Dietary n-3 polyunsaturated fatty acids and direct renin inhibition improve electrical remodeling in a model of high human renin hypertension.

Abstract

We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls. We performed electrocardiographic, magnetocardiographic, and programmed electrical stimulation. Dietary n-3 PUFAs increased the cardiac content of eicosapentaenoic and docosahexaenoic acid. At week 7, mortality in dTGRs was 31%, whereas none of the n-3 PUFA- or aliskiren-treated dTGRs died. Systolic blood pressure was modestly reduced in n-3 PUFA-treated (180+/-3 mm Hg) compared with dTGRs (208+/-5 mm Hg). Aliskiren-treated dTGRs and Sprague-Dawley rats were normotensive (110+/-3 and 119+/-6 mm Hg, respectively). Both n-3 PUFA-treated and untreated dTGRs showed cardiac hypertrophy and increased atrial natriuretic peptide levels. Prolonged QRS and QT(c) intervals and increased T-wave dispersion in dTGRs were reduced by n-3 PUFAs or aliskiren. Both treatments reduced arrhythmia induction from 75% in dTGRs to 17% versus 0% in Sprague-Dawley rats. Macrophage infiltration and fibrosis were reduced by n-3 PUFAs and aliskiren. Connexin 43, a mediator of intermyocyte conduction, was redistributed to the lateral cell membranes in dTGRs. n-3 PUFAs and aliskiren restored normal localization to the intercalated disks. Thus, n-3 PUFAs and aliskiren improved electrical remodeling, arrhythmia induction, and connexin 43 expression, despite a 70-mm Hg difference in blood pressure and the development of cardiac hypertrophy.

• Authors: Robert Fischer, Ralf Dechend, Fatimunnisa Qadri, Marija Markovic, Sandra Feldt, Florian Herse, Joon-Keun Park, Andrej Gapelyuk, Ines Schwarz, Udo B Zacharzowsky, Ralph Plehm, Erdal Safak, Arnd Heuser, Alexander Schirdewan, Friedrich C Luft, Wolf-Hagen Schunck, Dominik N Muller
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 51 Issue 2 Pg. 540-6 (Feb 2008) ISSN: 1524-4563 [Electronic] United States
• PMID: 18158339 (Publication Type: Journal Article)

Chemical References

• Amides
• Antihypertensive Agents
• Connexin 43
• Dietary Fats
• Fatty Acids, Omega-3
• Fumarates
• Angiotensinogen
• aliskiren
• Renin

Topics

• Amides (pharmacology)
• Angiotensinogen (genetics, metabolism)
• Animals
• Animals, Genetically Modified
• Antihypertensive Agents (pharmacology)
• Arrhythmias, Cardiac (etiology)
• Blood Pressure (drug effects)
• Cardiac Pacing, Artificial
• Cardiomegaly (etiology)
• Connexin 43 (metabolism)
• Dietary Fats (pharmacology)
• Disease Models, Animal
• Electrocardiography
• Electrophysiology
• Fatty Acids, Omega-3 (pharmacology)
• Fumarates (pharmacology)
• Humans
• Hypertension (complications, metabolism, mortality, physiopathology)
• Magnetocardiography
• Male
• Rats
• Rats, Sprague-Dawley
• Renin (antagonists & inhibitors, genetics, metabolism)
• Up-Regulation