Diabetes- and semi-starvation-induced changes in metabolism and regulation of Na,K-ATPase in rat heart.

AIMS/HYPOTHESIS: In comparison with healthy controls, rats with streptozotocin-induced diabetes exhibit retarded gain in body weight. This is generally attributed to lowered protein synthesis resulting from abnormal metabolism. Furthermore, decreased abundance and activity of Na,K-ATPase in heart and skeletal muscle has been described. However, decreased gain in body weight per se is accompanied by a down-regulation of skeletal muscle Na,K-ATPase. Thus, the aim of the present study was to evaluate cardiac Na,K-ATPase in semi-starvation and diabetes. METHODS: Diabetes was induced in male Wistar rats with streptozotocin. In healthy parallel running control rats body weight gain was kept reduced by limited food intake. RESULTS: Semi-starved and diabetic rats demonstrated 18 and 16% (p < 0.05) retarded gain in body weight after 63 days. As compared to semi-starved rats, diabetic animals exhibited a 59-273% (p < 0.05) increase in glucose, glycohaemoglobin, triglyceride and cholesterol plasma levels. Activity of heart K-pNPPase, reflecting Na,K-ATPase, in crude membrane homogenates was reduced by 29 and 10% (p < 0.05) by diabetes and semi-starvation. The age-dependent reduction in heart K-pNPPase in normal controls was 6%. After subtracting the age-dependent change, the reductions were 25 and 4% in diabetes and semi-starvation, respectively. After subtracting the semi-starvation-associated change, the diabetes-induced reduction was 22-27%. The reduction was in accord with measurements of Na,K-ATPase activities in partially purified membranes, Na,K-ATPase isoforms and cytochemical evaluations. Expressed per heart, the reduction in Na,K-ATPase was 30%. CONCLUSIONS/INTERPRETATION: Streptozotocin-induced diabetes selectively reduces heart Na,K-ATPase concentration by around 1/4, which reduces the capacity of the heart for maintaining K- and Ca-homeostasis. This may pose a risk of arrhythmias and may be associated with heart failure in diabetic cardiomyopathy.

Chronic K-supplementation decreases myocardial [Na,K-ATPase] and net K-uptake capacity in rodents.

The effects of high K intake on plasma K, myocardial K content and Na,K-ATPase concentration and on myocardial K uptake during KCl infusion were evaluated in rodents. Myocardial Na,K-ATPase was quantified in crude homogenates by K-dependent pNPPase activity in rats, and in intact samples by3H-ouabain binding in guinea pigs. Na, K-ATPase alpha isoform distribution was assessed by immunoblotting. Plasma K was monitored in anesthetized rats during intravenous infusion of 0.75 mmol KCl/100 g body weight/h. A significant increase in plasma K was observed after 2 days of K supplementation, 4.9+/-0.2 (mean+/-s.e.m.)v 3.0+/-0.2 mmol/l in weight matched controls ( P<0.01,n=5) and this difference remained stable. After 1 day, a significant myocardial K content increase was obtained, 86. 2+/-3.0v 76.7+/-1.9 micromol/g wet weight (P<0.05, n=5); after 4 days myocardial K stabilized 4.9+/-1.2 micromol/g wet weight above control level (P<0.05,n=5). From the 4th day, a significant decrease in myocardial K-dependent pNPPase activity was observed, 1.18+/-0.04v 1. 31+/-0.01 micromol/min/g wet weight in weight matched controls (P<0. 05,n=5); after 2 weeks the decrease was 29% (P<0.05,n=5), with a reduction in alpha1-isoform abundance by 24% (P<0.05,n=5), and a tendency to a decrease in alpha2 of 10% (n.s.,n=5). The measurements were validated by 3H-ouabain binding to myocardial samples from guinea pigs K-supplemented for 2 weeks, showing a decrease of 21% (P<0.05,n=5). During KCl infusion, the myocardial K content increase rate was reduced by 52% (P<0.05) in the K-supplemented rats. The observed effects of K-supplementation on plasma K, myocardial K content and myocardial K-dependent pNPPase activity were abolished within 2 days after reallocation to chow with normal K content. In conclusion, high K-intake is associated with significantly and reversible increased plasma and myocardial K content, and decreased myocardial Na,K-ATPase concentration and net myocardial K uptake capacity. Thus, the heart is protected from major increases in intracellular K concentrations during chronically-high K-intake.

[Local intra-arterial thrombolysis in acute ischemia of an extremity]. / Lokal intraarteriel trombolyse ved akut ekstremitetsiskaemi.

The effect of intra-arterial local thrombolysis or peripheral arterial occlusions seems to be well documented. As assessed by angiography, primary recanalisation is achieved in 65-90%. Using recombinant tissue plasminogen activator thrombolysis is achieved more frequently (90% vs 65-85%) and faster (4-8 hours vs 12-48 hours) than when using streptokinase or urokinase. The most frequently used dosages are streptokinase 5000 IU/h, and recombinant tissue plasminogen activator 0.5 mg/h. So far, results from randomized trials between thrombolytic therapy and surgery have not been published.

[Thrombolytic therapy in acute lower extremity ischemia]. / Trombolysebehandling ved akut underekstremitetsiskaemi.

During a period of four and a half years 37 lower extremities with acute ischaemia were treated with thrombolysis. Angiographically, 35 cases demonstrated no suitable arteries for distal reconstruction. In two cases vascular surgery was not performed because of cardiac incompensation. Two patients died within one month and limb salvage was 69%. During 22 months (3-48) of follow-up another six patients were amputated two to nine months later. The 18 salvaged lower extremities (49%) had an ankle-brachial pressure index of 0.63 (0.30-1.-09). Review of all angiograms revealed a demonstrable effect of thrombolytic therapy only in 13 (35%) cases. In conclusion, thrombolytic therapy should be considered in the case of acute lower extremity ischaemia unsuitable for reconstructive procedures. Even though the effect of thrombolytic therapy cannot be demonstrated on the angiogram, that should not necessarily deem the treatment to be a failure.