Preconditioning
Modulates Susceptibility to Ischemia-Induced
Arrhythmias in the Rat Heart: The Role of
a-Adrenergic Stimulation and K(ATP) Channels
T.
RAVINGEROVÁ, D. PANCZA, A. ZIEGELHOFFER, J. STYK
Institute for Heart Research, Slovak Academy of
Sciences, Bratislava, Slovak Republic
Received May 17, 2001
Accepted July 27, 2001
Summary
A new concept of cardioprotection based
on the exploitation of endogenous mechanisms is
known as ischemic preconditioning (IPC). It has
been hypothesized that substances released during
brief ischemic stress (e.g. catecholamines)
stimulate the receptors and trigger multiple cell
signaling cascades. Opening of ATP-sensitive K+
channels [K(ATP)] has been suggested as a
possible final step in the mechanisms of
protection. In this study, the role of adrenergic
activation was tested in Langendorff-perfused rat
hearts subjected to test ischemia (TI; 30 min
occlusion of LAD coronary artery) by: 1)
mimicking IPC (5 min ischemia, 10 min
reperfusion) with short-term (5 min)
administration of norepinephrine (NE, 1 µM), 15
min prior to TI; 2) blockade with b- or
a1-receptor antagonists, propranolol (10 µM) and
prazosin (2 µM), respectively, applied 15 min
prior to TI during IPC. The role of K(ATP)
opening was examined by perfusion with a K(ATP)
blocker glibenclamide (10 mM) during IPC. Both
IPC and NE-induced PC effectively reduced the
incidence of ventricular tachycardia (VT) to 33 %
and 37 %, respectively, vs 100 % in the non-PC
controls, whereby ventricular fibrillation (VF)
was totally abolished by IPC and markedly
suppressed by PC with NE (0 % and 10 %,
respectively, vs 70 % in the non-PC hearts;
P<0.05). The severity of arrhythmias
(arrhythmia score, AS) was also markedly
attenuated by both interventions (IPC: AS
1.7±0.4; NE-PC: AS 1.8±0.3 vs AS 4.1±0.2 in
the controls; P<0.05). Protection was not
suppressed by propranolol (VT 28 %; VF 14 %; AS
2.2±0.6), whereas prazosin reversed the
protective effect of PC (VT 83 %; VF 67 %; AS
4.0±0.8). Antiarrhythmic protection afforded by
NE-PC was abolished by pretreatment of rats with
pertussis toxin (25 mg/kg, i.p.) given 48 h prior
to the experiments. Glibenclamide did not
suppress the IPC-induced protection. In
conclusion, the sensitivity of the rat heart to
ischemic arrhythmias can be modulated by IPC.
Protection is mediated via stimulation of
a1-adrenergic receptors coupled with Gi-proteins
but glibenclamide-sensitive K(ATP) channels do
not appear to be involved in the mechanisms of
antiarrhythmic protection in this model.
.
Key
words
Ischemic
preconditioning · Arrhythmias · Adrenergic
stimulation · K(ATP) channels
Reprint
requests
Dr. T. Ravingerová, Institute for Heart
Research, Slovak Academy of Sciences, Dúbravská
cesta 9, 842 33 Bratislava, Slovak Republic.
Phone: 421 7 5477 4405. Fax: 421 7 5477 6637.
E-mail: usrdravi@savba.sk
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