E. Aughey

Effects of L-canavanine, an inhibitor of inducible nitric oxide synthase, on endotoxin mediated shock in rats

The effects of L-canavanine, an inhibitor of nitric oxide synthase, on endotoxin-induced shock was investigated in the pentobarbitone anesthetized rat. Endotoxin infusion (2.5 mg kg-1 h-1 over 6 h) produced progressive and marked hypotension and hypoglycemia. Electron microscopy showed marked changes in the kidney, comprising severe endothelial cell disruption and the accumulation of platelets in the blood vessels. In the lung, there was marked accumulation of polymorphonuclear leukocytes in small blood vessels and endothelial disruption. Treatment with L-canavanine (10 mg kg-1 by bolus injection each hour starting 70 min after endotoxin or saline infusion) significantly reduced endotoxin-induced hypotension, without any effect on the hypoglycemia. This treatment markedly reduced the endotoxin-induced electron microscopical changes in the kidneys and lungs. Although L-canavanine, like L-NAME, inhibited both cerebellar constitutive and splenic inducible nitric oxide synthase in vitro, in contrast to L-NAME it did not modify either arterial blood pressure or carotid artery blood flow in control rats. The data are consistent with L-canavanine being a selective inhibitor of inducible nitric oxide synthase, at least in vivo, and suggest that inhibitors of this enzyme may be beneficial in endotoxin-induced shock.

Coronary endothelial dysfunction increases the severity of ischaemia-induced ventricular arrhythmias in rat isolated perfused hearts.

Abstract In order to determine the role of coronary vascular endothelial cells in generating cardioprotective substances during myocardial ischaemia, rat isolated hearts, perfused at constant flow by the Langendorff technique, were subjected to treatment with the detergent Triton X100 and the responses of these hearts to a 30 or 60 min period of coronary artery occlusion was determined. Endothelial damage or denudation was shown both by histological examination and by the altered vasodilator response to the endothelium-dependent vasodilator bradykinin (100 nM), which was reversed to vasoconstriction in hearts treated with Triton X100. In contrast, the responses to sodium nitroprusside (100 μM) were unimpaired in these hearts and were not different from control responses. Ventricular ectopic activity was much more pronounced in hearts with endothelial dysfunction (e.g., 3329±361 ventricular premature beats over a 30 min occlusion period compared to 243±34 in controls; P<0.01), and the duration of ventricular tachycardia was greatly increased (1162±391 s v 9±12 s in the controls; P<0.01). Ventricular ectopic activity was still marked when the occlusion was prolonged to 1 h and was still apparent at the end of this 1 h occlusion period. Reperfusion arrhythmias (ventricular tachycardia and ventricular fibrillation) were marked in endothelium-damaged hearts (50%); whereas there were no such arrhythmias after a 30 or 60 min occlusion period in control hearts. Hearts were also preconditioned by a 3 min coronary artery occlusion period 10 min prior to a 30 min coronary artery occlusion. This reduced ventricular ectopic activity in both control and endothelium-damaged hearts to about the same extent (between 80 and 90% suppression).The results suggest that under normal conditions substances generated from endothelial cells protect the myocardium against ventricular arrhythmias both during ischaemia and reperfusion. However, in this species, preconditioning is still possible in hearts from which the coronary vascular endothelium has been removed. If these results can be extrapolated to the clinical situation, it suggests that in patients with endothelial dysfunction ventricular arrhythmias may be more pronounced following a period of ischaemia and especially of reperfusion.

An ultrastructural study of the kidney of normal, copper poisoned and thiomolybdate-treated sheep

Histological, ultrastructural and kidney function techniques were used to assess changes in the kidney of sheep given either copper (Cu) or Cu and the Cu complexing agent thiomolybdate (TM), or TM alone. Kidney function was normal in sheep given Cu and TM together or TM alone. In these animals the cells lining cortical tubules accumulated Cu within numerous, large, electron-dense lysosomes. Sheep given Cu alone developed haemolysis, impaired kidney function and a variety of morphological defects including an increase in number of large lysosomes in cells of the cortical tubules. There was a breakdown of the glomerular endothelial lining and fusion of foot processes. Cells of the cortical tubules showed degeneration and necrosis and an increase in microbodies and rough endoplasmic reticulum. Cortical and medullary blood vessels were dilated, with evidence of breakdown of the endothelial lining. Copper appeared to injure kidney tissue at three sites, tubular epithelium, glomerular basal lamina and capillary blood vessels. Changes reported here are similar to the renal lesions in cadmium toxicity.

The effects of oral zinc supplementation in the mouse

Abstract C3H mice were given zinc sulphate in their drinking water for periods of up to one year. Histological confirmation of hypertrophy of the adrenal cortex and the pancreatic islets after three months was obtained and changes consistent with hyperactivity were noted in the pituitary. Further work is suggested to correlate structural changes with possible functional changes in the islets, the adrenal cortex and the pars distalis. Zinc content of the liver, spleen and skin was not altered. Plasma insulin and glucose concentrations in zinc-supplemented animals were not significantly different from control values.