102 research outputs found
Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase activity? : a contribution to the ongoing discussion
The aim of the study presented here was an attempt
to answer the question posed in the title: Is the mechanism of nitroglycerin tolerance associated with aldehyde dehydrogenase (ALDH) activity? Here, we investigated the effect of administration (separately or jointly) of lipoic acid (LA), nitroglycerin (GTN), and disulfiram (DSF; an irreversible in vivo inhibitor of all ALDH
isozymes (including ALDH2)), on the development of
tolerance to GTN. We also assessed the total activity
of ALDH in the rat liver homogenates. Our data revealed that not only DSF and GTN inhibited the total
ALDH activity in the rat liver, but LA also proved to
be an inhibitor of this enzyme. At the same time, the
obtained results demonstrated that the GTN tolerance
did not develop in GTN, DSF and LA jointly treated
rats, but did develop in GTN and DSF jointly treated
rats. This means that the ability of LA to prevent GTN
tolerance is not associated with the total ALDH activity in the rat liver. In this context, the fact that animals
jointly receiving GTN and DSF developed tolerance to
GTN, and in animals that in addition to GTN and DSF
also received LA such tolerance did not develop, is -
in our opinion - a sufficient premise to conclude that
the nitrate tolerance certainly is not caused by a decrease in the activity of any of the ALDH isoenzymes
present in the rat liver, including ALDH2. However,
many questions still await an answer, including the
basic one: What is the mechanism of tolerance to nitroglycerin
Can lipoic acid attenuate cardiovascular disturbances induced by ethanol and disulfiram administration separately or jointly in rats?
HBK-14 and HBK-15 do not influence blood pressure, lipid profile, glucose level, or liver enzymes activity after chronic treatment in rats
Older and even new antidepressants cause adverse effects, such as orthostatic hypotension, hyper- or hypoglycemia, liver injury or lipid disorders. In our previous experiments we showed significant antidepressant- and anxiolytic-like activities of dual 5-HT1A and 5-HT7 antagonists with α1-adrenolitic properties i.e. 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15). Here, we evaluated the influence of chronic administration of HBK-14 and HBK-15 on blood pressure (non-invasive blood pressure measurement system for rodents), lipid profile (total cholesterol, low density lipoproteins-LDL, high density lipoproteins-HDL, triglycerides), glucose level, and liver enzymes activity (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase). We determined potential antihistaminic (isolated guinea pig ileum) and antioxidant properties (ferric reducing ability of plasma-FRAP, non-protein thiols-NPSH, stable free radical diphenylpicrylhydrazyl-DPPH) cytotoxicity. Our experiments revealed that HBK-14 and HBK-15 did not influence blood pressure, lipid profile, glucose level or liver enzymes activity in rats after 2-week treatment. We also showed that none of the compounds possessed antioxidant or cytotoxic properties at antidepressant- and anxiolytic-like doses. HBK-14 and HBK-15 very weakly blocked H1 receptors in guinea pig ileum. Positive results of our preliminary experiments on the safety of HBK-14 and HBK-15 encourage further studies concerning their effectiveness in the treatment of depression and/or anxiety disorders
Yohimbine improves lipid and carbohydrate profiles without reduction in body weight in obese leptin-deficient ob/ob mice
The effect of lipoic acid administration on the urinary excretion of thiocyanate in rats exposed to potassium cyanide
The oxidation of cyanide (CN-) to a much less toxic thiocyanate (SCN-) is the main in vivo biochemical pathway for CN- detoxification. SCN- is excreted mainly in urine. This study was performed to investigate the effect of lipoic acid (LA) on the urinary excretion of thiocyanate (SCN- ; rhodanate) in rats. Groups of the animals were treated intraperitoneally (i.p.) as follows: group 1: potassium cyanide (KCN) (1 mg/kg); group 2: KCN (1 mg/kg) + LA (100 mg/kg). Urine was collected for 24 h and the pooled samples were examined for SCN- levels. The obtained results indicated that the treatment of animals with potassium cyanide and LA in combination significantly increased the urinary excretion of SCN- in comparison w ith the respective values in the KCN-alone-treated group. It indicates that LA increased the rate of CN- detoxification in rats
Idalopirdine : a small molecule antagonist of 5-HT_6 with therapeutic potential against obesity
