The effects of selective phosphodiesterase III and V inhibitors on adrenergic and non-adrenergic, non-cholinergic relaxation responses of guinea-pig pulmonary arteries.
1. The aim of the present study was to investigate the role of several possible neurotransmitters in mediating non-adrenergic, non-cholinergic (NANC) relaxation, and the effects of phosphodiesterase (PDE) III and V inhibitors on adrenergic and NANC relaxation in branch pulmonary artery (PA) of guinea-pig. 2. Under the NANC conditions, electrical field stimulation (EFS, 60 V, 0.2 ms, 20 Hz) induced a tetrodotoxin-sensitive relaxation of the histamine-precontracted PA rings. The nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 10(-4) m) and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10(-5) m) partially inhibited the EFS-induced relaxation. The inhibitory effect of l-NAME was reversed completely by l-arginine (10(-3) m), but not d-arginine (10(-3) m). 3. This NANC relaxation was attenuated by 8-phenyltheophylline (10(-5) m), a P1-purinoceptor antagonist. 4. The NANC response was potentiated by 10-6 m zaprinast, a type V PDE inhibitor, but was unaffected by 3 x 10-6 m milrinone, a type III PDE inhibitor. 5. Sodium nitroprusside (SNP) caused a concentration-dependent vasodilator effect which was potentiated by zaprinast, but unaffected by milrinone. Moreover, the effect of combination of zaprinast with milrinone was not significantly different from that observed with zaprinast alone. 6. Isoprenaline produced a concentration-dependent vasodilatation in branch PA of guinea-pig which was potentiated by both zaprinast and milrinone, the efficacy of milrinone being greater than zaprinast. 7. These results suggest that both nitrergic and purinergic pathways are involved in mediating the NANC relaxation in branch PA of guinea-pig. The combination of PDE III or V inhibitors with vasorelaxant drugs may be a hopeful approach for the treatment of pulmonary hypertension.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000241:Adenosine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004357:Drug Synergism; D004558:Electric Stimulation; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011688:Purinones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011810:Quinoxalines; D011941:Receptors, Adrenergic; D011950:Receptors, Cholinergic; D009599:Nitroprusside; D013779:Tetrodotoxin; D006632:Histamine; D001120:Arginine; D013806:Theophylline; C028322:8-phenyltheophylline; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C011145:zaprinast; D020105:Milrinone; D000241:Adenosine; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester