The effect of hypergastrinemia following sleeve gastrectomy and pantoprazole on type 2 diabetes mellitus and beta-cell mass in Goto-Kakizaki rats.

PURPOSE: Metabolic surgery alters the secretion of gastrointestinal hormones that influence glycemic control. Elevated gastrin has been suggested to benefit patients with type 2 diabetes and has been reported following sleeve gastrectomy in rats. The present study compares the effect of hypergastrinemia following sleeve gastrectomy with proton-pump inhibitor therapy on glycemic control and beta-cell mass in lean, diabetic animals. METHODS: Thirty-three diabetic Goto-Kakizaki rats were randomized into pantoprazole + sham operation (GK-PPI), sleeve gastrectomy (GK-SG) and vehicle + sham operation (GK-V). Body weight, glucose parameters, HbA1c, glucagon-like peptide 1, gastrin, insulin and lipids were evaluated for eighteen postoperative weeks. Total beta-cell mass was quantified by optical projection tomography. RESULTS: After surgery, body weight development was equal among groups (P g = 0.75). Fasting and stimulated gastrin increased for GK-PPI and GK-SG vs. GK-V (p < 0.05 for all). Fasting blood glucose was decreased for GK-PPI and GK-SG vs. GK-V (p < 0.05 and p = 0.052). HbA1c was lower for GK-SG vs. GK-V at 6 weeks and for GK-PPI vs. GK-V at twelve- and eighteen weeks postoperative (p < 0.05 for all); a borderline difference was observed for GK-SG vs. GK-V at 18 weeks (p = 0.054). Total- and LDL cholesterol was elevated for GK-PPI compared to the other two groups (p < 0.05 for all). Beta-cell mass did not differ among groups (p = 0.35). CONCLUSIONS: Hypergastrinemia following sleeve gastrectomy and pantoprazole has a similar, modest effect on glycemic control in Goto-Kakizaki rats but does not enhance beta-cell mass after 18 weeks. Hypergastrinemia in the setting of T2DM might be of clinical relevance.

Reduced pH and contractility in failing rat cardiomyocytes.

AIM: To determine whether reduced cardiomyocyte contractility in heart failure is associated with reduced intracellular pH (pH(i)). Involvement of the Na(+)/H(+) exchanger and the H(+)/K(+) ATPase were investigated with specific blockers. METHODS: Myocardial infarction and subsequent heart failure in Sprague-Dawley rats were induced by chronic occlusion of the left coronary artery. 6 weeks post-ligation, contractility (cell shortening) and pH(i) (BCECF fluorescence) were recorded in freshly dissociated cardiomyocytes during 2-10 Hz electrical stimulation, with or without either Na(+)/H(+) exchanger or H(+)/K(+) ATPase inhibition. RESULTS: Elevated end-diastolic and reduced peak systolic pressures confirmed heart failure. Increased heart weights (20-30%; P < or = 0.01) and cardiomyocyte lengths and widths (22-25%; P < or = 0.01) confirmed substantial cardiac hypertrophy. In myocytes isolated from sham operated rats, a positive staircase response occurred with stimulation rates from 2 to 7 Hz; further increases in stimulation rate up to 10 Hz reduced contractility. In contrast, pH(i) fell progressively over the entire stimulation range. In failing myocytes, pH(i) was consistently 0.07 pH units lower and contractility 40% lower (P < or = 0.01) than sham control values; the shape of the contractility staircase remained similar to controls. At all stimulation frequencies, Na(+)/H(+) exchanger inhibition reduced pH(i) by 0.05 pH units (P < or = 0.01) and contractility by 22% (P < or = 0.05) in cardiomyocytes from the heart failure group. A significantly smaller decrease of pH(i) and reduction in contractility was observed after inhibition of Na(+)/H(+) exchanger (10 micro m HOE694) in sham myocytes. H(+)/K(+) ATPase inhibition (100 micro m SCH28080) had no effect on pH(i). CONCLUSION: Reduced pH(i) is accompanied by reduced cardiomyocyte contractility in isolated myocytes from post-MI heart failure. The data suggest compensatory Na(+)/H(+) exchanger activation in heart failure, whereas H(+)/K(+) ATPase does not appear to contribute significantly to pH(i) maintenance.

Effect of magnesium infusion on bleeding time in healthy male volunteers.

Intravenous magnesium has proved to be valuable in the treatment of cardiac arrhythmias and eclampsia, but the specific mode of action is not established. In this study the effect of magnesium sulphate (MgSO4) infusion on bleeding time and endogenous prostacyclin (PGI2) production in healthy male volunteers was investigated. Thirty-five males (age 18-30 years) randomized in a double-blind, placebo-controlled, cross-over study were investigated. MgSO4 was given as a bolus (8 mmol, 12 min) followed by continuous infusion (8 mmol in 108 ml saline, 120 min). Control was equal volumes of physiological saline. Heart rate, blood pressure and bleeding time (according to Ivy) were recorded as well as blood concentrations of magnesium and creatinine. Urine PGI2 was analysed as the stable metabolite 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha). Treatment with MgSO4 did not affect bleeding time (MgSO4; 8.4+/-3.5 vs. control 8.0+/-2.7 min) nor the production of PGI2 (MgSO4; 1.2 microg 6-keto-PGF1alpha/g creatinine vs. control; 1.1 microg 6-keto-PGF1alpha/g creatinine). Intravenous infusion of MgSO4 does not affect the PGI2/platelet axis in healthy male volunteers. Studies in patients with endothelium dysfunction and/or concomitant drug therapy are required before the anti-thrombogenic effect of MgSO4 in vivo is discarded.

Chronic carbon monoxide exposure in vivo induces myocardial endothelin-1 expression and hypertrophy in rat.

Smoking is associated with endothelial dysfunction and increased plasma levels of endothelin-1. The component of tobacco smoke inducing these effects is unknown. Carbon monoxide induces hypoxia, and there is evidence of carbon monoxide acting as a local mediator in both endothelial and smooth muscle cells. The purpose of this study was to determine whether chronic carbon monoxide exposure similar to that experienced by smokers affects myocardial endothelin-1 expression. Sprague-Dawley female rats were exposed to carbon monoxide 100 ppm for one week or to 100 ppm for one week and 200 ppm for a second week. Carboxyhaemoglobin was 12+/-0.9% in the low and 23+/-1.1% in the high carbon monoxide exposure group. Endothelin-1 expression was measured by competitive reverse transcriptase polymerase chain reaction. High carbon monoxide exposure increased endothelin-1 mRNA by 54+/-12% (P<0.001) in the left ventricle and by 53+/-12% (P<0.001) in the right ventricle. In the low carbon monoxide exposure group corresponding changes were 43+/-14% (P=0.06) and 12+/-16%(P=0.29). Right ventricular weight increased by 18+/-7% (P=0.02) after high and by 16+/-5% (P=0.02) after low exposure. Left ventricular weight was elevated by 5+/-2% (P=0.05) when both exposure groups were compared to controls. We conclude that chronic carbon monoxide exposure leading to carboxyhaemoglobin levels similar to those observed in smokers increases endothelin-1 gene expression and induces myocardial hypertrophy in the rat.