Contribution of the Na(+) channel and Na(+)/H(+) exchanger to the anoxic rise of [Na(+)] in ventricular myocytes.
The aim of this study was to quantify the contribution of the Na(+)/H(+) exchanger (NHE) and the Na(+) channel to the rise in cytosolic Na(+) concentration ([Na(+)]) that is seen in anoxic guinea pig ventricular myocytes. [Na(+)] was measured with the use of microfluorometry and was found to rise to 44 mM after prolonged anoxia. This rise was partially sensitive to either TTX or HOE-642, selective inhibitors of the Na(+) channel and NHE1, respectively. [Na(+)] did not significantly rise when both drugs were present, suggesting that other routes of Na(+) entry were insignificant. However, the relative contributions of the NHE and the Na(+) channel were found to be remarkably sensitive to ionic conditions expected to occur during ischemia. The Na(+) channel was the dominant Na(+) source during acidic anoxia. However, the NHE was the dominant Na(+) source during both hyperkalemic anoxia and simulated ischemia (hyperkalemia, low pH, and anoxia). The data suggest that the NHE may prove to be the best pharmacological target to reduce Na(+) entry during true ischemia and that inhibition of Na(+) influx could contribute strongly to the cardioprotective effects of NHE inhibitors.
Eigel
B N
BN
Department of Pharmacology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0084, USA.
Hadley
R W
RW
D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D006168:Guinea Pigs; D006352:Heart Ventricles; D006863:Hydrogen-Ion Concentration; D006947:Hyperkalemia / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D007552:Isotonic Solutions / Q000737:chemistry / Q000494:pharmacology; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009994:Osmolar Concentration; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology*
D007552:Isotonic Solutions; D015222:Sodium Channels; D017923:Sodium-Hydrogen Exchangers; C037692:Tyrode's solution; D012964:Sodium