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Hypertension‐Related Intermyocyte Junction Remodelling is Associated with a Higher Incidence of Low‐K+‐Induced Lethal Arrhythmias in Isolated Rat Heart

The aim of this study was to characterise the arrhythmogenic mechanisms involved in hypokalaemia‐induced sustained ventricular fibrillation (SVF), in hypertensive rats. The hearts from rats with hypertension induced by the nitric oxide synthase inhibitor L‐NAME, and age‐matched normotensive controls, were perfused in Langendorff mode with oxygenated Krebs‐Henseleit solution followed by a K+‐deficient solution. In additional experiments, free intracellular Ca2+ concentration ([Ca2+]i) was measured using fura‐2 in conjunction with an epicardial optical probe. The epicardial electrocardiogram was continuously monitored during all experiments. The gap junction protein connexin‐43 and the ultrastructure of the cardiomyocytes were examined, and selected enzyme activities were measured in situ. There was a higher incidence of low‐K+‐induced SVF in the hearts of hypertensive compared to normotensive rats (83% vs. 33%, P < 0.05). Perfusion with a low‐K+‐containing solution lead to elevation of diastolic [Ca2+]i that was accompanied by premature beats, bigeminy, ventricular tachycardia and transient ventricular fibrillation. These events occurred earlier with increased incidence and duration in the hearts of hypertensive rats (arrhythmia scores: hypertensive, 4.9 ± 0.7; normotensive, 3.1 ± 0.1; P < 0.05), which exhibited apparent remodelling accompanied by a significant decrease in the density of connexin‐43‐positive gap junctions. Moreover, low‐K+‐related myocardial changes, including local impairment of intermyocyte junctions, ultrastructural alterations due to Ca2+ overload and intercellular uncoupling, and decreased enzyme activities were more pronounced and more dispersed in hypertensive than normotensive rats. In conclusion, nitric oxide‐deficient hypertension is associated with decreased myocardial coupling at gap junctions. The further localised deterioration of junctional coupling, due to low‐K+‐induced Ca2+ disturbances, as well as spatial heterogeneity of myocardial alterations including interstitial fibrosis, probably provide the mechanisms for re‐entry and sustaining ventricular fibrillation.