Induction of immediate early genes expression in the mouse striatum following acute administration of synthetic cathinones.

BACKGROUND: Synthetic cathinones (SCs) form one of the most prominent group of the New Psychoactive Substances. SCs enhance central dopaminergic and noradrenergic neurotransmission, and are used as substitutes for illicit psychostimulants, namely cocaine, amphetamine, and methamphetamine. Changes in the expression of immediate early genes (IEGs) in the striatum underlie the addictive potential of drugs of abuse belonging to distinct pharmacologic groups. This work was aimed to assess the impact of acute administration of the prominent SCs on the mRNA levels of IEGs in the mouse striatum. METHODS: Effects of 3,4-MDPV, 2,3-MDPV, α-PVP, PV8, PV9, methcathinone (MC) and 3-fluoromethcathinone (3-FMC) on the mRNA levels of ten IEGs, one and two hours after exposure, were measured in the mouse striatum using the quantitative RT-PCR technique. RESULTS: All SCs used in the study produced increased mRNA levels of the following IEGs: Areg, c-fos, Csrnp1, Dusp1, Dusp14, Egr2, Egr4 and FosB. Additionally, the majority of SCs increased the expression of Homer1 and c-jun. The magnitude of observed changes varied by the drug, analyzed gene and, in many cases, by time after administration. CONCLUSIONS: This study demonstrates that SCs increase the expression of IEGs in the mouse striatum, which may lead to a plethora of effects, as proteins encoded by the analyzed genes are involved in diverse actions, including an acute response to the drug and the neuroplasticity underlying the development of addiction.

Methcathinone and 3-Fluoromethcathinone Stimulate Spontaneous Horizontal Locomotor Activity in Mice and Elevate Extracellular Dopamine and Serotonin Levels in the Mouse Striatum.

Methcathinone (MC) and 3-fluoromethcathinone (3-FMC) are well-known members of the synthetic cathinone derivatives, the second most abused group of novel psychoactive substances (NPS). They are considered as methamphetamine-like cathinones, as they elicit their psychostimulatory effects via inhibition of monoamine uptake and enhanced release. The present study examines the effects of MC and 3-FMC on the spontaneous locomotor activity of mice and extracellular levels of dopamine and serotonin in the mouse striatum. Both MC and 3-FMC produced a dose-dependent increase of horizontal locomotor activity, but no significant changes in rearing behavior were observed. The locomotor stimulation induced by MC and 3-FMC is mediated by activation of dopaminergic neurotransmission, as selective D1-dopamine receptor antagonist, SCH 23390, abolished the effects of both drugs. In line with pharmacological data obtained by previous in vitro studies, MC and 3-FMC produced potent increases of extracellular dopamine and serotonin levels in the mouse striatum. Taken together, results presented within this study confirm previous findings and expand our knowledge on the pharmacology of MC and 3-FMC along with their behavioral effects.

Effects of the new generation α-pyrrolidinophenones on spontaneous locomotor activities in mice, and on extracellular dopamine and serotonin levels in the mouse striatum.

