Calcium antagonist and antiperoxidant properties of some hindered phenols

Abstract

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 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 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 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 also inhibited in a concentration-dependent fashion CaCl2 contractions of 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 5LM Ca2+ or 500 gM 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 compound or on lipid peroxidation of rat liver microsomes promoted by Fe2+ 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 pICso (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 ischaemiareperfusion injury.

Blockade of swelling‐induced chloride channels by phenol derivatives

“…A tight link between NDGA-lipoxygenase and RVD (Doroshenko, 1991;Mastracola et al, 1991;Mochizuki et al, 1992), potassium channels (Piomelli et al, 1987;Kim et al, 1989;Kurachi et al, 1989), calcium channels (Peppelenbosch et al, 1992) and sodium channels (Cantiello et al, 1990) was also proposed. The present experiments suggest that the blocking effect of NDGA on the swelling-induced chloride channels could also be explained by a direct interaction of NDGA with the channel itself as was shown for calcium channels (Sgaragli et al, 1993;Wang et al, 1993).…”

Action of probucol in arteries from normal and hypercholesterolaemic rabbits

“…In this experiment probucol was found to be the most potent compound studied (Sgaragli et al, 1993). Furthermore, khellin has been shown to depress both contractility and 45Ca2+ uptake in vascular smooth muscle (Ubeda et al, 1991).…”

Hyperosmolar Solution Effects in Guinea Pig Airways. III. Studies on the Identity of Epithelium-Derived Relaxing Factor in Isolated Perfused Trachea Using Pharmacological Agents

“…The mechanism by which this effect occurred is not clear, because gossypol inhibits endothelium-dependent relaxation factor-mediated relaxation (Radermacher et al, 1990), lipoxygenase (Kulkarni and Sajan, 1997), phospholipase A 2 (Soubeyrand et al, 1997), protein kinase C (Pelosin et al, 1990), gap junctions (Ye et al, 1990), and Ca 2ϩ chan- nels (Sgaragli et al, 1993;Bai and Shi, 2002). Of relevant importance, gossypol inhibits channels and transporters that are involved in cell volume regulation, i.e., taurine channels (Ballatori et al, 1995), myo-inositol uptake (Strange et al, 1993) and volume-activated Cl Ϫ channels that are also sensitive to 4,4Ј-diisothiocyano-2,2Ј-stilbene disulfonate (Gschwentner et al, 1996;Szucs et al, 1996), an agent that blocks EpDRF-induced relaxation .…”