CALCIUM-ANTAGONIST AND ANTIPEROXIDANT PROPERTIES OF SOME HINDERED PHENOLS

1 The calcium antagonist and antioxidant activities of certain synthet ic and natural phenols, related to BHA (2-t-butyl-4-methoxyphenol), we re evaluated in rat ileal longitudinal muscle and in lipid peroxidatio n models respectively. 2 Compounds with a phenol or a phenol derivativ e moiety, with the exception of -dihydroxy-3,-3'-di-t-butyl-5,5'-dimet hoxydiphenyl (di-BHA), inhibited in a concentration-dependent manner t he BaCl2-induced contraction of muscle incubated in a Ca2+-free medium . Calculated pIC50 (m) values ranged between 3.32 (probucol) and 4.96 [3,5-di-t-butyl-4-hydroxyanisole (di-t-BHA)], with intermediate activi ty shown by khellin < gossypol < quercetin < 3-t-butylanisole < BHA < nordihydroguaiaretic acid (NDGA) < 2,6-di-t-butyl-4-methylphenol (BHT) and papaverine. 3 The Ca2+ channel activator Bay K 8644 overcame the inhibition sustained by nifedipine, BHA and BHT, while only partially reversing that of papaverine. 4 BHA, BHT, nifedipine and papaverine al so inhibited in a concentration-dependent fashion CaCl2 contractions o f muscle depolarized by a K+-rich medium. This inhibition appeared to be inversely affected by the Ca2+-concentration used. 5 The inhibitory effects of nifedipine, papaverine, BHA and BHT were no longer present when muscle contraction was elicited in skinned fibres by 5 mum Ca2or 500 muM Ba2+, suggesting a plasmalemmal involvement of target sites in spasmolysis. 6 Comparative antioxidant capability was assessed in two peroxyl radical scavenging assay systems. These were based either on the oxidation of linoleic acid initiated by a heat labile azo compo und or on lipid peroxidation of rat liver microsomes promoted by Fe2ions. Across both model systems, di-t-BHA, NDGA, BHT, di-BHA, BHA and quercetin ranked as the most potent inhibitors of lipid oxidation, wit h calculated pIC50 (m) values ranging between 7.4 and 5.7. 7 Of the 32 compounds studied only 15 phenolic derivatives exhibited both antispa smogenic and antioxidant activity. Within this subgroup a linear and s ignificant correlation was found between antispasmogenic activity and antioxidation. These bifunctional compounds were characterized by the presence of at least one hydroxyl group on the aromatic ring and a hig hly lipophilic area in the molecule. 8 Di-t-BHA is proposed as a lead reference compound for future synthesis of new antioxidants combining two potentially useful properties in the prevention of tissue damage a fter ischaemia-reperfusion injury.