PURPOSE: Pyrovalerone derivatives (α-pyrrolidinophenones) form a distinct branch of synthetic cathinones, a popular group of novel psychoactive substances, and exert strong psychostimulatory effects resulting from their high potency to inhibit dopamine (DA) and norepinephrine transporters, with negligible activity at the serotonin (5-HT) transporter. In contrast to the old generation α-pyrrolidinophenones, 3,4-MDPV and α-PVP, there is limited data on the pharmacology and toxicology of the novel analogs. Therefore, the present study assesses the in vivo effects of two new pyrovalerones, PV8 and PV9, along with those of α-PVP, on spontaneous locomotor activities of mice and extracellular DA and 5-HT levels in the mouse striatum. METHODS: Spontaneous locomotor activity was measured using Opto-Varimex Auto-Track. Effects of tested compounds on extracellular levels of DA and 5-HT in the striatum were studied by an in vivo microdialysis technique; their concentrations in dialysate fractions were analyzed by high-performance liquid chromatography with electrochemical detection. RESULTS: α-PVP, PV8 and PV9 stimulated mice locomotor activity (an effect being blocked by D1-dopamine receptor antagonist, SCH 23390), and increased extracellular levels of DA and 5-HT in the striatum. Observed effects depend on dose, time and compound under investigation, with α-PVP being more potent than PV8 and PV9. When used at the same dose, the pyrovalerones produced effects significantly weaker than a model, old generation psychostimulant, methamphetamine. CONCLUSIONS: Enhancement of dopaminergic neurotransmission plays a dominant role in the psychomotor stimulation caused by α-PVP, PV8 and PV9. Extending an aliphatic side chain beyond a certain point leads to the decrease in their potency in vivo.

Cytotoxicity of α-Pyrrolidinophenones: an Impact of α-Aliphatic Side-chain Length and Changes in the Plasma Membrane Fluidity.

Pyrovalerone derivatives (α-pyrrolidinophenones) form a branch of synthetic cathinones, a second most prominent group of novel psychoactive substances. Although the toxicity of 3,4-MDPV, a progenitor of the α-pyrrolidinophenones, is well described, little is known of the potential cytotoxicity of the new members of this group entering the recreational drug market each year. The present study assesses the cytotoxicity of members of the α-pyrrolidinophenone group, i.e., α-PVP, its longer side-chain derivatives PV8 and PV9, and their 4-fluoro- and 4-methoxy-analogs, against model cell lines for the nervous system (SH-SY5Y), liver (Hep G2) and upper airway epithelium (RPMI 2650), and cardiomyocytes (H9C2(2-1)). Additionally, an impact of pyrovalerones on the fluidity of the plasma membrane, as the potential mechanism of their cytotoxicity, was examined. The longer side-chain α-pyrrolidinophenones and their fluoro- and methoxy-analogs produce more pronounced maximal cytotoxicity, with regard to mitochondrial activity and cell membrane integrity, than the five-carbon α-PVP and its substituted derivatives. The report demonstrates, for the first time, that changes of fluidity of the interior part of plasma membrane contribute to the cytotoxicity of pyrovalerone derivatives, in addition to the previously reported mechanisms. Taking into consideration our previous findings that PV8 and PV9 produce weaker psychostimulatory effects than α-PVP, the higher cytotoxicity of the new generation of pyrovalerones can pose a serious threat to abusers, as it is possible that longer-chain compounds may be taken in higher doses to obtain similar levels of stimulation.

The effects of topiramate on lipopolysaccharide (LPS)-induced proinflammatory cytokine release from primary rat microglial cell cultures.

A growing body of evidence suggests that inflammatory processes and activation of glial cells could contribute to seizures and epileptogenesis. In various animal studies on epilepsy, proinflammatory cytokines have been demonstrated to exert a proconvulsive activity. On the other hand, it is suggested that antiepileptic drugs could modulate immune system activity. The aim of the present study was to investigate whether topiramate, a new generation antiepileptic drug with a complex mechanism of action, could affect the lipopolysaccharide (LPS)-induced release of TNF-α, IL-1ß and IL-6 from primary rat microglial cell cultures. Proinflammatory cytokines were measured in supernatants of primary rat microglial cell culture with enzyme-linked immunosorbent assay kits. Additionally, the effect of the drug on LPS-evoked changes in mitochondrial metabolic activity was evaluated with the aid of the MTT test. Topiramate (1, 10, 100µg/ml; 24h incubation) produced a statistically significant decrease in LPS-stimulated IL-1ß and IL-6 levels from primary rat microglial cells in a concentration-dependent manner. The drug used at a concentration of 100µg/ml also significantly suppressed TNF-α release. Incubation of microglial cells with topiramate for 24h prevented the LPS-induced increase in their mitochondrial activity. It is suggested that the anti-cytokine action of topiramate could provide an additional mechanism in its antiepileptic activity.

