Abstract
Cytosolic reducing cofactors, such as NADPH and NADH, are thought to regulate vascular smooth muscle ion channel activity and vascular tone. In this study, the effects of pentose phosphate pathway (PPP) inhibitors, 6-aminonicotinamide (6-AN), epiandrosterone (EPI), and dehydroepiandrosterone (DHEA), on vascular tone were studied in isolated perfused lungs and pulmonary artery (PA) and aortic rings from rats. In addition, effects of 6-AN on voltage-gated K+(Kv) current in PA smooth muscle cells (SMCs) were also examined. Pretreatment of lungs with 6-AN and EPI reduced the pressor response to acute hypoxia and decreased tissue NADPH levels. 6-AN, EPI, and DHEA relaxed isolated PA and aortic rings precontracted with 30 mM KCl in a dose-dependent manner. The PPP inhibitor-induced PA relaxations were reduced in PA rings precontracted with 80 mM KCl but not by pretreatment with nitro-l-arginine or endothelial removal. Pretreatment of PA rings with tetraethylammonium chloride or 4-aminopyridine caused rightward shifts of concentration-relaxation curves for 6-AN, EPI, and DHEA. In contrast, glybenclamide, charybdotoxin, or apamin did not inhibit the relaxant effects of 6-AN, EPI, and DHEA. 6-AN caused an increase in Kv current in PASMC. These results indicate that reduction of NADPH by the PPP inhibitors causes vasodilation at least partly through opening of Kv channels.
Footnotes
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This study was supported in part by the Juntendo University for interlaboratory collaborative project and a grant-in-aid by Kyoristu International Foundation, Tokyo, Japan (to S.A.G.) and by a Beginning grant-in-aid from the American Heart Association (to M.O.).
- Abbreviations:
- NO
- nitric oxide
- PPP
- pentose phosphate pathway
- 6-AN
- 6-aminonicotinamide
- EPI
- epiandrosterone
- DHEA
- dehydroepiandrosterone
- GSSG
- oxidized glutathione
- PA
- pulmonary artery
- SMC
- smooth muscle cell
- sGC
- soluble guanylyl cyclase
- HPV
- hypoxic pulmonary vasoconstriction
- A-II
- angiotensin II
- 4-AP
- 4-aminopyridine
- GLY
- glybenclamide
- CTX
- chrybdotoxine
- APA
- apamine
- l-NNA
- nitro-l-arginine
- DMSO
- dimethyl sulfoxide
- ODQ
- 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
- PSS
- physiological salt solution
- Kv
- voltage-gated K+
- KCa
- calcium-sensitive K+
- KATP
- ATP-dependent K+
- HPLC
- high-pressure liquid chromatography
- ANOVA
- analysis of variance
- VSMC
- vascular SMC
- Received September 5, 2001.
- Accepted December 4, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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