Depression of efferent parasympathetic control of heart rate in rats with myocardial infarction: effect of losartan.
Heart failure is associated with attenuation of parasympathetic nervous function and enhanced renin-angiotensin activity. We tested whether there was a dysfunction in the efferent cholinergic neurotransmission in the heart of rats with chronic myocardial infarction (MI) and the potential role of angiotensin II (Ang II) receptors in such changes. Rats with MI and sham-operation were anesthetized, and heart rate (HR) reduction in response to vagal nerve stimulation was measured before and after losartan administration (10 mg/kg, i.v.) in the presence or absence of physostigmine to inhibit acetylcholinesterase. Infarcted rats had an average infarct size (IS) of 38% of the left ventricle (LV), depressed LV dP/dtmax, elevated LVEDP, and cardiac hypertrophy. Nerve stimulation (1-16 Hz) reduced HR in a frequency-dependent manner. The bradycardiac responses were significantly attenuated in infarcted versus control rats (p < 0.01), indicating an impaired efferent vagal tone. In contrast, the bradycardic response to exogenous acetylcholine was similar in both groups, implying an unchanged muscarinic receptor responsiveness in hearts with MI. HR response to nerve stimulation was potentiated by losartan in infarcted rats by 21 +/- 4 versus 4 +/- 2 beats/min (p < 0.01) but was unaffected in control rats. This effect of losartan was inversely related to the extent of attenuation of vagally mediated HR reduction. IS was correlated with both the extent of attenuation in vagally mediated bradycardia and the effect of losartan. In conclusion, the efferent vagal control of HR is attenuated in rats with MI and heart failure. This attenuation may be partly due to a presynaptic inhibition of acetylcholine release through the tonic activation, by Ang II, of neuronal AT1 receptors.
Du
X J
XJ
Alfred and Baker Medical Unit, Baker Medical Research Institute, and Alfred Hospital, Melbourne, Australia.
Cox
H S
HS
Dart
A M
AM
Esler
M D
MD
D000109:Acetylcholine / Q000008:administration & dosage; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000502:physiology; D001919:Bradycardia / Q000188:drug therapy; D006339:Heart Rate / Q000502:physiology*; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014630:Vagus Nerve / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents; D019808:Losartan; D000109:Acetylcholine