Cytotoxic Activity of Pyrovalerone Derivatives, an Emerging Group of Psychostimulant Designer Cathinones.

The growing popularity of novel psychoactive substances (NPS) has aroused the concerns of public health specialists. The pyrovalerone derivatives are a branch of synthetic cathinones, a very popular group of psychostimulant NPS. Despite numerous case reports of fatal intoxications, little is known about the cytotoxicity of these substances. Therefore, this study was aimed to evaluate the toxic properties of pyrovalerone, its highly prevalent derivative 3,4-methylenedioxypyrovalerone (3,4-MDPV) with its two major metabolites (catechol-MDPV and methylcatechol-MDPV) and the structural isomer 2,3-MDPV, together with newer members of the group, i.e., α-pyrrolidinovalerothiophenone (α-PVT) and α-pyrrolidinooctanophenone (PV9), using model human cell lines for neurons (SH-SY5Y), hepatocytes (Hep G2), and upper airway epithelium (RPMI 2650). We found that the first generation pyrovalerones (pyrovalerone, 3,4-MDPV, and 2,3-MDPV) produced a modest decrease of mitochondrial activity in the three examined cell lines, but were active in lower concentrations than methamphetamine used as a reference psychostimulant compound. Since catechol-MDPV displayed greater toxic potential than the parent compound, we suggest that the toxicity of 3,4-MDPV could be attributed to activity of this metabolite. Strikingly, the two new generation pyrovalerones, α-PVT and PV9, seem to be the most potent cytotoxic compounds: both induced highly pronounced mitochondrial dysfunction; the latter also demonstrated significant damage to cell membranes. The reported in vitro toxic activity of pyrovalerone cathinones against different cell types reinforces existing concerns regarding the health risks associated with the intake of these drugs.

Does retigabine affect the development of alcohol dependence?--A pharmaco-EEG study.

New antiepileptic drugs have been investigated for their potential role in the treatment of alcohol dependence. One of these drugs is retigabine and this study examines the effect of retigabine co-administered with ethanol on the development of alcohol dependence and the course of acute withdrawal syndrome. A pharmaco-EEG method was used to examine this impact in selected brain structures of rabbits (midbrain reticular formation, hippocampus and frontal cortex). Retigabine was administered p.o. at a dose of 5mg/kg/day with ethanol ad libitum for 6 weeks and then alone for 2 weeks during an abstinence period. Changes in bioelectric activity, which demonstrated the inhibitory effect of alcohol on the brain structures, were already visible after 2 weeks of ethanol administration. In the abstinence period, changes were of a different nature and significant neuronal hyperactivity was observed, particularly in the midbrain reticular formation and the hippocampus. This findings reveal that retigabine decreased ethanol-induced changes during both alcohol administration and abstinence periods. In particular, the modulatory effect of retigabine on the hippocampus may be a significant element of its mechanism of action in alcohol dependence therapy.

Next generation of novel psychoactive substances on the horizon - A complex problem to face.

BACKGROUND: The last decade has seen a rapid and continuous growth in the availability and use of novel psychoactive substances (NPS) across the world. Although various products are labeled with warnings "not for human consumption", they are intended to mimic psychoactive effects of illicit drugs of abuse. Once some compounds become regulated, new analogues appear in order to satisfy consumers' demands and at the same time to avoid criminalization. This review presents updated information on the second generation of NPS, introduced as replacements of the already banned substances from this class, focusing on their pharmacological properties and metabolism, routes of administration, and effects in humans. METHODS: Literature search, covering years 2013-2015, was performed using the following keywords alone or in combination: "novel psychoactive substances", "cathinones", "synthetic cannabinoids", "benzofurans", "phenethylamines", "2C-drugs", "NBOMe", "methoxetamine", "opioids", "toxicity", and "metabolism". RESULTS: More than 400 NPS have been reported in Europe, with 255 detected in 2012-2014. The most popular are synthetic cannabimimetics and psychostimulant cathinones; use of psychedelics and opioids is less common. Accumulating experimental and clinical data indicate that potential harms associated with the use of second generation NPS could be even more serious than those described for the already banned drugs. CONCLUSIONS: NPS are constantly emerging on the illicit drug market and represent an important health problem. A significant amount of research is needed in order to fully quantify both the short and long term effects of the second generation NPS, and their interaction with other drugs of abuse.

