Introduction:
Isoproterenol-induced acute stressor state simulates injury from burns or trauma, and results in Ca
2+
overloading and oxidative stress in diverse tissues, including cardiac myocytes and their subsarcolemmal mitochondria (SSM), overwhelming endogenous Zn
2+
-based antioxidant defenses.
We hypothesized
that pretreatment with nebivolol (Nebi), having dual beta-1 antagonistic and novel beta-3 receptor agonistic properties, would prevent Ca
2+
overloading and oxidative stress and upregulate Zn
2+
-based antioxidant defenses, thus enhancing its overall cardioprotective potential in acute stressor state.
Methods:
Eight-week-old male Sprague-Dawley rats received a single subcutaneous dose of isoproterenol (1 mg/kg) and compared to those treated with Nebi (10 mg/kg by gavage) for 10 days prior to isoproterenol. SSM were harvested from cardiac tissue at sacrifice. Total Ca
2+
, Zn
2+
and 8-isoprostane levels in tissue, and mitochondrial permeability transition pore (mPTP) opening, free [Ca
2+
]
m
and H
2
O
2
production in SSM were monitored. Untreated, age-/sex-matched rats served as controls; each group had six rats and data shown as mean±SEM.
Results:
Compared to controls, isoproterenol rats revealed:
(1)
Significantly (*p<0.05) increased cardiac tissue Ca
2+
(8.2±0.8 vs. 13.7±1.0*, nEq/mg fat-free dry tissue (FFDT)), which was abrogated (
#
p<0.05) by Nebi (8.9±0.4
#
);
(2)
Reduced cardiac Zn
2+
(82.8±2.4 vs. 78.5±1.0*, ng/mg FFDT), but restored by Nebi (82.4±0.6
#
);
(3)
Two-fold rise in cardiac 8-isoprostane (111.4±13.7 vs. 232.1±17.2*, pmoles/mg protein), and negated by Nebi (122.3+14.5
#
);
(4)
Greater opening propensity for mPTP that diminished by Nebi;
(5)
Elevated [Ca
2+
]
m
(88.8±2.5 vs. 161.5±1.0*, nM), but normalized by Nebi (93.3±2.7
#
); and
(6)
Increased H
2
O
2
production by SSM (97.4±5.3 vs. 142.8±7.0*, pmoles/mg protein/min), and nullified by Nebi (106.8±9.0
#
).
Conclusions
: Cardioprotection conferred by Nebi, a unique beta-blocker, prevented Ca
2+
overloading and oxidative stress in cardiac tissue and SSM, while simultaneously augmenting antioxidant capacity and promoting mPTP stability. Therapeutic potential of Nebi in patients with acute stressor states remains a provocative possibility that deserves to be explored.
Mitochondrial permeability transition and oxidative stress