Role of neuronal KATP channels and extraneuronal monoamine transporter on norepinephrine overflow in a model of myocardial low flow ischemia.
Global myocardial low flow ischemia results in an uniform suppression of norepinephrine (NE) overflow from the heart. We hypothesized that opening of neuronal ATP-sensitive potassium (K(ATP)) channels as well as activation of the extraneuronal monoamine transporter (EMT) mediates attenuation of NE overflow during low flow ischemia. Isolated rat hearts were subjected to low coronary flow of 0.4 ml min(-1). Release of endogenous NE was induced by electrical field stimulation. EMT activity was measured as the transport rate of the substrate N-[methyl-3H]4-phenylpyridinium ([3H]MPP+). NE overflow decreased by 57 +/- 2% within 120 min of low flow. Five minutes of reperfusion at normal flow (8 ml min(-1)) restored NE overflow to baseline. K(ATP) channel blockade with glibenclamide as well as EMT blockade with corticosterone increased NE overflow 1.5- and 2-fold at 120 min of low flow, whereas neither drug affected NE overflow in the absence of flow reduction. At normal flow, K(ATP) channel opening with cromakalim suppressed NE overflow, both in the presence and absence of EMT blockade (14 +/- 4 and 9 +/- 1%). However, cromakalim had no effect on EMT activity as indicated by an unaffected [3H]MPP+ overflow. In conclusion, activation of both K(ATP) channels and EMT mediate suppression of NE overflow during low flow ischemia. K(ATP) channels impair NE release directly at presynaptic nerve endings, whereas EMT increases NE elimination in a manner independent of K(ATP) channels.
Burgdorf
Christof
C
Institut für experimentelle und klinische Pharmakologie und Toxikologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. chbrg@compuserve.de
Dendorfer
Andreas
A
Kurz
Thomas
T
Schömig
Edgar
E
Stölting
Ines
I
Schütte
Frank
F
Richardt
Gert
G
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D015221:Potassium Channels; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D014316:Tritium
D008565:Membrane Proteins; D015221:Potassium Channels; D043682:Receptor, Adenosine A1; C117780:mitochondrial K(ATP) channel; D014316:Tritium; D015655:1-Methyl-4-phenylpyridinium; D009638:Norepinephrine