© 1998 American Heart Association, Inc.
Original Contributions |
Depressed Heart Rate Variability and Arterial Baroreflex in Conscious Transgenic Mice With Overexpression of Cardiac Gs
From the Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences (M.U., K.A., A.S., N.S., Y.I., D.E.V., R.P.S., S.F.V.), Pittsburgh, Pa; the Department of Molecular and Cellular Biology, The Edison Institute, Ohio University (T.E.W.), Athens, Ohio; the First Department of Internal Medicine, Nippon Medical School (M.O., H.H.), Tokyo, Japan; and COR Therapeutics (C.J.H.), South San Francisco, Calif.
Correspondence to Stephen F. Vatner, MD, George J. Magovern Chair and Director, Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, 320 East North Ave, Pittsburgh, PA 15212.
Abstract—Recently, we developed a
transgenic mouse with cardiac-specific Gs
overexpression (TG mouse), which exhibits enhanced postsynaptic
ß-adrenergic receptor signaling, ultimately developing a
cardiomyopathy. The goal of the present study
was to determine whether cardiac Gs
overexpression alters autonomic cardiovascular control,
which could shed light on the mechanism responsible for the later
development of cardiomyopathy. Mean
arterial pressure was increased (P<.05) in
conscious, chronically instrumented TG mice (123±1 mm Hg)
compared with age-matched wild-type (WT) control mice (103±1
mm Hg). Respiratory frequency was increased (P<.05) in
TG mice (269±26/min) compared with WT mice (210±20/min). By use of
telemetric techniques, baseline heart rate (HR) was elevated
(P<.05) in conscious, untethered TG mice (696±13 bpm)
compared with WT mice (568±28 bpm). Intrinsic HR, after
propranolol and atropine or after ganglionic blockade with
hexamethonium, was not different between TG and WT
mice. Both the normal minute-to-minute and circadian variations of HR
observed in WT mice were markedly blunted in TG mice. HR variability
was assessed by the time-domain and frequency-domain methods. At
baseline, time-domain analysis indices were reduced
(P<.05) in TG mice compared with WT mice. Although the
low frequency (LF) component was higher (P<.05) than
the high frequency (HF) component in WT mice, the LF component was less
(P<.05) than the HF component in TG mice. In addition,
arterial baroreflex regulation of HR was markedly blunted
in TG mice in response to both nitroglycerin-induced
hypotension and phenylephrine-induced hypertension. The
reduced LF/HF ratio in TG mice was surprising in view of enhanced
ß-adrenergic signaling and may be due to reduced neural tone
secondary to the elevated arterial pressure or alterations
in arterial baroreflex control. Dobutamine
infusion in WT mice also resulted in depressed HR variability. The
combination of elevated baseline HR, arterial pressure, and
respiratory frequency suggests that enhanced ß-adrenergic signaling
in TG mice results in reduced HR variability, in terms of both
minute-to-minute variability and the lack of circadian variations in
HR. The lack of normal HR variability in general and the failure of HR
to decline, even during sleep, may actually be critical mechanisms
contributing to the ultimate development of
cardiomyopathy in these animals.
Key Words: spectral analysis • sympathetic nervous system • ß-adrenergic receptor • circadian rhythm • arterial baroreflex
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