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First published online October 10, 2003

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A role for nitric oxide in hypoxia-induced activation of cardiac K_ATP channels in goldfish (Carassius auratus)

John S. Cameron^*, Kristin E. Hoffmann, Cindy Zia, Heidi M. Hemmett, Allyson Kronsteiner and Connie M. Lee

Department of Biological Sciences, Wellesley College, Wellesley, MA 02481, USA

View larger version (25K): [in a new window]   Fig. 1. Effects of hypoxia on action potential duration at 50% (APD50) and 90% (APD90) of full repolarization (N=8). Action potentials recorded in isolated ventricles were significantly shortened after 10 min hypoxia (6.1±0.2 kPa), an effect that was reversible upon a return to normoxic solution (washout). Inset shows representative action potential configuration in one experiment. Values are means ± 1 S.E.M. *, significantly different from values recorded under normoxic conditions (P<0.05).

View larger version (26K): [in a new window]   Fig. 2. Effects of hypoxia with simultaneous application of the KATP channel antagonist BDM (60 µmol l-1) on cardiac muscle action potential duration (APD). No significant change in APD50 or APD90 was recorded when BDM was present during hypoxia (N=6). Values are means ± 1 S.E.M.

View larger version (16K): [in a new window]   Fig. 3. Effect of SNAP (100 µmol l-1), an NO donor, on cardiac muscle action potential duration (APD) in goldfish ventricle (N=8). Under normoxic conditions, APD50 and APD90 were significantly shortened upon 3 min exposure to SNAP. Inset shows a control action potential (left) and one recorded in the presence of SNAP (right, and superimposed at arrow). Values are means ± 1 S.E.M. *, significantly different from control (P<0.05).

View larger version (18K): [in a new window]   Fig. 4. Cardiac sarcolemmal KATP channel activity was increased during hypoxia (6.0±0.3 kPa) in cell-attached patches on isolated goldfish ventricular myocytes. In a representative experiment, duration histograms display the relative frequency of dwell times (s) between transitions from any one current level to another in a patch containing multiple KATP channels. While channel closed- and open-lifetime distribution was unchanged, overall activity was enhanced. Recordings were obtained within the first 10 s after application of a depolarizing holding potential (+80 mV).

View larger version (19K): [in a new window]   Fig. 5. Effects of 30 min hypoxia alone and in combination with other agents on the activity of sarcolemmal KATP channels in cell-attached patches. Channel open state probability (Po) was significantly increased in response to hypoxia, a response that was maximal after 20 min (N=8; mean ± 1 S.E.M.) and reversible upon the return of normoxic solution (washout). The inset shows a representative recording of KATP channel activity from a single experiment; after only 10 min hypoxia, the number of active channels/patch was substantially increased. Channel openings are shown as upward deflections in response to depolarization by 80 mV; c, all channels closed. Simultaneous application of hypoxia and BDM (N=4), or hypoxia and an inhibitor of NO-sensitive guanylate cyclase (ODQ; 20 µmol l-1; N=6), eliminated the hypoxia-induced increase in channel activity. Hypoxia plus an inhibitor of NO synthase (L-NAME; 50 µmol l-1; N=4) reduced the magnitude of the increase in Po seen with 20 min hypoxia alone. *, significantly different from normoxia (P<0.05).

View larger version (10K): [in a new window]   Fig. 6. The cell-free, inside-out patch clamp recording configuration was used to assess the effects on KATP channel open-state probability (Po) of the NO donor SNAP (100 µmol l-1; left), the stable cGMP analog 8-Br-cGMP (200 µmol l-1) and 8-Br-cGMP in combination with the KATP antagonist BDM (60 µmol l-1; right), all under normoxic conditions. Three min exposure to SNAP at the intracellular face of the membrane significantly increased Po (N=6). The cGMP analog also raised Po (N=4), an effect that was substantially eliminated by simultaneous administration of the KATP antagonist (N = 4). Values are means ± 1 S.E.M. *, significantly different from control (P<0.05).

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