© 1998 American Heart Association, Inc.
Original Contributions |
Reduced Reperfusion–Induced Ins(1,4,5)P3 Generation and Arrhythmias in Hearts Expressing Constitutively Active 
1B-Adrenergic Receptors
From the Cellular Biochemistry (S.N.H., B.H.W., E.A.W.), Molecular Physiology (D.J.A.), and Experimental Cardiology Laboratories (X.-J.D.), Baker Medical Research Institute, Melbourne, Victoria, Australia, and Howard Hughes Medical Institute, Duke University Medical Center (C.M.), Durham, NC.
Correspondence to Dr E.A. Woodcock, Baker Medical Research Institute, Commercial Rd, Prahran 3181, Victoria, Australia. E-mail liz.woodcock{at}baker.edu.au
Abstract—Reperfusion of globally
ischemic rat hearts causes the generation of
inositol(1,4,5)trisphosphate
[Ins(1,4,5)P3] and the initiation of arrhythmias.
These responses are mediated by 1-adrenergic receptors
(ARs), but the subtype of receptor involved has not been identified.
Under normoxic conditions, hearts from transgenic animals expressing
constitutively active 1B-ARs in heart
(1B-constitutively active mutant [CAM]) showed higher
[3H] inositol phosphate responses to
norepinephrine (2.3-fold) than hearts from nontransgenic
animals (1B-WT) (1.6-fold). 1B-WT hearts
responded to 2 minutes of reperfusion after 20 minutes of global
ischemia by generation of Ins(1,4,5)P3 (5301±1310
to 11 413±1597 CPM/g tissue; mean±SEM; n=6; P<0.01
in [3H] labeling studies and 3.8±0.2 to 6.3±0.6 nmol/g
by mass analysis, n=6; P<0.05). In contrast to
findings in normoxia, hearts from 1B-CAM animals showed
no Ins(1,4,5)P3 response in early reperfusion. In parallel
studies, 1B-WT hearts developed ventricular
tachycardia and ventricular premature beats
(VPB) during 5 minutes of reperfusion after 20 minutes of
ischemia. The incidence of these arrhythmias was
reduced in the 1B-CAM hearts (95% to 62% for VPB and
47% to 12% for ventricular tachycardia; both
P<0.05). The resistance of the 1B-CAM
hearts was not due to 1B-AR–mediated preconditioning,
as the Ins(1,4,5)P3 response to thrombin receptor
activation during reperfusion was not different between the 2 groups.
To investigate the possibility of reduced 1A-receptor
activity in the 1B-CAM hearts, expression of the mRNA
for 1A- and 1B-receptors was measured.
1B-WT hearts contained mRNA for both receptor subtypes,
but the levels of 1B-receptor mRNA were 5-fold higher
than 1A-receptor mRNA. 1B-CAM hearts
contained very high levels of 1B-receptor mRNA (26-fold
increase), but the expression of mRNA for the
1A-receptors (0.141±0.035 amol/µg RNA; mean±SEM;
n=6) was reduced by 50% relative to 1B-WT controls
(0.276±0.046 amol/µg RNA; n=6; P<0.01). The
reduction in arrhythmogenic and Ins(1,4,5)P3 responses in
1B-CAM hearts provides evidence that these response are
not mediated by 1B-receptors.
Key Words: 1B-adrenergic receptor • 1A-adrenergic receptor • Ins(1,4,5)P3 • reperfusion • arrhythmia
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