+2 [F1+2], thrombin antithrombin complex [TAT], von Willebrand factor [vWF] and blood platelet count during normal pregnancy, preeclampsia and eclampsia and to determine which are the most relevant and accurate to perform in clinical practice for estimating the severity of preeclampsia. Twenty patients with mild preeclampsia, twenty patients with severe preeclampsia, ten eclamptic cases and ten normotensive pregnant women were included in the study. All cases and controls were with gestational age ranging between 28 and 38 weeks. All five markers increased and platelet count decreased in the severe preeclampsia and eclampsia groups. A highly significant negative correlation was found between platelet count and both P-selectin and Pf4 in the three studied hypertensive groups. Moving from mild to severe preeclampsia to eclampsia, vWF and Pf4 showed an increasingly abnormal results. Pf4 was the only haemostatic marker elevated in the mild preeclampsia group as compared with the normal pregnant group [P=0.000]. [1] Platelet activation may play an important role in the pathogenesis of preeclampsia; [2] Plasma levels of vWF and Pf4 could reflect the severity of this disease, [3] Pf4 appears to be an interesting marker for detecting early alterations in the haemostatic system in pregnancies complicated by preeclampsia. It seems that measurements of haemostatic markers in patients with preeclampsia may have prognostic value in determining the outcome of pregnancy in this pregnancy disorder. They offer possibilities of early assessment of therapeutic approaches aimed at limiting vascular endothelial damage and platelet activation

Systemic arterial compliance and cardiac function in young patients with type 1 diabetes mellitus

Arterial elastic properties are altered with increasing age and in various disease states, including non-insulin-dependent diabetes mellitus [NIDDM]. Whether young patients with insulin-dependent diabetes mellitus [IDDM] have reduced arterial compliance before developing endothelial dysfunction or overt micro-and macrovacular disease is unclear. A total of 30 young patients with IDDM and 20 healthy subjects underwent [1] systemic arterial compliance determination by vessel wall movement detector system [complior], [2] common carotid artery-intimal medial thickness [IMT] by B-mode ultrasound, [3] echocardiographic assessment of systolic and diastolic left ventricular function, [4] brachial artery responses to reactive hyperemia [with increased flow causing endothelium-dependent dilatation] and sublingual isosorbide dinitrate [causing endothelium-independent dilatation], [5] lipid profile and hemoglobin A1c, and [6] 24-h urine collection for albumin excretion rate [AER] Arterial compliance was 23.1% lower in IDDM subjects compared with control subjects [4.86 +/- 0.445 vs. 6.32 +/- 0.889 cm4/dyn. 10[-7], P = 0.000]. IMT and all indexes of systolic and diastolic ventricular function were similar in both groups. Flow-mediated dilatation [FMD] was significantly impaired in diabetic patients. The ratio of FMD to isosorbide dinitrate induced dilatation was significantly lower in the diabetic subjects indicating that impaired dilatation to increased flow was out of the proportion to the impairment of the isosorbide dinitrate response in these subjects. The median AER was 5.98 micro g/min in the DM group and 2.92 micro g/min in the control group [P = 0.005]. Hemoglobin A1c correlated inversely with compliance [r = -0.993, P = 0.000], FMD [r = -0.929, P = 0.000] and isosorbide dinitrate -induced dilatation [r = -0.938, P = 0.000] in diabetic patients A significant positive correlation was found between arterial compliance and both FMD [r = 0.900, P = 0.000] and isosorbide dinitrate-mediated dilatation [r = 0.911, P= 0.000]. This study indicates that early changes in macrovascular function namely impaired arterial compliance and reactivity, may precede abnormalities in cardiac function or in arterial IMT in young individuals with short duration type 1 DM. Arterial compliance and reactivity may prove to be predictive of future atherosclerotic complications in patients with diabetes; therefore the noninvasive long-term assessment of arterial physiology and its relationship to the progression of cardiovascular risk factors is required. The present study also supports a relationship between metabolic control, arterial compliance and endothelial function

