A calcium-channel blocker, amlodipine, attenuates insulin antinatriuresis but does not modulate insulin-mediated attenuation of cardiovascular reactivity in healthy man

Background: Insulin exerts an antinatriuretic effect when administered acutely in vivo. Interestingly, insulin fails to reduce sodium excretion in rats receiving verapamil. The present study was undertaken in order to investigate whether the calcium-channel blocker amlodipine attenuates the antinatriuretic effect of insulin in humans. Method: Eight healthy lean men (32±2 years) were investigated on three different occasions; i.e. time-control, insulin infusion alone, and insulin infusion following pretreatment with amlodipine (5 mg x 1 during 10 days). During the experiments renal haemodynamics (insulin and PAH clearances) and segmental tubular sodium handling (sodium and lithium clearances) were investigated. The cardiovascular reactivity was also assessed by a graded noradrenaline infusion at the end of each experiment. Results: Insulin infusion alone was accompanied by a significant 50% reduction in urinary sodium excretion. Following amlodipine pretreatment, euglycaemic insulin infusion was associated with an attenuated antinatriuretic response and the cumulative sodium excretion following 135 min of insulin infusion was significantly higher (24±4 vs 18± mmol; P <0.05) as compared to insulin infusion alone. No significant differences in the proximal and distal tubular sodium handling respectively, were seen following CCB pretreatment. The results also show that the doses of noradrenaline required to increase the basal mean arterial blood pressure by 10 mmHg (262±38 vs 150±25 ng/g/min; p <0.05) and by 20 mmHg (431±36 vs 350±38 ng/kg/min; P<0.05) respectively, were significantly higher during the insulin infusion than during the time-control experiment. Pretreatment with amlodipine did not further modulate the cardiovascular reactivity. Conclusion: Pretreatment with a calcium-channel blocker, amlodipine, attenuates the antinatriuretic effects of insulin leading to a significantly higher cumulative sodium excretion at the end of insulin infusion, which may be of clinical importance. Moreover, insulin attenuates the cardiovascular reactivity to a graded noradrenaline infusion, suggesting that insulin causes vasodilatation in healthy man.     

Reduction of Blood Pressure Retards the Progression of Chronic Renal Failure in Man

The effect of blood pressure reduction on the progression rateof chronic renal failure (CRF) was studied in 28 patients withCRF of diverse aetiology entering a prospective study (observationtime 7–24 months, mean 16 months). Endogenous creatinineclearance was 12–66 ml/mm (mean 30±3 ml/mm). Weaimed to keep the blood pressure below 160/90 mmlHg. Dietaryprotein was not restricted. The progression rate of CRF wasassessed from the regression coefficients of the regressionsof creatinine clearance and the inverse of s-creatinine, respectively,on time. Progression rate and the means of all recordings ofmean arterial blood pressure (MAP) and urinary protein excretion,respectively, in each patient during the prospective phase werecompared with retro spective data from the proceeding period(observation time 4–25 months, mean 19 months). The patientsreceived various combinations of antihypertensive drugs includingdiuretics, beta-blockers and vasodilatory drugs. In 19 patientsMAP decreased from 109±2 to 102±2 mmHg (groupI), whereas MAP increased from 105±2 to l08±2mmHgin nine patients (group II). In group I proteinuria was significantlylower (P<0.05) and the progression of CRF was approximately50% slower (P.<0.01) in the prospective phase than in theretrospective phase; no changes were observed in group II. Calculatedfor all patients, significant correlations were observed betweenthe change in MAP and the change in progression rate and proteinexcretion, respectively. These results indicate that loweringof blood pressure results in decreased proteinuria and retardationof the progression of CRF irrespective of the aetiology.     

Effects of high doses of glucocorticoids on free amino acids,ribosomes and protein turnover in human muscle

BACKGROUND: Treatment with glucocorticosteroids causes a negative nitrogen balance, but the kinetic mechanisms responsible for this catabolic effect are controversial. We investigated the effects of 60 mg day(-1) prednisolone on protein synthesis and degradation in human skeletal muscle. MATERIALS AND METHODS: Healthy adults (n = 9) were studied in the postabsorptive state, before and after 3 days of prednisolone treatment. The L-[ring 2,6(-3)H(5)]-phenylalanine tracer technique, concentration and size distribution of the ribosomes, mRNA content of the ubiquitin-proteasome pathway components in muscle, phenylalanine flux across the leg, and the free amino acid concentrations in skeletal muscle were used to study muscle protein metabolism. RESULTS: The concentrations of most amino acids in arterial blood increased after prednisolone. There were also increased effluxes of phenylalanine, asparagine, arginine, alanine, methionine and isoleucine from the leg. The rate of protein degradation, as measured by the appearance rate (Ra) of phenylalanine, increased by 67% (P = 0.023) which, together with a doubling of the net release of phenylalanine from the leg (P = 0.007), indicated accelerated protein degradation. The pathway was not identified but there was no significant increase in mRNAs' encoding components of the ubiquitin-proteasome pathway. There was a 6% reduction in polyribosomes (P = 0.007), suggesting a decrease in the capacity for protein synthesis, although there was no measured decrease in the rate of protein synthesis. CONCLUSIONS: These findings indicate that high doses of prednisolone lead to a sharp increase in net protein catabolism, which depends more on enhanced protein breakdown, and an uncertain effect on protein synthesis. The mechanisms stimulating proteolysis and the pathway stimulated to increase muscle protein degradation should be explored.     

