Mechanism of the pulmonary vasoconstrictor action of digoxin in the dog.
The pulmonary vascular effects of a subarrhythmic dose of digoxin (60 micrograms/kg i.v.) were examined in the canine in situ perfused lung. Digoxin produced an increase in pulmonary vascular resistance (66.1%) and pulmonary arterial pressure (8.2 mm Hg) at 70 min after injection in the constant-flow, blood-perfused lung preparation. The digoxin-treated group exhibited higher plasma levels of norepinephrine compared with control dogs. The pulmonary vasoconstrictor response to digoxin was abolished by prior treatment with the alpha-adrenergic antagonists phenoxybenzamine and phentolamine. This vasoconstriction does not involve inhibition of synthesis or action of vasodilator prostaglandins by digoxin, as pretreatment with indomethacin did not attenuate, and even tended to increase, the pressor response to digoxin. The response was prevented by prior treatment with blockers of nonneuronal uptake of catecholamines normetanephrine and hydrocortisone, but not with cocaine, a blocker of neuronal uptake. In the lung preparation perfused with Krebs buffer solution, digoxin failed to produce vasoconstriction when administered intravenously (60 micrograms/kg) or in the perfusate at a concentration of 8 ng/ml, the blood level at the peak of the pressor response. Sodium-pump activity (ouabain-sensitive 86Rb+ uptake) of intralobular pulmonary arteries excised after 90 min of exposure to digoxin was the same as activity in arteries from control dogs. In conclusion, digoxin produces a pulmonary vasoconstriction through an alpha-adrenergic mechanism. Since the pressor response was observed only in the blood-perfused lung, blood-borne catecholamines are apparently involved.
Mecca
T E
TE
Elam
J T
JT
Caldwell
R W
RW
D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D004077:Digoxin / Q000494:pharmacology*; D004285:Dogs; D004837:Epinephrine / Q000097:blood; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000097:blood; D009647:Normetanephrine / Q000494:pharmacology; D010643:Phenoxybenzamine / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*
D009647:Normetanephrine; D010643:Phenoxybenzamine; D004077:Digoxin; D003042:Cocaine; D009638:Norepinephrine; D007213:Indomethacin; D004837:Epinephrine; D010646:Phentolamine