Endothelin-1 receptor antagonists reduce cardiac electrical instability induced by high glucose in rats

Abstract

Endothelin-1 (ET-1) influences the electrical activity of the heart by causing arrhythmias associated with lengthening of the QT interval in the electrocardiogram. Recent results from our laboratory have shown a primary role for a high plasma glucose concentration in determining cardiac QT prolongation. Since high glucose up-regulates the ET-1 system, the aim of the present study was to determine whether the increase of the QT interval and coronary vascular tone induced by high glucose in the heart involves increased activity of the ET system. Perfusion of isolated hearts with a high glucose concentrations (33.3 mM) prolonged the QT interval significantly and increased coronary perfusion pressure (CPP) ( P<0.01). The increases in the QT interval and CPP induced by high glucose were accompanied by increases in cardiac ET-1 levels, and were significantly reduced by an ET-1 antiserum ( P<0.01). Perfusion of the hearts with the selective ET(A) receptor antagonist FR139317 or with the non-selective ET(A)/ET(B) antagonist SB209670, but not with the selective ET(B) receptor antagonist BQ-788, reduced the glucose-induced QT prolongation. In addition, the increase in cardiac vascular tone, as evidenced by the increase in CPP, induced by high glucose was reversed partially by cardiac perfusion with either the non-selective ET(A)/ET(B) receptor antagonist or the ET(B)-selective BQ-788, whereas the ET(A) antagonist was without effect. By increasing the production of ET-1, a high glucose concentration may activate parallel pathways that contribute to a state of increased vasomotor tone and electrical ventricular instability. Antagonism at cardiac ET receptors could be helpful in these cardiovascular complications of diabetes.

Inhibition of aldose-reductase-2 by a benzofuroxane derivative bf-5m increases the expression of kcne1, kcnq1 in high glucose cultured H9c2 cardiac cells and sudden cardiac death

“…Marfella et al described for the first time the effect of acute hyperglycemia on QTc duration in healthy men [ 27 ]. D’Amico et al in 2001 demonstrated that high glucose levels into the heart induce ventricular instability characterized by QT interval prolongation [ 8 ], an evidence subsequently continued by Di Filippo et al, in 2002 [ 28 ]. More appropriately, Morales-Cano et al, found that hyperglycemia down-regulates KV7 potassium channels at the level of coronary artery influencing their reactivity [ 29 ].…”

Suboptimal Glycemic Control, Independently of QT Interval Duration, Is Associated with Increased Risk of Ventricular Arrhythmias in a High‐Risk Population

“…Hyperglycemia was found to impair the human ether‐a‐go‐go‐related gene (HERG) function by reducing HERG current, and causing significant increases in the intracellular levels of reactive oxygen species 26 . Additionally, hyperglycemia has been shown to upregulate endothelin‐1 levels, which may contribute to electrical instability in the heart 27 …”

Effects of the New Aldose Reductase Inhibitor Benzofuroxane Derivative BF-5m on High Glucose Induced Prolongation of Cardiac QT Interval and Increase of Coronary Perfusion Pressure

“…Of these, 12 were excluded having a sinus rate of <210 beats per minute or a coronary perfusion pressure (CPP) <60 mmHg between 5 and 15 min after beginning of the perfusion; hearts not in sinus rhythm during the study were also excluded. The remaining 70 hearts having a sinus rate of >210 beats per minute or CPP > 60 mmHg, between 5 and 15 min after beginning, were used in the study and divided into the following experimental groups ( n = 10 rats for each group): (i) control: hearts perfused for 2 hours with a Krebs solution containing D-glucose at 11.1 mM [ 4 , 5 ]; (ii) high glu: hearts perfused for 2 hours with Krebs solution containing D-glucose at 33.3 mM [ 4 , 5 ]; (iii) high glu + DMSO: hearts perfused with Krebs solution containing 1% DMSO + D-glucose at 33.3 mM; (iv) high glu + BF-5m: hearts perfused for 2 hours with Krebs solution containing D-glucose at 33.3 mM + BF-5m (0.01 μ M in 1% DMSO); (v) high glu + BF-5m: hearts perfused for 2 hours with Krebs solution containing D-glucose at 33.3 mM + BF-5m (0.05 μ M, in 1% DMSO); (vi) high glu + BF-5m: hearts perfused for two hours with Krebs solution containing D-glucose at 33.3 mM + BF-5m (0.1 μ M, in 1% DMSO). Moreover, in order to assess the role of SIRT1 in the BF-5m cardiac effects additional studies were done on 10 hearts excised from rats pretreated for 7 days (10 mg/kg/day i.p.)…”

“…Temperature was maintained constant by means of a heated (37°C) water jacket. On establishing a stable value (20–30 min following cannulation) CPP was calculated according to Di Filippo et al [ 4 ]. Briefly, CPP value was expressed either as the mean of each 10-min value throughout the entire experiment or as the mean of the steady-state increment above baseline when an increase of CPP was evident during an experiment.…”

“…Among these, the most dangerous consequence of the hyperglycemia is the prolongation of the cardiac QT interval, which leads diabetic patients to sudden death [ 2 ]. Long cardiac QT interval is partly sensitive to antioxidant drugs acting on the nitric oxide bioavailability, glycosylated products, accumulation of reactive oxygen species, and impairment of ionic pumps in models of isolated high glucose perfused heart [ 3 , 4 ]. Increased interest, therefore, has gained the discovery of new drugs that may modulate pathways involved in glucose metabolism and hyperglycemia-induced modifications, in order to produce cardiovascular protection.…”