Almitrine mimics hypoxic vasoconstriction in isolated rat lungs.
The effect of almitrine bimesylate or the solvent malic acid on pulmonary vascular perfusion pressure was assessed in isolated rat lungs and on the contractile behavior of rat aorta and main pulmonary artery rings. Addition of almitrine to the lung perfusate during normoxia caused a dose-dependent, transient increase in pulmonary artery pressure with no change of the lung microvascular pressure. In systemic or pulmonary conduit arteries, the contractile tension was unaffected by almitrine. This indicates a precapillary locus of drug action. We also examined almitrine's effect on hypoxic pulmonary vasoconstriction (HPVC) in isolated lungs perfused with blood or with physiological salt solution (PSS). Low-dose almitrine potentiated hypoxic vasoconstriction in blood- but not in PSS-perfused lungs. However, a high dose of almitrine reduced hypoxic vasoconstriction dose dependently. When almitrine was added to the lung perfusate during hypoxia- or cyanide-induced (NaCN, 5 x 10(-5) M) pulmonary vasoconstriction, almitrine caused no further vasoconstriction. However, when the pulmonary perfusion pressure was elevated by KCl (20 mM) to the same magnitude as by alveolar hypoxia or cyanide, almitrine elicited a pressor response comparable to that observed during normoxia. Almitrine-induced pulmonary vasoconstriction resembled hypoxic vasoconstriction in that agents known to enhance hypoxic vasoconstriction (phorbol myristate acetate, vanadate, and 4-aminopyridine) enhanced, and known inhibitors of HPVC (the Ca2+ entry blocker nifedipine and hypothermia) inhibited, the almitrine-induced vasoconstriction. These findings lead us to speculate that almitrine also affects the oxygen-sensing limb of the hypoxic pressor response, not simply the effector (contractile apparatus of the vascular muscle cell).
Gottschall
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EB
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver 80262.
Fernyak
S
S
Wuertemberger
G
G
Voelkel
N F
NF
D015765:Almitrine / Q000494:pharmacology*; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D011312:Pressure; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012966:Sodium Cyanide / Q000494:pharmacology; D014661:Vasoconstriction
D016861:Cyclooxygenase Inhibitors; D015765:Almitrine; D012966:Sodium Cyanide