Nicorandil and leukocyte activation

Area of Science:

• Cardiovascular Research
• Pharmacology
• Cell Biology

Background:

• Nicorandil, a KATP channel opener and nitric oxide donor, is known to preserve microvascular integrity in myocardial infarction.
• Polymorphonuclear leukocytes (PMNLs) play a critical role in ischemia/reperfusion injury.

Purpose of the Study:

• To investigate the hypothesis that nicorandil suppresses PMNL activation and migration during ischemia/reperfusion.
• To elucidate the mechanisms underlying nicorandil's effects on PMNLs.

Main Methods:

• Human PMNLs were treated with formyl-methionyl-leucyl-phenylalanine (FMLP) and subjected to shear stress.
• Effects of nicorandil, diazoxide, nitroglycerin, and isosorbide dinitrate on PMNL pseudopod projection and intracellular calcium ([Ca2+]) were assessed.
• KATP channel blockers (5-hydroxydecanoate, glibenclamide) were used to investigate the role of KATP channels.
• Reverse transcription polymerase chain reaction (RT-PCR) was performed on rat PMNL mRNA.
• Leukocyte migration and microvascular obstruction were evaluated in a rat mesenteric ischemia/reperfusion model.

Main Results:

• Nicorandil, diazoxide, nitroglycerin, and isosorbide dinitrate suppressed FMLP-induced PMNL pseudopod projection.
• Nicorandil and diazoxide suppressed FMLP-induced increase in intracellular calcium ([Ca2+]) in PMNLs.
• KATP channel blockers reversed the suppressive effects of nicorandil and diazoxide on PMNL activation.
• RT-PCR confirmed the presence of Kir6.2 and Kir6.1 mRNA in rat PMNLs.
• Nicorandil, diazoxide, and isosorbide dinitrate reduced leukocyte migration and microvascular obstruction in vivo.

Conclusions:

• Nicorandil attenuates ischemia/reperfusion-induced PMNL activation.
• The effects of nicorandil are mediated through nitric oxide donation and a KATP channel-related cascade.
• Nicorandil's actions contribute to the preservation of microvascular integrity during reperfusion.