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 Ca(2+) concentration ([Ca(2+)](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 [Ca(2+)](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 Ca(2+) 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 Ca(2+) disturbances, as well as spatial heterogeneity of myocardial alterations including interstitial fibrosis, probably provide the mechanisms for re-entry and sustaining ventricular fibrillation.
Tribulova
N
N
Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic. usrdtri@savba.sk
Okruhlicova
L
L
Novakova
S
S
Pancza
D
D
Bernatova
I
I
Pechanova
O
O
Weismann
P
P
Manoach
M
M
Seki
S
S
Mochizuki
S
S
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology*; D007008:Hypokalemia / Q000503:physiopathology; D066298:In Vitro Techniques; D015994:Incidence; D007365:Intercellular Junctions / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D018485:Muscle Fibers, Skeletal / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014693:Ventricular Fibrillation / Q000453:epidemiology / Q000473:pathology / Q000503:physiopathology*
D004791:Enzyme Inhibitors; D011188:Potassium; D019331:NG-Nitroarginine Methyl Ester