1. To further understand the vasodilator actions of atrial natriuretic peptide and its role in hypoxic pulmonary hypertension, we studied the effects of atrial natriuretic peptide in the isolated perfused rat lung during normoxic ventilation and after elevation of pulmonary artery pressure by either hypoxic ventilation or infusion of prostaglandin F2α. Control animals were compared with littermates that had become adapted to a 10% O2 environment for 3 weeks. Atrial natriuretic peptide was compared with atriopeptin I and atriopeptin III in order to study its structure-activity relationship.
2. Five experiments, each involving six control and six chronically hypoxic rats, were performed. During normoxic ventilation, atrial natriuretic peptide (30 ng-3 μg) produced a dose-dependent reduction in pulmonary artery pressure in chronically hypoxic rats, but had no action in the control animals.
3. Atrial natriuretic peptide dose-dependently abolished hypoxic pulmonary vasoconstriction to a greater extent in chronically hypoxic rats (EC50 98 ng) than in control rats (EC50 298 ng; P < 0.001). Bolus atrial natriuretic peptide (100 ng) produced a plasma concentration of 22.6 pmol/l at 1 min, which is within the pathophysiological range. Initial plasma atrial natriuretic peptide levels were 9.4 pmol/l in control animals and 27.4 pmol/l in chronically hypoxic rats.
4. Chronically hypoxic rats were more sensitive to atriopeptin I, atriopeptin III and atrial natriuretic peptide than were the control rats (P < 0.05). Atrial natriuretic peptide and atriopeptin III were equipotent and were 10 times more potent than atriopeptide I in both groups (P < 0.001).
5. Although atrial natriuretic peptide lowered pulmonary artery pressure in isolated perfused lungs pre-constricted with prostaglandin F2α (5 μg/min), there was no difference between the control and chronically hypoxic groups, and the EC50 296 ng in the chronically hypoxic rats was significantly (P < 0.001) less than that seen in the chronically hypoxic despite similar levels of induced constriction by the two stimuli.
6. A set dose of atrial natriuretic peptide produced the same percentage reduction in hypoxic pulmonary vasoconstriction despite differing levels of pre-constriction produced by ventilating with 7%, 5%, 3% or 0% O2. There was no change in the arterial partial pressure of O2 or the alveolar-arterial gradient after injection of atrial natriuretic peptide, suggesting that its effects are not due to a reduction in pulmonary oedema.
7. Atrial natriuretic peptide relaxes pre-constricted pulmonary arteries in the isolated perfused rat lung in a dose-dependent manner within the pathophysiological range. The greater action of atrial natriuretic peptide in chronic hypoxia could be due to its action at the new sites of hypoxic pulmonary vasoconstriction, the newly muscularized alveolar arteries which develop during adaptation to hypoxia.
