Nicorandil opens mitochondrial K(ATP) channels not only directly but also through a NO-PKG-dependent pathway.
Nicorandil, a hybrid of nitrate generator and potassium channel opener, protects ischemic myocardium by opening mitochondrial ATP sensitive potassium (mitoK(ATP)) channels. We recently found that nitric oxide (NO) opened K(ATP) channels in rabbit hearts by a protein kinase G (PKG) mechanism. This study examined whether the NO-donor property of nicorandil also contributes to opening of mitoK(ATP) channels through PKG. MitoK(ATP) channel opening was monitored in adult rabbit cardiomyocytes by measuring reactive oxygen species (ROS) production, an established marker of channel opening. Nicorandil increased ROS production in a dose-dependent manner. The selective mitoK(ATP) channel inhibitor 5-hydroxydecanoate (200 microM) completely blocked ROS production by nicorandil at all doses. The PKG inhibitor 8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rpisomer (Rp-8-Br-cGMPs, 50 microM) shifted the dose-ROS production curve to the right with an increase of the EC(50) from 2.4 x 10(-5) M to 6.9 x 10(-5) M. Rp- 8-Br-cGMPs did not affect the increase in ROS production by the selective mitoK(ATP) channel opener diazoxide while it completely blocked increased ROS production from the NO donor S-nitroso-N-acetylpenicillamine (1 microM). Furthermore ODQ, an antagonist of soluble guanylyl cyclase, blocked nicorandil's ability to increase ROS generation. These results indicate that nicorandil, in addition to its direct effect on the channels, opens mitoK(ATP) channels indirectly via a NO-PKG signaling pathway.
Kuno
Atsushi
A
Dept. of Physiology, MSB 3070, College of Medicine University of South Alabama, Mobile, AL 36688, USA.
Critz
Stuart D
SD
Cohen
Michael V
MV
Downey
James M
JM
D000818:Animals; D002478:Cells, Cultured; D017869:Cyclic GMP-Dependent Protein Kinases / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D020108:Nicorandil / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015221:Potassium Channels / Q000187:drug effects*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
D015221:Potassium Channels; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D020108:Nicorandil; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase