While the normal transition from fetus to newborn requires pulmonary vasodilation mediated by nitric oxide (NO), the mechanism for this remains incompletely understood. Recent evidence suggests that NO acts through K+ channel activation. We hypothesized that NO mediates perinatal pulmonary vasodilation through release of intracellular calcium, from a ryanodine-sensitive store to cause activation of a calcium-sensitive K+ (KCa) channel. To test this hypothesis we studied the effect of: (i) KCa block; (ii) voltage-gated K+ (Kv) channel block; and (iii) blockade of the ryanodine-sensitive store on NO-induced pulmonary vasodilation in acutely prepared, late-gestation fetal lambs (n=5). After a minimum recovery period of one hour, nitro-L-arginine (L-NA, 1 mg/min for 30 min), an NO inhibitor, was infused into the left pulmonary artery (LPA), and tracheotomy placed. Animals were ventilated with 100% O2 for 20 minutes, followed by ventilation with 100% O2 + inhaled NO (iNO) at 20 ppm for 10 minutes. In separate protocols, animals received intrapulmonary infusion of: (i) tetraethylammonium (TEA, 1 mg/min for 50 min), a preferential KCa blocker; (ii) 4-aminopyridine (4-AP, 1 mg/min for 17 min,), a Kv channel blocker; and (iii) ryanodine (5μg/min for 30 min), a blocker of intracellular calcium release, and ventilated as above.

Results: LPA blood flow (cc/min) Means±SE; * p<0.05, vs control Table

Table 1 No caption available.
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We conclude that iNO causes perinatal pulmonary vasodilation through activation of a KCa channel whose activity is modulated by release of intracellular calcium from a ryanodine-sensitive store.