Beneficial versus harmful effects of Angiotensin (1-7) on impulse propagation and cardiac arrhythmias in the failing heart.
BACKGROUND
The presence of Angiotensin (1-7) (Ang 1-7) and ACE 2 in the ventricle of cardiomyopathic hamsters as well as the influence of Ang (1-7) on membrane potential, impulse propagation and cardiac excitability were investigated.


METHODS
Histology and immunochemistry were used to demonstrate the presence of Ang (1-7) and ACE 2 in the ventricle of cardiomyopathic hamsters. Measurements of transmembrane potentials, conduction velocity and refractoriness were made using conventional intracellular microelectrodes. The influence of Ang (1-7) on sodium pump current was investigated in voltageclamped myocytes isolated from the ventricle.


RESULTS
The results indicated the presence of Ang (1-7) and ACE 2 in myocytes of cardiomyopathic hamsters. Moreover,Ang (1-7) (10(-8) M) hyperpolarised the heart cell, increased the conduction velocity, and reduced transiently the action potential duration. The cardiac refractoriness was also increased by the heptapeptide, an effect in part reduced by an inhibitor of mas receptor. These findings indicate that Ang (1-7) has important antiarrhythmic properties. However, the beneficial effects of Ang (1-7) are dose-dependent because at higher concentration (10(-7) M) the heptapeptide elicited an appreciable increase of action potential duration and early-after depolarisations. Since losartan (10(-7) M) did not counteract this effect of the high dose of the heptapeptide, it is possible to conclude that activation of AT(1)-receptors is not involved in this effect of Ang (1-7). To investigate the mechanism of the hyperpolarising action of Ang (1-7) the influence of the heptapeptide on the sodium potassium pump current was studied in myocytes isolated from the ventricle of cardiomyopathic hamsters. The peak pump current density was measured under voltage clamp using the whole cell configuration. The results indicated that Ang (1-7) (10(-8) M) enhanced the electrogenic sodium pump, an effect suppressed by ouabain (10(-7) M).


CONCLUSIONS
Ang (1-7) has beneficial effects on the failing heart by activating the sodium pump, hyperpolarising the cell membrane and increasing the conduction velocity. These effects as well as the increment of refractoriness indicate that Ang (1-7) has antiarrhythmic properties. At higher concentrations (10(-7) M), however, the heptapeptide induced early-after depolarisations which leads to the conclusion that an optimal generation of Ang (1-7) must be achieved to permit a protective role of Ang (1-7) on cardiac arrhythmias.
De Mello
Walmor C
WC
Department of Pharmacology, Medical Sciences Campus, School of Medicine, UPR, PR, USA. wmello@rcm.upr.edu
Ferrario
Carlos M
CM
Jessup
Jewell A
JA
D000803:Angiotensin I / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D009202:Cardiomyopathies / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D006224:Cricetinae; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects*; D007150:Immunohistochemistry; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000473:pathology; D010446:Peptide Fragments / Q000627:therapeutic use*; D015222:Sodium Channels / Q000187:drug effects
D000959:Antihypertensive Agents; D010446:Peptide Fragments; D015222:Sodium Channels; D000803:Angiotensin I; C118790:angiotensin I (1-7)