Ventricular fibrillation (VF) is a major cause of sudden cardiac death in which myocardial ischemia plays a leading role. During ischaemia activation of ATP-sensitive potassium channels (K(ATP)) occurs, leading to potassium efflux from cardiomyocytes and shortening of the action potential favoring the genesis of ventricular fibrillation. In confirmation of this concept the sulfonylurea glibenclamide, which stimulates insulin release by inhibition of pancreatic K(ATP) channels, has been shown to inhibit VF in different models of ischaemia by inhibition of myocardial K(ATP) channels. HMR 1883 (1-[15-12-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) was designed as a cardioselective K(ATP) channel blocker. The aim of this study was to show that with this compound it is possible to separate the antifibrillatory from the insulin-releasing effect for the treatment of patients at risk of ischaemia-induced arrhythmias and sudden death. In the present study HMR 1883 reduced VF in Sprague-Dawley rats during prolonged ischaemia and also diminished mortality and the duration of VF in a separate reperfusion experiment at 3 mg/kg and 10 mg/kg with no effect on blood glucose or insulin. Glibenclamide, which was antifibrillatory at 0.3 mg/kg and 1 mg/kg, increased plasma insulin and lowered blood glucose already at a dose as low as 0.01 mg/kg. In conclusion, based on its antifibrillatory action and the absence of significant pancreatic effects at therapeutic doses, HMR 1883 is of potential clinical utility for the prevention of severe arrhythmias in patients with ischaemic heart disease.

Grötsch, Hropot, Klaus, Malerczyk and Mattenheimer: Enzymuria of the rat: Biorhythms and sex differences 343 Summary: Alanine aminopeptidase, -glutamyltransferase and N-acetyl-ß-Z)-glucosaminidase were measured daily over 65 days in 24-hour urine of male and female Wistar rats. The mathematical evaluation was based on the Föw/er-analysis. The excretion of alanine aminopeptidase and -glutamyltransferase was higher in male than in female rats. This sex-dependent difference was not observed for N-acetyl-ß-/)-glucosaminidase. The excretion of the 3 enzymes followed a biorhythm with a dominant period of 7 days forglutamyltransferase and N-acetyl-ß-£>-glucosaminidase and one of 9 days for alanine aminopeptidase. Biorhythms and sex differences of enzymuria should be considered in experimental designs. Enzymurie der Ratte: Biorhythmen und GeschlechtsdifferenzenZusammenfassung: Alaninaminopeptidase, -Glutamyltransferase und N-Acetyl-ß-D-glucosaminidase wurden täglich über 65 Tage bei männlichen und weiblichen Wistar-Ratten im 24 h-Urin gemessen. Die Ergebnisse wurden vermittels fbwr/er-Anälyse ausgewertet. Die Ausscheidung von Alaninaminopeptidase und -Glutamyltransferase zeigte deutliche geschlechtsabhängige Unterschiede, wobei von männlichen Ratten mehr ausgeschieden wurde als von weiblichen Tieren. N-Acetyl-ß-/)-glucosaminidase zeigt diese Unterschiede nicht. Die Ausscheidung der drei Enzyme unterlag Biorhythmen mit Periodenlängen von sieben Tagen für -Glutamyltransferase und N-Acetyl-ß-jp-glucosaminidase und neun Tagen für Alaninaminopeptidase. Biorhythmen und Geschlecht$differenzen in der Enzymurie sind bei Versuchsplanungen zu berücksichtigen. Introduction. , « , , years the rat has been used äs the main experimental Urine enzymes äre being used with increasing animal in enzyine excretion studies. This animal frequency äs sensitive indicatöfs for early detection shows significant enzymuria when substances are of renal damage. Many investigatiöns include a administered which cause increased enzymuria in discussipn of biörhythms in man and animals, re-man. The rat tolerates well single-cage housing in speetively (l -3), A few reports on experimental ani-long term experiments. Enzymes with the smallest mal models document this coherence of biörhythms experimental Variation and good reproducibility are and nephrptoxicity with a close correlation between alanine aminopeptidase, -glutamyltransferase and enzyme excretion and renal damage. Of the large N-acetyl-ß^jD-glucosaminidase. The aim of this study nuinber of urine enzymes, it is mainly those from the was to apply modern mathematical methods to the proximal tübular cells that are of particular interest investigation of biörhythms and sex-specific for toxicological and clinical investigatiöns. In recent differences in the excretion of these enzymes over a

Inhibition of the angiotensin converting enzyme (ACE) with ramipril was studied in male Wistar rats during long-term inhibition of nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester (L-NAME). Chronic treatment with L-NAME in a dose of 25 mg/kg per day over 6 weeks caused myocardial hypertrophy and a significant increase in systolic blood pressure (245 +/- 16 mmHg) as compared to controls (155 +/- 4 mmHg). Animals receiving simultaneously L-NAME and ramipril were protected against blood pressure increase and partially against myocardial hypertrophy. L-NAME caused a significant reduction in glomerular filtration rate (GFR: 2.56 +/- 0.73 ml.kg-1.min-1) and renal plasma flow (RPF: 6.93 +/- 1.70 ml.kg-1.min-1) as compared to control (GFR: 7.29 +/- 0.69, RPF: 21.36 +/- 2.33 ml.kg-1.min-1). Addition of ramipril prevented L-NAME-induced reduction in GFR and renal plasma flow. L-NAME produced an elevation in urinary protein excretion and serum creatinine and a decrease in potassium excretion which was antagonised by ramipril. L-NAME-induced increase in plasma renin activity (PRA) was further elevated with ramipril treatment. Isolated hearts from rats treated with L-NAME showed increased post-ischaemic reperfusion injuries. Compared to controls duration of ventricular fibrillation was increased and coronary flow reduced. During ischemia the cytosolic enzymes lactate dehydrogenase and creatine kinase, as well as lactate in the venous effluent were increased. Myocardial tissue values of glycogen, ATP, and creatine phosphate were decreased, whereas lactate was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of sample prepafations by dialysis and gel filtration on the catalytic concentrations of alanine aminopeptidase, N-acetyl-ß-D-glucosaminidase, and ß-glucuronidase are described. Individual urines were collected during 24 hours on 3 consecutive days from 10 male rats. Gel filtration (Sephadex G25) was more effective than dialysis against water in the removal of inhibitors of N-acetyl-ß-£>-glucosaminidase and ß-glucuronidase. For alanine aminopeptidase, slightly higher results were obtained by dialysis. Inhibitor contents varied from day to day. Activity decreases of ß-glucuronidase and N-acetyl-ß-D-glucosaminidase were found in some of the urine samples and interpreted äs removal of activators. Gel filtration is recommended for the preparation of rat urine for the measurement of these three eiizymes. The slightly inferior effect of gel filtration ön alanine aminopeptidase should be disregarded for the sake of practicality.

No abstract