Abstract
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 (KATP) 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. KATP 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, KATP 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 KATP channels and EMT mediate suppression of NE overflow during low flow ischemia. KATP channels impair NE release directly at presynaptic nerve endings, whereas EMT increases NE elimination in a manner independent of KATP channels.
Footnotes
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This study was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG: RI 423/4-2). A preliminary version of these findings was presented at the 75th Scientific Sessions of the American Heart Association, November 2002, Chicago, IL, and was published in abstract form in Circulation (2002) 106:II-67.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.059832.
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ABBREVIATIONS: NE, norepinephrine; NET, neuronal monoamine transporter; KATP channel, ATP-sensitive potassium channel; EMT, extraneuronal monoamine transporter; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; CCPA, 2-chloro-N6-cyclopentyladenosine; [3H]MPP+, N-[methyl-3 phenylpyridinium; SUR, sulfonylurea receptor.
- Received September 10, 2003.
- Accepted December 5, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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