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KATP-channel openers protect against increased cytosolic calcium during ischaemia and reperfusion
1Division of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Abstract:
There is ample evidence that potassium channel openers protect the ischaemic myocardium. Although the protective mechanism is unknown, indirect evidence suggests that potassium channel openers reduce calcium influx during ischaemia which may explain their protective effects. However, recently discovered potassium channel openers such as BMS-180448 are cardioprotective without displaying classical indications of calcium lowering. The current study was designed to provide direct evidence that potassium channel openers delay or prevent increased intracellular free calcium in the myocardium during ischaemia and reperfusion. Cytosolic calcium concentrations were directly measured in perfused rat hearts during global ischaemia by 19F-NMR of the calcium chelator 5F-BAPTA. The cytosolic Ca2+ concentration in vehicle-treated hearts increased from a pre-ischaemia average of 310 +/- 40 nM to 1000 +/- 130 nM during 25 min of ischaemia, followed by partial recovery to 530 +/- 100 nM during 19 min of reperfusion. In contrast, the cytosolic Ca2+ concentration in hearts treated with potassium channel openers BMS-180448 and cromakalim remained low throughout ischaemia, changing from pre-ischaemia averages of 270 +/- 30 nM to 230 +/- 60 nM and from 240 +/- 20 nM to 170 +/- 30 nM during 25 min of ischaemia, respectively. The cytosolic Ca2+ concentrations in these hearts increased to 440 +/- 110 nM in BMS-180448 treated hearts and 290 +/- 60 nM in cromakalim treated hearts during the first 6 min of reperfusion, and were 460 +/- 60 nM for BMS-180448 and 600 +/- 70 nM for after cromakalim 19 min of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Potassium channel openers, like BMS-180448 and cromakalim, prevent harmful rises in intracellular calcium during heart ischemia and reperfusion. This finding supports their cardioprotective effects by directly measuring calcium levels in rat hearts.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Biochemistry
Background:
- Potassium channel openers (PCOs) are known to protect the ischemic myocardium.
- The exact protective mechanism remains unclear, though PCOs are thought to reduce calcium influx during ischemia.
- Some novel PCOs, like BMS-180448, show cardioprotection without typical calcium-lowering effects.
Purpose of the Study:
- To provide direct evidence that PCOs prevent or delay increases in intracellular free calcium in the myocardium during ischemia and reperfusion.
- To investigate the role of calcium handling in the cardioprotective effects of PCOs.
Main Methods:
- Cytosolic calcium concentrations were directly measured in perfused rat hearts using 19F-NMR with the calcium chelator 5F-BAPTA.
- Global ischemia was induced, followed by a reperfusion period.
- Hearts were treated with either vehicle, BMS-180448, or cromakalim.
Main Results:
- Vehicle-treated hearts showed a significant increase in cytosolic Ca2+ from 310 nM to 1000 nM during ischemia, with partial recovery to 530 nM during reperfusion.
- Hearts treated with BMS-180448 and cromakalim maintained low cytosolic Ca2+ levels during ischemia (230 nM and 170 nM, respectively).
- During reperfusion, Ca2+ levels increased in PCO-treated hearts but remained lower than in vehicle-treated hearts.
Conclusions:
- Potassium channel openers BMS-180448 and cromakalim effectively delay or prevent the rise in intracellular free calcium during myocardial ischemia and reperfusion.
- This direct measurement of intracellular calcium supports the hypothesis that modulating calcium levels is a key mechanism underlying PCO-mediated cardioprotection.