Key result
In guinea-pig pulmonary arteries, NANC relaxation involves nitrergic and purinergic pathways and is potentiated by the PDE V inhibitor zaprinast but unaffected by the PDE III inhibitor milrinone.
Both nitrergic and purinergic pathways mediate NANC relaxation in guinea-pig pulmonary arteries, suggesting that combining PDE III or V inhibitors with vasorelaxants may be a promising approach for treating pulmonary hypertension.
Hypothesis-generating for PDE V selectivity in pulmonary relaxation models; leaves open translation to human pulmonary hypertension.
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.
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Taşatargil et al. (2003) studied this question. Phosphodiesterase III and V inhibitors (zaprinast, milrinone) was evaluated on Non-adrenergic, non-cholinergic (NANC) relaxation responses. In guinea-pig pulmonary arteries, NANC relaxation involves nitrergic and purinergic pathways and is potentiated by the PDE V inhibitor zaprinast but unaffected by the PDE III inhibitor milrinone.
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