Effects of insulin on renal haemodynamics and the proximal and distal tubular sodium handling in healthy subjects

Summary The effects of insulin on renal haemodynamics and renal sodium handling were studied in 10 healthy males. Using the euglycaemic insulin clamp technique, insulin was infused on separate days resulting in two levels of hyperinsulinaemia (41 ± 3 and 90 ± 7 mU/1, respectively). Renal haemodynamics and the proximal and distal tubular sodium handling were studied using inulin, para-amino-hippuric acid, sodium and lithium clearances. Low- and high-dose insulin infusions were followed by a fall in sodium clearance from 1.6 ± 0.1 ml/min to 1.2 ± 0.1 and 1.0 ± 0.1 ml/min, respectively. Both levels of hyperinsulinaemia resulted in increased distal tubular sodium reabsorption. The distal antinatriuretic effect of insulin was associated with dose- and time-dependent decline in proximal tubular sodium reabsorption. The changes in proximal tubular sodium handling occurred without any significant changes in natriuretic factors, such as renal dopamine and plasma atrial natriuretic peptide levels. However, hyperinsulinaemia resulted in time- and dose-dependent increases in renal plasma flow, and renal vasodilatation could, possibly via changes in renal interstitial pressure, have contributed to the fall in the proximal tubular sodium reabsorption. The results also suggest that decreased proximal sodium reabsorption may be a compensatory mechanism counteracting the insulin-induced sodium retention.     

Insulin resistance in uremia.

Tissue sensitivity to insulin was examined with the euglycemic insulin clamp technique in 17 chronically uremic and 36 control subjects. The plasma insulin concentration was raised by approximately 100 microU/ml and the plasma glucose concentration was maintained at the basal level with a variable glucose infusion. Under these steady-state conditions of euglycemia, the glucose infusion rate is a measure of the amount of glucose taken up by the entire body. In uremic subjects insulin-mediated glucose metabolism was reduced by 47% compared with controls (3.71 +/- 0.20 vs. 7.38 +/- 0.26 mg/kg . min; P less than 0.001). Basal hepatic glucose production (measured with [3H]-3-glucose) was normal in uremic subjects (2.17 +/- 0.04 mg/kg . min) and suppressed normally by 94 +/- 2% following insulin administration. In six uremic and six control subjects, net splanchnic glucose balance was also measured directly by the hepatic venous catheterization technique. In the postabsorptive state splanchnic glucose production was similar in uremics (1.57 +/- 0.03 mg/kg . min) and controls (1.79 +/- 0.20 mg/kg . min). After 90 min of sustained hyperinsulinemia, splanchnic glucose balance reverted to a net uptake which was similar in uremics (0.42 +/- 0.11 mg/kg . min) and controls (0.53 +/- 0.12 mg/kg . min). In contrast, glucose uptake by the leg was reduced by 60% in the uremic group (21 +/- 1 vs. 52 +/- 8 mumol/min . kg of leg wt; P less than 0.005) and this decrease closely paralleled the decrease in total glucose metabolism by the entire body. These results indicate that: (a) suppression of hepatic glucose production by physiologic hyperinsulinemia is not impaired by uremia, (b) insulin-mediated glucose uptake by the liver is normal in uremic subjects, and (c) tissue insensitivity to insulin is the primary cause of insulin resistance in uremia.     

Intracellular pH and bicarbonate concentration as determined in biopsy samples from the quadriceps muscle of man at rest.

1. A method for measuring intracellular pH and bicarbonate concentration of human muscle is described. 2. Muscle biopsies from the quadriceps muscle of 13 healthy subjects at rest were analysed for acid-labile carbon dioxide and volume of extra- and intra-cellular water. Extracellular water volume was estimated from the chloride content and intracellular water volume from the potassium content, or alternatively derived from the sample weight. 3. The measured total carbon dioxide content in muscle was 9-84+/-1-39 mmol/kg. 4. Assuming a normal membrane potential (88 mV) and PCO2 of muscle equal to venous blood, calculated intracellular pH was 7-00+/-0-06 and intracellular bicarbonate concentration was 10-2+/-1-2 mmol/l of water.     

Elevated concentration of 5-hydroxytryptamine in ultrafiltrate of human liver vein plasma after infusion of amino acids

Intragastric infusion of amino acids causes the release from the liver of a factor with stimulatory effect on smooth muscle. The effect of liver vein plasma ultrafiltrate was tested on isolated preparations of rat fundus. The ultrafiltrates collected after amino acid infusion had a 3-5 times higher stimulatory effect on smooth muscle contraction than those collected from control plasma. The active principle was isolated, purified by different chromatographic procedures and identified as 5-hydroxytryptamine (serotonin). No other compound with contractile effect on smooth muscle was detected.     

Dissolving intravenous cyclosporin A in a fat emulsion carrier prevents acute renal side effects in the rat

Cyclosporin A (CyA)-induced nephrotoxicity is still a serious clinical problem. The nephrotoxicity seems to be more pronounced when CyA (solubilized in water with Cremophore EL, as in Sandimmun) is given intravenously than when it is given orally. Using soybean oil in which CyA was dissolved, we prepared an intravenous fat emulsion without an artificial detergent, such as Cremophore EL. The renal effects of our new formula were compared with those of Sandimmun and Cremophore EL in a rat model. CyA in the fat emulsion did not significantly affect the glomerular filtration rate (GFR). Both Sandimmun and Cremophore EL significantly reduced the GFR. These results suggest that a change in the vehicle may obviate the acute nephrotoxic side effects caused by intravenous administration of CyA solubilized by Cremophore EL.     

Colour vision and light sensitivity in tunnel workers previously exposed to acrylamide and N-methylolacrylamide containing grouting agents

OBJECTIVES: The aim of the study was to examine possible persisting visual system effects in tunnel workers previously exposed to acrylamide and N-methylolacrylamide during grouting work. MATERIAL AND METHODS: Visual field light sensitivity threshold and colour vision has been examined among 44 tunnel workers 2-10 years after exposure to acrylamide and N-methylolacrylamide containing grouting agents. Forty-four tunnel workers not involved in grouting operations served as control group. Information on exposure and background variables was obtained for all participants from a questionnaire. Visual light sensitivity threshold was measured using Humphrey Visual Field Static Perimeter 740, program 30-2 Fastpack, with red stimuli on white background, and colour vision, using Lanthony D-15 Desaturated Color test. Based on D-15d test results, colour confusion index (CCI), and a severity index (C-index) was calculated. RESULTS: The exposed group had a significantly higher threshold for detecting single stimuli in all parts of the inner 30 degrees of the visual field compared to the control group. The foveal threshold group difference was 1.4 dB (p=0.002) (mean value, both eyes). On the Lanthony 15 Hue Desaturated test, the exposed subjects made more errors in sorting blue colours, and a statistically significant increase in C-index was observed. Surrogate measures for duration and intensity of exposure gave no further improvement of the model. CONCLUSIONS: The results indicate slightly reduced light sensitivity and reduced colour discrimination among the exposed subjects compared to the controls. The findings may be due to previous exposure to acrylamide containing grouts among the tunnel workers.     

Hemodynamic effects of endothelin-1 and big endothelin-1 in chronic hemodialysis patients

Increased plasma concentrations of endothelin-1 (ET-1) and big endothelin-1 (big ET-1) have been reported in patients with end-stage renal failure (ESRD). In the present study, which included hemodialysis (HD) patients with (n = 21) and without (n = 32) ischemic heart disease, the putative association between plasma levels of ET-1 and big ET-1 and ischemic heart disease and the influence of the dialysis procedure on ET concentrations was investigated. This study also examined in an additional five HD patients without cardiac disease whether intravenously infused ET-1 and big ET-1 (0.2, 1, and 4 pmol/kg per min, each dose for 20 min) preserve their vasoactive potency and whether exogenous big ET-1, which in healthy humans is converted in the kidney, is still converted to ET-1 in ESRD. HD patients with ischemic heart disease demonstrated higher plasma levels of ET-1 and big ET-1 than HD patients without this disorder, and HD reduced plasma ET-1 and big ET-1 concentrations. In HD patients, the big ET-1 infusion, resulting in a 1.5-fold increase in plasma ET-1, caused a more marked and prolonged rise in mean arterial BP than ET-1 (20% versus 13%, P = 0.0001) and a slightly smaller but more prolonged decrease in estimated splanchnic blood flow than ET-1 (37% versus 44%, P = 0.02). Furthermore, big ET-1 lowered heart rate by 9% (P = 0.01) but ET-1 did not. Plasma half-lives of ET-1 and big ET-1 were longer in HD patients than in healthy humans. Thus, ET-1 and big ET-1 preserve their vasoactive potency, and circulating big ET-1 is still converted to active ET-1 in ESRD. Consequently, the increased plasma levels of ET-1 and big ET-1 noted in HD patients, especially in patients with ischemic heart disease, might play a role in the development of uremic cardiovascular complications.