Neuroprotection afforded by some hindered phenols and alpha-tocopherol in guinea-pig detrusor strips subjected to anoxia-glucopenia and reperfusion-like conditions.
2-t-butyl-4-methoxyphenol (BHA), 3,5-di-t-butyl-hydroxyanisole (DTBHA), 2,6-diisopropylphenol (propofol), alpha-tocopherol (alpha-TOC) and two newly synthesised analogues of BHA, namely 1-O-(4-hydroxy-3-t-butyl)phenyl-2,3,4,6-tetra-O-acetyl-beta-D-glucopyranose (beta-TAG) and 1-O-(4-hydroxy-3-t-butyl)phenyl-beta-D-glucopyranose (beta-GLU), were tested for their capability to protect the intrinsic nerves of guinea-pig urinary bladder from damage due to anoxia-glucopenia and re-exposure to glucose and O2. Guinea-pig detrusor strips were mounted for tension recording in small organ baths, superfused with warmed Krebs solution and the nerves stimulated electrically either under control or ischaemia-like (anoxia-glucopenia) and reperfusion-like conditions (normal medium re-superfusion). The Ca2+ antagonist activity of the compounds was assessed by their effect on the contraction of detrusor strips induced by 60 mM K+ Krebs solution in the presence of either 0.5 mM or 5 mM Ca2+. The antioxidant activity was illustrated by the ability of the compounds to scavenge peroxyl radicals generated by linoleic acid oxidation. All the compounds, except beta-GLU and alpha-TOC, inhibited in a concentration-dependent manner K+-induced contractions of detrusor muscles, the inhibition being inversely related to the Ca2+ concentration of the perfusion solution; moreover, they exhibited a marked antiperoxidant activity with pIC50 values decreasing in the order: DTBHA > alpha-TOC > BHA > beta-TAG > propofol > beta-GLU. alpha-TOC, BHA, DTBHA and beta-TAG improved significantly the response of the strips to electrical field stimulation either during the anoxia-glucopenia phase or thereafter when recovering during reperfusion, as compared to untreated tissues. The neuroprotection afforded by the phenol derivatives as well as by alpha-TOC was positively correlated to their antioxidant activity, but not to their Ca2+ antagonist activity.
Pessina
F
F
Istituto di Scienze Farmacologiche, Università di Siena, Via E.S. Piccolomini 170, 53100 Siena, Italy.
Kalfin
R
R
Esposito
L
L
Fusi
F
F
Valoti
M
M
Ponticelli
F
F
Sgaragli
G
G
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D005260:Female; D006168:Guinea Pigs; D000860:Hypoxia; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010636:Phenols / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D024502:alpha-Tocopherol / Q000627:therapeutic use*
D000975:Antioxidants; D018696:Neuroprotective Agents; D010636:Phenols; D024502:alpha-Tocopherol