Voluntary alcohol consumption and plasma beta-endorphin levels in alcohol preferring rats chronically treated with lamotrigine.

Several recent studies have indicated that lamotrigine, similarly to other antiepileptic drugs, may be useful in the therapy of alcohol dependence. The rationale for using lamotrigine in the treatment of alcohol addiction is based on its multiple mechanisms of action which include inhibition of voltage-sensitive sodium channels, modulation voltage-gated calcium currents and transient potassium outward current. However, the known mechanism of lamotrigine does not fully explain its efficacy in alcohol addiction therapy. For this reason we have decided to examine the effect of lamotrigine on the opioid system. Our previous studies showed that topiramate and levetiracetam (antiepileptic drugs) as well as the most effective drugs in alcohol addiction therapy i.e. naltrexone and acamprosate, when given repeatedly, all increased plasma beta endorphin (an endogenous opioid peptide) level, despite operating through different pharmacological mechanisms. It is known that low beta-endorphin level is often associated with alcohol addiction and also that alcohol consumption elevates the level of this peptide. This study aims to assess the effect of repeated treatment with lamotrigine on voluntary alcohol intake and beta-endorphin plasma level in alcohol preferring rats (Warsaw high preferring (WHP) rats). We observed a decrease in alcohol consumption in rats treated with lamotrigine. However we didn't observe significant changes in beta-endorphin level during withdrawal of alcohol, which may indicate that the drug does not affect the opioid system. We suppose that lamotrigine may be useful in alcohol dependence therapy and presents a potential area for further study.

The effects of celiprolol on serum concentrations of proinflammatory cytokines in hypertensive (SHR) and normotensive (WKY) rats.

BACKGROUND: A growing body of evidence suggests that some cardiovascular drugs could modulate the level of proinflammatory cytokines. Therefore, the aim of the present study was to investigate whether celiprolol, a third generation ß-adrenoceptor blocker, affects lipopolysaccharide (LPS)-induced serum concentrations of TNF-α, IL-1ß, IL-6 in normotensive (WKY) and spontaneously hypertensive (SHR) rats. METHODS: Celiprolol (150 mgkg(-1)) or vehicle was administered by gavage once daily for 21 days. Arterial blood pressure was measured in conscious rats, using the tail-cuff method. Serum concentrations of proinflammatory cytokines were measured with enzyme-linked immunosorbent assay kits. Additionally, plasma concentrations of total cholesterol, HDL-cholesterol and triglycerides were evaluated. RESULTS: In normotensive WKY rats celiprolol did not affect heart rate, blood pressure, or the serum concentrations of triglycerides, total cholesterol or HDL-cholesterol. In hypertensive animals the drug decreased lipid parameters, increased diastolic and mean blood pressure after the first week of administration, and produced a small but significant decrease in heart rate after the first two weeks of the treatment. In both groups of animals, celiprolol decreased LPS-stimulated serum concentration of IL-6 but did not affect levels of TNF-α and IL-1ß. CONCLUSIONS: It is suggested that the IL-6-modulating properties of celiprolol could provide additional value to the therapeutic effectiveness of the drug in the treatment of hypertension.

Effect of repeated treatment with topiramate on voluntary alcohol intake and beta-endorphin plasma level in Warsaw alcohol high-preferring rats.

