Abstract
Rats harboring the human renin and angiotensinogen genes (dTGR) feature angiotensin (ANG) II/hypertension-induced cardiac damage and die suddenly between wk 7 and 8. We observed by electrocardiogram (ECG) telemetry that ventricular tachycardia (VT) is a common terminal event in these animals. Our aim was to investigate electrical remodeling. We used ECG telemetry, noninvasive cardiac magnetic field mapping (CMFM) at wk 5 and 7, and performed in vivo programmed electrical stimulation at wk 7. We also investigated whether or not losartan (Los; 30 mg x kg(-1) x day(-1)) would prevent electrical remodeling. Cardiac hypertrophy and systolic blood pressure progressively increased in dTGR compared with Sprague-Dawley (SD) controls. Already by wk 5, untreated dTGR showed increased perivascular and interstitial fibrosis, connective tissue growth factor expression, and monocyte infiltration compared with SD rats, differences that progressed through time. Left-ventricular mRNA expression of potassium channel subunit Kv4.3 and gap-junction protein connexin 43 were significantly reduced in dTGR compared with Los-treated dTGR and SD. CMFM showed that depolarization and repolarization were prolonged and inhomogeneous. Los ameliorated all disturbances. VT could be induced in 88% of dTGR but only in 33% of Los-treated dTGR and could not be induced in SD. Untreated dTGR show electrical remodeling and probably die from VT. Los treatment reduces myocardial remodeling and predisposition to arrhythmias. ANG II target organ damage induces VT.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / metabolism*
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Angiotensin II Type 1 Receptor Blockers / pharmacology
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Angiotensin II Type 1 Receptor Blockers / therapeutic use
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Angiotensinogen / genetics
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Angiotensinogen / metabolism*
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Animals
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Animals, Genetically Modified
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Blood Pressure
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Cardiac Pacing, Artificial
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Cardiomegaly / complications
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Cardiomegaly / etiology
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Cardiomegaly / metabolism
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Cardiomegaly / pathology
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Cardiomegaly / physiopathology
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Cardiomegaly / prevention & control
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Connexin 43 / genetics
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Connexin 43 / metabolism
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Death, Sudden, Cardiac / etiology*
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Death, Sudden, Cardiac / prevention & control
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Disease Models, Animal
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Electrocardiography
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Heart Conduction System / drug effects
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Heart Conduction System / metabolism
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Heart Conduction System / physiopathology*
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Hypertension / complications
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Hypertension / drug therapy
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Hypertension / metabolism
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Hypertension / pathology
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Hypertension / physiopathology*
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Losartan / pharmacology
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Losartan / therapeutic use
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Male
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Myocardium / metabolism
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Myocardium / pathology
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley / genetics
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Renin / genetics
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Renin / metabolism*
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Shal Potassium Channels / genetics
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Shal Potassium Channels / metabolism
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Tachycardia, Ventricular / complications
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Tachycardia, Ventricular / etiology*
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Tachycardia, Ventricular / metabolism
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Tachycardia, Ventricular / physiopathology
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Tachycardia, Ventricular / prevention & control
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Telemetry
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Time Factors
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Ventricular Remodeling* / drug effects
Substances
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Angiotensin II Type 1 Receptor Blockers
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Connexin 43
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RNA, Messenger
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Shal Potassium Channels
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Angiotensinogen
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Angiotensin II
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Renin
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Losartan