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Sarcolemmal and mitochondrial K(atp)channels mediate cardioprotection in chronically hypoxic hearts
X Kong1, J S Tweddell, G J Gross
1Division of Pediatric Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Insights
Chronic hypoxia in neonatal rabbits enhances heart resistance to ischemia. This cardioprotection is mediated by both sarcolemmal and mitochondrial K(ATP)channels, crucial for recovery after ischemic events.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Neonatal Physiology
Background:
- Neonatal hearts exhibit increased resistance to ischemia following chronic hypoxia.
- The underlying mechanisms for this cardioprotection are not fully elucidated.
- Adenosine triphosphate-sensitive potassium channels (KATP channels) are implicated in cardiac protection.
Purpose of the Study:
- To investigate the role of sarcolemmal and mitochondrial KATP channels in mediating cardioprotection in chronically hypoxic neonatal rabbit hearts.
- To determine if KATP channel activation is responsible for the enhanced resistance to ischemia observed in these hearts.
Main Methods:
- Neonatal rabbits were exposed to normoxic or hypoxic environments for 8-10 days.
- Isolated hearts were perfused and subjected to global ischemia followed by reperfusion.
- Mitochondrial-selective (5-hydroxydecanoate, 5-HD) and sarcolemmal-selective (HMR 1098) KATP channel blockers were administered.
Main Results:
- Chronically hypoxic hearts showed significantly higher recovery of ventricular developed pressure compared to normoxic hearts.
- Selective and combined blockade of KATP channels partially or completely abolished the cardioprotective effect of chronic hypoxia.
- Neither blocker affected the recovery of normoxic hearts, indicating a specific role in the hypoxic adaptation.
Conclusions:
- Both sarcolemmal and mitochondrial KATP channels play a significant role in the cardioprotection observed in chronically hypoxic neonatal hearts.
- Targeting these KATP channels could be a therapeutic strategy for preventing ischemic injury in vulnerable neonatal populations.
Abstract:
X. Kong, J. S. Tweddell, G. J. Gross and J. E. Baker. Sarcolemmal and Mitochondrial K(ATP)Channels Mediate Cardioprotection in Chronically Hypoxic Hearts. Journal of Molecular and Cellular Cardiology (2001) 33, 1041-1045. Hypoxia from birth increases the resistance of the isolated neonatal heart to ischemia. We determined if increased resistance to ischemia was due to activation of sarcolemmal or mitochondrial K(ATP)channels. Rabbits (n=8/group) were raised from birth in a normoxic (F(I)O(2)=0.21) or hypoxic (F(I)O(2)=0.12) environment for 8-10 days and the heart perfused with Krebs-Henseleit bicarbonate buffer. A mitochondrial-selective K(ATP)channel blocker 5-hydroxydecanoate (5-HD) (300 micromol/l) or a sarcolemmal-selective K(ATP)channel blocker HMR 1098 (30 micromol/l) were added alone or in combination for 20 min prior to a global ischemic period of 30 min, followed by 35 min reperfusion. Recovery of ventricular developed pressure was higher in chronically hypoxic than normoxic hearts. 5-HD and HMR 1098 partially reduced the cardioprotective effect of chronic hypoxia, but had no effect in normoxic hearts. The combination of 5-HD and HMR 1098 abolished the cardioprotective effect of chronic hypoxia. We conclude that both sarcolemmal and mitochondrial K(ATP)channels contribute to cardioprotection in the chronically hypoxic heart.