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Perfused hearts (n = 127) were exposed to acute hypoxia (10% O2 for 12 or 20 min) or left atrial stretch (increase in atrial pressure) in the presence or absence of 100 mumol/l ATP-sensitive potassium channel blocker (tolbutamide) or openers (pinacidil and diazoxide). Hypoxia alone elicited a prolonged atrial natriuretic factor (ANF) release, peaking at 74% over baseline (P < 0.01); with tolbutamide, ANF secretion peaked at 132% over baseline (P < 0.01). Pinacidil and diazoxide abolished the ANF response to hypoxia (P < 0.01). Atrial stretch alone (1 mmHg) transiently (2 min) increased ANF by 56% (P < 0.05); with tolbutamide, ANF increased transiently by 124% and showed a prolonged increase of 52% (P < 0.05). With tolbutamide, graded stretch (0.5-2.3 mmHg) induced a bell-shaped transient (2-min) increase of ANF release [-3% at 0.5 mmHg, 124% (P < 0.05) at 1.0 mmHg, 80% (P < 0.05) at 1.48 mmHg, and 14% at 2.22 mmHg] and a saturating prolonged ANF response. Tolbutamide increased the ANF response nonsignificantly at lower doses (30 mumol/l) and had no effect at 1 mumol/l. Pinacidil abolished the stretch-induced ANF release. These results suggest that ATP-sensitive potassium channels are extremely potent modulators of stimulated ANF secretion.

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