Interrelationship between nitric oxide synthase and myocardial tumor necrosis factor-alpha effect on cardiac contractile function in preconditioned anesthetized dogs

Brief periods of myocardial ischemia and reperfusion render the myocardium tolerant to a subsequent sustained ischemia. This phenomenon has been known as ischemic preconditioning [PC]. It has recently become apparent that ischemic PC consists of two phases: an early phase, which occurs within minutes and disappears within 2 to 4 hours from the PC ischemia, and a late phase, which becomes manifest 24 hours later. The purpose of the present study was to test the hypothesis that the protective effect of ischemic PC is mediated by augmented nitric oxide [NO] formation. This study also aims at examining the effect of ischemic PC on postischemic myocardial tumor necrosis factor-alpha [TNF-alpha] production. This study was carried out on 38 healthy adult dogs of either sex. Six dogs were sacrificed and left ventricular myocardium was excised, homogenized and cardiac TNF-alpha homogenate was determined by chemiluminescence. Thirty-two dogs were randomized into 4 equal groups; Group I [preconditioned group], Group II [ischemic control group], Group III [preconditioned N-nitro-L-arginine methyl-ester [L-NA] treated group] and Group IV [ischemic L-NA treated group]. All groups were allowed 3 hours of reperfusion thereafter. Left ventricular systolic pressure [LVSP] and cardiac output [COP] were measured before and after left anterior descending coronary artery [LAD] occlusion reperfusion [O/R] in the four studied groups. After the three hours of reperfusion, TNF-alpha was measured in the cardiac homogenate of all groups. There was no statistically significant difference in LVSP and COP when comparing the four groups after LAD O/R However, there was a significant drop in both parameters in each of the four studied groups after LAD O/R. The absent short-term beneficial role of PC on myocardial contractility following O/R could be attributed to stunning of the myocardium: Furthermore, inhibition of NO synthesis did not attenuate myocardial stunning in preconditioned and ischemic anesthetized dogs. The present study also demonstrated that O/R increases cardiac TNF-alpha levels and that ischemic PC decreases ischemia-induced cardiac TNF-alpha production, which is still significantly higher in the preconditioned groups, compared with control group. This drop in myocardial TNF-alpha following ischemic PC did not improve postischemic functional recovery in anesthetized dogs. The absent short-term beneficial role of pretreatment with a NOS inhibitor could be explained by the fact that inducible NO synthase [iNOS] mediated only the late dysfunction induced by TNF-alpha

Effect of cholecystectomy on sphincter of oddi motility in dogs

Gallbladder and sphincter of Oddi [SO] function are controlled by a balance of both hormonal and neuronal factors. Neuronal connections pass between the gallbladder and the SO via the cystic duct. It is therefore possible that cholecystectomy may alter SO motility. The present study investigated the effect of cholecystectomy on SO function in anesthetized dogs. Biliary manometry was performed in a group of anesthetized dogs undergoing cholecystectomy and compared with a control group of matched weight and sex. The cholecystectomized dogs compared with the controls showed a significant increase in mean common bile duct [CBD] pressure together with a significant decrease in mean basal SO pressure and SO phasic frequency. There was also a significant increase in the duration of phasic contractions in the cholecystectomy group compared with the control group. No significant change was noticed in the amplitude of phasic contractions and in the duodenal pressure when comparing both groups. These findings show that the gallbladder serves as a reservoir dampening increases in common duct pressure. The increase in intraductal tension following cholecystectomy in the canine model could overcome the choledochoduodenal sphincter resistance resulting in a drop in SO basal pressure associated with a decrease in the frequency of phasic contractions. It is also possible that ductal distension inhibits SO function by local reflexes. Removal of the gallbladder itself may eliminate a significant component of the neural circuity modulating biliary function. Such effects may ultimately lead to the SO manometric abnormalities, which have been described for SO dysfunction