Dissociation between ACE activity and autonomic response to ACE inhibition in patients with heart failure.
BACKGROUND
Administration of angiotensin-converting enzyme (ACE) inhibitors to patients with congestive heart failure has been shown to increase parasympathetic tone as indicated by increases in high-frequency heart rate variability. The mechanism for this effect, including its relation to changes in baroreflex activity, blood pressure variability, and suppression of ACE activity, remains undefined. This study was designed to test the relation of these variables, which may govern changes in autonomic activity, to the previously described increase in parasympathetic tone.


METHODS
Seven patients with heart failure received a 3-hour infusion of the ACE inhibitor enalaprilat. Hemodynamic variables and parameters of heart rate and blood pressure variability, baroreflex gain derived from the interaction of heart rate and blood pressure variability, and serum ACE activity were measured during and after the infusion. Measures of heart rate and blood pressure variability were also compared against a historic control group.


RESULTS
Serum ACE activity was significantly suppressed throughout and after enalaprilat infusion. Hemodynamic measures did not change other than a small decline in right atrial and pulmonary capillary wedge pressures. Parasympathetic tone showed an initial significant increase with a peak at 2 hours but then declined below baseline 8 hours after initiation of enalaprilat infusion. Sympathetically influenced low-frequency heart rate variability was significantly increased above baseline in the enalaprilat treatment group 8 hours after initiation of the infusion. Baroreflex gain showed a significant trend to an increase with the maximum value coinciding with the peak in parasympathetic tone. There was no change in blood pressure variability in the enalaprilat group and no change in baroreflex gain, heart rate variability, or blood pressure variability in the control group.


CONCLUSIONS
Parasympathetic tone and baroreflex gain increased with parenteral administration of an ACE inhibitor but subsequently decreased below baseline values despite continued suppression of serum ACE activity. The dissociation between ACE suppression and autonomic response to ACE inhibition indicates that enzyme systems not reflected by plasma ACE activity or independent from the classic pathways of angiotensin formation contribute to the regulation of the autonomic response to ACE inhibition in patients with heart failure. The absence of significant change in hemodynamic variables or in blood pressure variability indicates that these autonomic changes are not an indirect reflex response to ACE inhibitor-induced vasodilation or hemodynamic baroreceptor stimulation.
Binkley
P F
PF
Ohio State University, Columbus 43210, USA. Binkley-1@Medctr.Osu.Edu
Nunziata
E
E
Haas
G J
GJ
Starling
R C
RC
Leier
C V
CV
Cody
R J
RJ
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001341:Autonomic Nervous System / Q000187:drug effects / Q000502:physiology; D017704:Baroreflex / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects*; D004334:Drug Administration Schedule; D015773:Enalaprilat / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011336:Probability; D012016:Reference Values
D000806:Angiotensin-Converting Enzyme Inhibitors; D015773:Enalaprilat