5HT(6) receptor antagonists offer the potential for safe and effective drugs against obesity, because they can reduce weight without causing serious side effects in the cardiovascular system. Also, their anorexic effect is associated with reduced food intake via an enhancement of satiety. In the present study we investigated the anorexic effect of idalopirdine (LuAE58054) in a model of obesity induced by high-fat diet. To induce obesity in rats, the animals were treated with feed with a fat content of 40 %. Body weight was controlled and the amount of food and water consumed was determined. The influence of the test compound on the lipid profile and glucose level was measured, as well as locomotor activity in home cages on the 20th day of the treatment. LuAE58054, at 5 mg kg(−1)/day i.p., was significantly anorectic in this model of obesity. Animals treated with LuAE58054 weighed 8 and 9.2 % less than the control obese animals on the 12th and 21st days, respectively. It significantly reduced food intake and the amount of peritoneal fat in animals, and reduced the level of triglycerides in plasma. LuAE58054 did not have a statistically significant effect on the spontaneous activity of diet-induced obese rats. The present study clearly demonstrates the effectiveness of LuAE58054 in reducing body weight. This compound is in phase III of clinical trials for the treatment of cognitive deficits associated with Alzheimer’s disease and schizophrenia. It is a 5HT(6) receptor antagonist and is, therefore, free of those unacceptable side effects that preclude chronic use of anti-obesity drugs with other mechanisms of action. The search for an effective and safe anti-obesity drug is essential for an increasingly obese population; therefore, the anorectic action of LuAE58054 is important and there is a need for more research in this direction
Idalopirdine, a selective 5-HT_6 receptor antagonist, reduces food intake and body weight in a model of excessive eating
Metabolic benefits of 1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one : a non-selective α-adrenoceptor antagonist
Purpose Previous studies have shown that several components
of the metabolic syndrome, such as hypertension,
obesity or imbalanced lipid and carbohydrate homeostasis,
are associated with the sympathetic nervous system overactivity.
Therefore, the inhibition of the adrenergic nervous
system seems to be a reasonable and appropriate therapeutic
approach for the treatment of metabolic disturbances. It
has been suggested that non-selective adrenoceptor antagonists
could be particularly beneficial, since 1-adrenoceptor
antagonists can improve disrupted lipid and carbohydrate
profiles, while the inhibition of the 2-adrenoceptor may
contribute to body weight reduction. The aim of the present
study was to investigate the metabolic benefits deriving
from administration of a non-selective -adrenoceptor
antagonist from the group of pyrrolidin-2-one derivatives.
The aim of the present study was to investigate the potential
metabolic benefits deriving from chronic administration o a non-selective -adrenoceptor antagonist, from the group
of pyrrolidin-2-one derivatives.
Methods The 1- and 2-adrenoreceptor affinities of the
tested compound-1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)
pyrrolidin-2-one had been investigated previously by means
of the radioligand binding assay. In the present study, we
extended the pharmacological profile characteristics of the
selected molecule by additional intrinistic activity assays.
Next, we investigated the influence of the tested compound
on body weight, hyperglycemia, hypertriglyceridemia, blood
pressure in the animal model of obesity induced by a highfat
diet, and additionally we measured the spontaneous activity
and body temperature.
Results The intrinistic activity studies revealed that the
tested compound is a potent, non-selective antagonist of
1B and 2A-adrenoceptors. After the chronic administration
of the tested compound, we observed reduced level of
triglycerides and glucose in the rat plasma. Interestingly, the
tested did not reduce the body weight and did not influence
the blood pressure in normotensive animals. Additionally,
the administration of the tested compound did not change the
animals' spontaneous activity and body temperature.
Conclusion Non-selective -adrenoceptor antagonist
seems to carry potential benefits in the improvement of the
reduction of elevated glucose and triglyceride level. The lack
of influence on blood pressure suggests that compounds with
such a pharmacological profile may be particulary beneficial
for the patients with disturbed lipid and carbohydrate
profile, who do not suffer from hypertension. These results
are particulary valuable, since currently there are no safe
2A-adrenoceptor antagonist drugs available in clinical use
with the ability to modulate hyperglycemia that would not
affect blood pressure
Single administration of HBK-15 : a triple 5-HT_{1A}, 5-HT_{7}, and 5-HT_{3} receptor antagonist : reverses depressive-like behaviors in mouse model of depression induced by corticosterone
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