N Gondo1, K Kumagai, H Nakashima, K Saku. 1. Department of Second Internal Medicine, School of Medicine, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, 814-0180, Fukuoka, Japan.
Abstract
OBJECTIVE: The purpose of this study was to investigate whether angiotensin II provokes ventricular tachyarrhythmias and to clarify its mechanism using the cesium-induced arrhythmia model, which has been widely used as an afterdepolarization and triggered activity model. METHODS: Eighteen adult mongrel dogs of either sex weighing 9.6-23.0 kg were studied. The dogs were randomly divided into three groups. In the control group (n=6), the subjects received intravenous saline solution at a 0.45 ml/kg/h, and intravenous bolus injections of cesium (0.25, 0.5, 1.0 mmol/kg) were given at 20-min intervals. In the captopril-treated group (n=6), captopril was administered intravenously at 15 microg/kg/min, and cesium was injected as above. After the infusion of only captopril, in the captopril-treated group, angiotensin II was simultaneously infused at a dose of 0.1 ng/kg/min, and cesium was injected as above. When the dog survived, the dose of angiotensin II was increased to 1.0 ng/kg/min, and the same procedure was repeated. The remaining six dogs were simultaneously infused with captopril (15 microg/kg/min), angiotensin II (1.0 ng/kg/min), and U-73122 (10 microg/kg/min), a selective phospholipase C blocker, and injected with cesium (1.0 mmol/kg). Forty minutes after termination of U-73122 infusion, the dogs were injected with the same dose of cesium. RESULTS: Sustained ventricular tachycardia or ventricular fibrillation was induced by cesium in all of the dogs in the control group. In the captopril-treated group, none of the dogs showed these arrhythmias when only captopril was infused. The treatment of captopril significantly reduced lethal arrhythmias (P<0.01 vs. control group). During the simultaneous infusion of captopril and angiotensin II (0.1 ng/kg/min), cesium produced sustained ventricular tachycardia in all six dogs and the arrhythmia developed into ventricular fibrillation in three dogs. By increasing the dose of angiotensin II (1.0 ng/kg/min), the surviving three dogs died following induced ventricular fibrillation. The additional infusion of angiotensin II (0.1 and 1.0 ng/kg/min) significantly increased fatal arrhythmias (P<0.01 vs. only captopril- infused period, respectively). None of the dogs in the third group exhibited ventricular tachycardia during the infusion of U-73122, and ventricular fibrillations were recorded in all six dogs in the absence of U-73122. The treatment of U-73122 significantly reduced lethal arrhythmias. (P<0.01 vs. control period). CONCLUSIONS: These results suggest that angiotensin II provokes cesium-induced ventricular tachyarrhythmias by increasing calcium release from sarcoplasmic reticulum in myocytes via activation of a phosphatidylinositol response.
OBJECTIVE: The purpose of this study was to investigate whether angiotensin II provokes ventricular tachyarrhythmias and to clarify its mechanism using the cesium-induced arrhythmia model, which has been widely used as an afterdepolarization and triggered activity model. METHODS: Eighteen adult mongrel dogs of either sex weighing 9.6-23.0 kg were studied. The dogs were randomly divided into three groups. In the control group (n=6), the subjects received intravenous saline solution at a 0.45 ml/kg/h, and intravenous bolus injections of cesium (0.25, 0.5, 1.0 mmol/kg) were given at 20-min intervals. In the captopril-treated group (n=6), captopril was administered intravenously at 15 microg/kg/min, and cesium was injected as above. After the infusion of only captopril, in the captopril-treated group, angiotensin II was simultaneously infused at a dose of 0.1 ng/kg/min, and cesium was injected as above. When the dog survived, the dose of angiotensin II was increased to 1.0 ng/kg/min, and the same procedure was repeated. The remaining six dogs were simultaneously infused with captopril (15 microg/kg/min), angiotensin II (1.0 ng/kg/min), and U-73122 (10 microg/kg/min), a selective phospholipase C blocker, and injected with cesium (1.0 mmol/kg). Forty minutes after termination of U-73122 infusion, the dogs were injected with the same dose of cesium. RESULTS: Sustained ventricular tachycardia or ventricular fibrillation was induced by cesium in all of the dogs in the control group. In the captopril-treated group, none of the dogs showed these arrhythmias when only captopril was infused. The treatment of captopril significantly reduced lethal arrhythmias (P<0.01 vs. control group). During the simultaneous infusion of captopril and angiotensin II (0.1 ng/kg/min), cesium produced sustained ventricular tachycardia in all six dogs and the arrhythmia developed into ventricular fibrillation in three dogs. By increasing the dose of angiotensin II (1.0 ng/kg/min), the surviving three dogs died following induced ventricular fibrillation. The additional infusion of angiotensin II (0.1 and 1.0 ng/kg/min) significantly increased fatal arrhythmias (P<0.01 vs. only captopril- infused period, respectively). None of the dogs in the third group exhibited ventricular tachycardia during the infusion of U-73122, and ventricular fibrillations were recorded in all six dogs in the absence of U-73122. The treatment of U-73122 significantly reduced lethal arrhythmias. (P<0.01 vs. control period). CONCLUSIONS: These results suggest that angiotensin II provokes cesium-induced ventricular tachyarrhythmias by increasing calcium release from sarcoplasmic reticulum in myocytes via activation of a phosphatidylinositol response.
Authors: Alicia C Reid; Jacqueline A Brazin; Christopher Morrey; Randi B Silver; Roberto Levi Journal: Curr Pharm Des Date: 2011-11 Impact factor: 3.116