Sgaragli Gp

Calcium antagonist and antiperoxidant properties of some hindered phenols

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 5 μm Ca2+ or 500 μm 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 pIC50 (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.

(+/−)-Naringenin as large conductance Ca2+-activated K+ (BKCa) channel opener in vascular smooth muscle cells

The aim of this study was to investigate, in vascular smooth muscle cells, the mechanical and electrophysiological effects of (+/−)‐naringenin.

Interaction of butylated hydroxyanisole with mitochondrial oxidative phosphorylation.

The antioxidant, butylated hydroxyanisole (BHA), has a number of effects on mitochondrial oxidative phosphorylation. In this study we apply the novel approach developed by Brand (Brand MD, Biochim Biophys Acta 1018: 128-133, 1990) to investigate the site of action of BHA on oxidative phosphorylation in rat liver mitochondria. Using this approach we show that BHA increases the proton leak through the mitochondrial inner membrane and that it also inhibits the delta p (proton motive force across the mitochondrial inner membrane) generating system, but has no effect on the phosphorylation system. This demonstrates that compounds having pleiotypic effects on mitochondrial oxidative phosphorylation in vitro can be analysed and their many effects distinguished. This approach is of general use in analysing many other compounds of pharmacological interest which interact with mitochondria. The implications of these results for the mechanism of interaction of BHA with mitochondrial oxidative phosphorylation are discussed.

The effect of pulsed electromagnetic fields on the physiologic behaviour of a human astrocytoma cell line

We evaluated the effects of 50 Hz pulsed electromagnetic fields (EMFs) with a peak magnetic field of 3 mT on human astrocytoma cells. Our results clearly demonstrate that, after the cells were exposed to EMFs for 24 h, the basal [Ca(2+)](i) levels increased significantly from 124+/-51 nM to 200+/-79 nM. Pretreatment of the cells with 1.2 microM substance P increased the [Ca(2+)](i) to 555+/-278 nM, while EMF exposure caused a significant drop in [Ca(2+)](i) to 327+/-146 nM. The overall effect of EMFs probably depends on the prevailing Ca(2+) conditions of the cells. After exposure, the proliferative responses of both normal and substance P-pretreated cells increased slightly from 1.03 to 1.07 and 1.04 to 1.06, respectively. U-373 MG cells spontaneously released about 10 pg/ml of interleukin-6 which was significantly increased after the addition of substance P. Moreover, immediately after EMF exposure and 24 h thereafter, the interleukin-6 levels were more elevated (about 40%) than in controls. On the whole, our data suggest that, by changing the properties of cell membranes, EMFs can influence Ca(2+) transport processes and hence Ca(2+) homeostasis. The increased levels of interleukin-6 after 24 h of EMF exposure may confirm the complex connection between Ca(2+) levels, substance P and the cytokine network.

The flavonoid scaffold as a template for the design of modulators of the vascular Cav1.2 channels

BACKGROUND AND PURPOSE Previous studies have pointed to the plant flavonoids myricetin and quercetin as two structurally related stimulators of vascular Cav1.2 channel current (ICa1.2). Here we have tested the proposition that the flavonoid structure confers the ability to modulate Cav1.2 channels.

Synthesis and antiperoxidant activity of new phenolic O-glycosides.

We describe the synthesis of some 3-tert-butyl-4-hydroxyphenyl D-glycopyranosides by reaction of tert-butylhydroquinone with beta-D-pentaacetyl-glucose, beta-D-pentaacetyl-galactose, 2-acetamido- and 3,4,6-tri-O-acetyl-2-butanamido-2-deoxy-beta-D-glucopyranosyl chlorides as well as the formation of anomeric 3-tert-butyl-4-hydroxyphenyl 4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-2-eno-pyranosides by reaction between tert-butylhydroquinone and 3,4,6-tri-O-acetyl-D-glucal. All compounds, except 3-tert-butyl-4-hydroxyphenyl alpha- and beta-D-glucopyranosides, inhibited lipid peroxidation with a degree of potency comparable to that of tert-butyl hydroxyanisole.

Increase of extracellular brain calcium involved in interleukin‐1β‐induced pyresis in the rabbit: antagonism by dexamethasone

1 This study investigates the role of extracellular brain calcium in the hyperthermia induced by interleukin‐1β (IL‐1β). 2 Intracerebroventricular (i.c.v.) injection of IL‐1β (12.5 ng kg−1) in rabbits caused a prompt and sustained rise in cerebrospinal fluid (CSF) Ca2+ concentration ([Ca2+]) followed by enhanced prostaglandin E2 (PGE2) release and hyperthermia. 3 A linear and significant correlation was observed between the increase in [Ca2+] induced by IL‐1β and the rise in body temperature. 4 Ventriculo‐cisternal perfusion with artificial CSF containing the calcium chelator EGTA (1.3 mm) blocked the IL‐1‐induced PGE2 release and countered the febrile response. 5 I.c.v. administration of dexamethasone (Dex) (2.4 and 24 μg kg−1) 100 min prior to IL‐1β, dose‐dependently antagonized the cytokine‐induced Ca2+ increase, the PGE2 release and the febrile response. 6 These results suggest that changes in extracellular brain calcium are involved in the regulation of body temperature. In this light, the antipyretic action of Dex may be related to its effect on Ca2+ uptake.

Chlorimipramine-induced phospholipidosis: biochemical and pharmacokinetic observations in the rat.

Subchronic treatment of rats with the antidepressant drug chlorimipramine produced an accumulation of phospholipids (PL) which was particularly evident in lung and to a lesser extent in liver and spleen. The overall increase in PL was mostly sustained by phosphatidylcholine. Both chlorimipramine and its demethylated metabolite were preferentially accumulated by lung reaching levels of about two orders of magnitude higher than those found in plasma. A significant correlation between the percentage increase in phospholipid contents and drug metabolite tissue level was evidentiated.

In Vivo Release of Taurine from Rat Neostriatum and Substantia Nigra

Taurine has been shown to fulfil many of the criteria of a neurotransmitter in the basal ganglia. The neostriatum (STR) and substantia nigra (SN) contain high levels of taurine and its synthetic enzyme sulfinoalanine decarboxylase (EC 4.1.1.29, commonly referred to as cysteine sulfinic acid decarboxylase, CSDI)19, 29, 34, 41, 43, 45. The presence of a high affinity uptake system for taurine has been detected in both the STR11, 29 and SN14. Furthermore, uptake and release studies of exogenous radiolabelled taurine suggest that neurones identified as medium-size densely spiny striatonigral neurones contain taurine and release it at their terminals in the SN15 (see Table 1).

Quercetin relaxes rat tail main artery partly via a PKG-mediated stimulation of KCa1.1 channels

Protein kinases, activated by vasodilator substances, affect vascular function by regulating large conductance Ca2+‐activated K+ (KCa1.1) channels. Thus, the aim of the present investigation was to address the hypothesis that quercetin‐induced vasorelaxation is caused by a PKG‐mediated stimulation of KCa1.1 currents.