RATIONALE: Pharmacological treatment currently used for alcohol dependence is not sufficient for the all patients, and there is a crucial need to find more effective treatments. Recent studies indicate that topiramate is likely the most promising new medication for alcohol dependence. The rationale for topiramate as treatment for alcohol addiction is based on its multifaceted neurochemical activity that targets multiple neural pathways. OBJECTIVES: This study aims to assess the effect of repeated treatment with topiramate on voluntary alcohol intake and beta-endorphin plasma level in rats selectively bred for high alcohol preference. METHODS: Initially, Warsaw high preferring rats (N = 50) were given a 24-h/day free choice between a 10 % (v/v) alcohol solution and water for three consecutive weeks. Subsequently, rats were administered with topiramate (40 or 80 mg/kg b.w.) or vehicle for 14 days and ethanol intake was measured daily. Subsequently, we examined the effects of topiramate on plasma beta-endorphin levels, while alcohol was available and when it was not available for an extended period time. RESULTS: We observed significantly increase in the levels of beta-endorphin in rats with free access to alcohol both in a topiramate- or vehicle-treated group. However, in topiramate-treated group, a voluntary consumption of alcohol diminished in comparison with the vehicle-treated rats. CONCLUSION: The results from this study indicated that topiramate reduces voluntary alcohol intake and support our previous findings that the increase of beta-endorphin level is responsible at least partly for the effectiveness of drugs in treating the alcohol addiction.

[Health consequences of shift work]. / Skutki zdrowotne pracy zmianowej.

In humans many biochemical, physiological and behavioral processes occur in a rhythmic manner. Accumulating experimental and epidemiological evidence indicate that disturbances in biological rhythms could lead to unfavorable alterations in body function, thus exerting negative health impact. In industrialized countries, it is estimated that between 15 and 30% of the working population is involved in some kind of permanent night work and rotating shift work. Today, shift work is regarded as a significant occupational stressor which has marked negative effects on both health and well-being. This review surveys data on association between shift work and health problems, including sleep disorders, cardiovascular disease, peptic ulcer, metabolic syndrome, breast cancer and undesirable pregnancy outcome.

[Epilepsy and pro-inflammatory cytokines. Immunomodulating properties of antiepileptic drugs]. / Padaczka a cytokiny prozapalne. Immunomodulujace wlasciwosci leków przeciwpadaczkowych

Epilepsy is a complex and multifactorial phenomenon. Accumulating evidence suggests that the immune system may play an important role in neuronal excitability and epileptogenesis. In many animal models of epilepsy, seizures induced chemically or electrically cause glial activation and increased expression of pro-inflammatory cytokines (IL-1 ß, TNF- α, IL-6). The studies show that the IL-1 ß /IL-1Ra system may modulate epileptic activity and contribute to neuronal excitability. Exogenous IL-1 ß has pro-convulsive properties. The action of TNF- α and IL-6 is complex (either stimulating or inhibitory action of these cytokines on seizures, depending on their concentration and the type of receptors involved in the response). In vitro and in vivo experiments show that antiepileptic drugs could affect cytokine levels (e.g. valproate significantly inhibited production of TNF- α and IL-6 by human monocytic leukaemia cells). In epilepsy patients studies (including ex vivo) show elevated levels of IL-1 ß, IL-2, IL-5, IL-6 or TNF- α after carbamazepine, valproic acid and phenytoin. This review surveys the current state of knowledge regarding effects of pro-inflammatory cytokines on seizure pathogenesis. Cytokine modulatory actions of some antiepileptic drugs are also discussed.

Does nebivolol influence serum concentrations of proinflammatory cytokines in hypertensive (SHR) and normotensive (WKY) rats?

