Transgenic manipulation of the b-adrenergic receptor kinase 1 (
bark1) modifies contractile responsiveness to b1-adrenergic
stimulation in single cardiac myocytes.
Korzick, Donna H., Rui-Ping Xiao, Bruce D. Ziman, Walter J.
Koch[acute]a, Robert J. Lefkowitz, and Edward G. Lakatta.
Laboratory of Cardiovascular Science, GRC, NIA, NIH, Baltimore MD
and Departments of Surgery and Medicine[acute]a and the Howard Hughes
Medical Institute, Duke University, Durham NC
APStracts 3:0455H, 1996.
To determine the direct functional significance of the b-adrenergic
receptor kinase 1 (bARK1) on myocardial performance in the absence of
tonic sympathoadrenal neural activation and mechanical loading, we
measured the contractile responses to acute b1-adrenergic receptor
(b1-AR) stimulation in left ventricular myocytes isolated from non
-transgenic control (NTG) and transgenic mice overexpressing either
bARK1 (TGbK12) or a bARK1 inhibitor (TGMini27). Contractile response
to five concentrations (10-8 to 10-7 M) of the b1-AR agonist
norepinephrine (NE) plus prazosin (10-6M) was measured after a 60
second rest, i.e. rested state contraction (RSC), and during steady
state (SSC) stimulation at 0.5 Hz (23[acute]i C). At baseline,
resting cell length was significantly greater in the TGbK12 myocytes
(p<0.05) however there were no significant differences in RSC
or SSC among NTG, TGbK12 or TGMini27 mice. On the other hand, both
the dose-response and kinetics for the NE-induced SSC/RSC response
were significantly different among experimental groups
(p<0.001). Specifically, the maximal SSC induced by NE in
myocytes isolated from the TGbK12 group was only 70% of the response
observed in NTG control cells, and 50% of the response measured in
TGMini27 myocytes. These data suggest that (1) in the absence of
circulating catecholamines or basal sympathetic tone, bARK1 actions
in single myocytes are minimal, and (2) substantial functional bARK1
modulation of b1-AR signaling occurs in cardiac myocytes even during
short term b1-AR stimulation. These results are consistent with a
role for agonist-induced phosphorylation and desensitization of
cardiac b1-AR's by bARK1 in single myocytes and highlight the
potential functional importance of bARK1 as a critical determinant of
the cardiac b1-AR contractile response.
Received 9 August 1996; accepted in final form 14 October 1996.
APS Manuscript Number H730-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 November 1996