Hypoxic Vasoconstriction of Rat Main Pulmonary Artery: Role of Endogenous Nitric Oxide, Potassium Channels, and Phosphodiesterase Inhibition
| Autor: | Esteban J. Morcillo, Marc Bardou, Luc Rochette, Françoise Goirand, Philippe Devillier, Jean-Paul Dumas, Céline Rouget, Sandrine Marchand, Monique Dumas |
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| Rok vydání: | 2001 |
| Předmět: |
Male
medicine.medical_specialty Potassium Channels Phosphodiesterase Inhibitors Siguazodan Pulmonary Artery Nitric Oxide Apamin chemistry.chemical_compound Internal medicine Hypoxic pulmonary vasoconstriction medicine Animals Channel blocker Enzyme Inhibitors Rats Wistar Hypoxia Pharmacology Dose-Response Relationship Drug Chemistry Phosphodiesterase Potassium channel Rats Vasodilation NG-Nitroarginine Methyl Ester Endocrinology Vasoconstriction Nitric Oxide Synthase medicine.symptom Cardiology and Cardiovascular Medicine Zaprinast |
| Zdroj: | Journal of Cardiovascular Pharmacology. 38:325-334 |
| ISSN: | 0160-2446 |
| DOI: | 10.1097/00005344-200108000-00018 |
| Popis: | This study investigated the influence of NO, potassium (K+) channel blockade, and the phosphodiesterase inhibitors (PDEIs) theophylline (non-selective PDEI), siguazodan (PDE3I), rolipram (PDE4I), and zaprinast (PDE5I) on rat isolated main pulmonary artery hypoxic (95% N2 and 5% CO2) vasoconstriction. Hypoxic vasoconstriction increased by 27% (p < 0.01) in the presence of the NO synthase inhibitor L-NAME (10(-4) M), and by 15% (p < 0.05) in the presence of the K(ATP) channel blocker glibenclamide (10(-6) M), without potentiation by the combination of these two drugs. Hypoxic vasoconstriction decreased by 28% (p < 0.01) in presence of the Kv,-voltage-dependent channel blocker 4-aminopyridine (10(-3) M), whereas the other K+ channel blockers, charybdotoxin (BKCa, large-conductance Ca2+-sensitive K+ channels) and apamin (SKCa, small-conductance Ca2+-sensitive K+ channels) had no effect. The nonselective PDEI theophylline induced a concentration-dependent relaxation (pD2 = 4.05, Emax = 90% [expressed as a percentage of maximal relaxation induced by papaverine 10(-4) M]). Among the selective PDEIs, siguazodan was significantly (p < 0.01) more efficient than rolipram and zaprinast (Emax values were 84%, 67%, and 58%, respectively) and significantly (p < 0.05) more potent than zaprinast (pD2 values were 6.48, 6.34, and 6.16 for siguazodan, rolipram, and zaprinast). Glibenclamide and L-NAME significantly (p < 0.05) shifted the concentration-response curve (CRC) for zaprinast to the right, and L-NAME shifted the CRC significantly to the right for siguazodan. In the presence of L-NAME, glibenclamide had no effect on the CRC of zaprinast. We conclude that (a) NO exerts a permanent inhibitory effect against hypoxic vasoconstriction that might be mediated in part by an activation of K(ATP) channels; (b) a 4-aminopyridine-sensitive K+ channel is involved in vasoconstriction under hypoxic conditions; (c) PDEs 3 and 5 are the predominant PDE isoforms in rat pulmonary artery relaxation; and (d) NO and K(ATP), but neither BK(Ca), SK(Ca), nor Kv channels, are involved in the relaxant effect of PDEIs. |
| Databáze: | OpenAIRE |
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