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Calcium antagonist and antiperoxidant properties of some hindered phenols
Author(s) -
Sgaragli G.P.,
Valoti M.,
Gorelli B.,
Fusi F.,
Palmi M.,
Mantovani P.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13819.x
Subject(s) - chemistry , nifedipine , papaverine , butylated hydroxyanisole , verapamil , antioxidant , linoleic acid , phenols , calcium , propyl gallate , pharmacology , biochemistry , stereochemistry , endocrinology , organic chemistry , medicine , fatty acid
1 The calcium antagonist and antioxidant activities of certain synthetic and natural phenols, related to BHA (2‐ t ‐butyl‐4‐methoxyphenol), were evaluated in rat ileal longitudinal muscle and in lipid peroxidation models respectively. 2 Compounds with a phenol or a phenol derivative moiety, with the exception of 2,2′‐dihydroxy‐3,‐3′‐di‐ t ‐butyl‐5,5′‐dimethoxydiphenyl (di‐BHA), inhibited in a concentration‐dependent manner the BaCl 2 ‐induced contraction of muscle incubated in a Ca 2+ ‐free medium. Calculated pIC 50 ( m ) values ranged between 3.32 (probucol) and 4.96 [3,5‐di‐ t ‐butyl‐4‐hydroxyanisole (di‐ t ‐BHA)], with intermediate activity shown by khellin < gossypol < quercetin < 3‐ t ‐butylanisole < BHA < nordihydroguaiaretic acid (NDGA) < 2,6‐di‐ t ‐butyl‐4‐methylphenol (BHT) and papaverine. 3 The Ca 2+ 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 also inhibited in a concentration‐dependent fashion CaCl 2 contractions of muscle depolarized by a K + ‐rich medium. This inhibition appeared to be inversely affected by the Ca 2+ ‐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 μ m Ca 2+ or 500 μ m Ba 2+ , 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 compound or on lipid peroxidation of rat liver microsomes promoted by Fe 2+ ions. Across both model systems, di‐ t ‐BHA, NDGA, BHT, di‐BHA, BHA and quercetin ranked as the most potent inhibitors of lipid oxidation, with calculated pIC 50 ( m ) values ranging between 7.4 and 5.7. 7 Of the 32 compounds studied only 15 phenolic derivatives exhibited both antispasmogenic and antioxidant activity. Within this subgroup a linear and significant 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 highly 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 after ischaemia‐reperfusion injury.