A growing body of evidence suggests that some drugs used in cardiovascular diseases may modulate the level of proinflammatory cytokines. In the present study we examined whether nebivolol, a third generation beta-adrenergic blocker, influences lipopolysaccharide (LPS)-induced serum concentrations of TNF-alpha, IL-1beta, and IL-6 in normotensive (WKY) and spontaneously hypertensive rats (SHR). Nebivolol (5 mg/kg and 10 mg/kg) or vehicle were administered by gavage once a day for 21 days. The drug (5 mg/kg and 10 mg/kg) did not modify LPS-stimulated serum concentrations of TNF-alpha, IL-1beta and IL-6 in normotensive or hypertensive rats and did not affect the total cholesterol and HDL cholesterol level. Nebivolol, at the dose of 10 mg/kg, significantly increased the triglyceride concentration in SHR only. The results were accompanied by a statistically significant decrease in systolic, diastolic and mean blood pressure after 21 days of both of the drug doses. In hypertensive and normotensive rats, nebivolol had a hypotensive activity and neutral effect on lipid profile. In our in vivo model, the immunomodulating effect of the drug was not significant and probably did not depend on hemodynamic action.

[Angiotensin (1-7): a new link in the renin-angiotensin-aldosterone system (RAAS)]. / Angiotensyna (1-7)--nowe ogniwo ukladu renina-angiotensyna-aldosteron (RAA).

The discovery of a new angiotensin-converting enzyme (ACE2) and studies of the biological activity of angiotensin (1-7) indicate the complexity of the functioning of the renin-angiotensinaldosterone system (RAAS). In this paper the activities of angiotensin (1-7) are summarized. Angiotensin (1-7) has vasodilating, antiproliferative, antifibrotic, and antithrombotic properties which antagonize the action of angiotensin II. This indicates new possibilities for the future use of these effects for better treatment efficiency of cardiovascular diseases.

Influence of mirtazapine on the hypotensive activity of enalapril and propranolol in spontaneously hypertensive rats.

Mirtazapine is a noradrenergic and specific serotonergic antidepressant. The influence of the drug on the cardiovascular system has not been definitely determined. Therefore, we made an attempt to evaluate the influence of chronic administration of mirtazapine on the hypotensive action of a single administered dose of propranolol and enalapril in spontaneously hypertensive rats. The animals were divided into eight experimental groups. Mirtazapine (5 and 10 mg/kg) was administered intraperitoneally for 14 days. Twenty-four hours after the last administration of the drug, the rats received a single intraperitoneal dose of hypotensive drugs (propranolol 5 mg/kg or enalapril 10 mg/kg) or 1% solution of methylcellulose. Mirtazapine administered chronically did not affect the hypotensive effect of a single dose of propranolol or enalapril in spontaneously hypertensive rats. It seems that mirtazapine could be a useful drug in patients with depression accompanied by hypertension.

Influence of enalapril, quinapril and losartan on lipopolysaccharide (LPS)-induced serum concentrations of TNF-alpha, IL-1 beta, IL-6 in spontaneously hypertensive rats (SHR).

Immunopharmacological studies of drugs used in cardiovascular diseases provide new data concerning their modulating effect on the levels of proinflammatory cytokines, chemokines and adhesion molecules. Therefore, we have made an attempt to find out whether enalapril, quinapril and losartan (drugs used in the treatment of arterial hypertension) are able to modulate lipopolysaccharide (LPS)-induced proinflammatory cytokine serum concentrations (tumor necrosis factor alpha - TNF-alpha, interleukin-1 beta _ IL-1 beta, interleukin-6 - IL-6) in spontaneously hypertensive rats (SHR). The animals were divided into four groups as follows: SHR + M (control rats receiving 1% solution of methylcellulose), SHR + E (rats receiving enalapril - 10 mg/kg), SHR + Q (rats receiving quinapril - 10 mg/kg) and SHR + L(rats receiving losartan - 20 mg/kg). 1% solution of methylcellulose and hypotensive drugs were administered by a gavage for 21 days. Arterial blood pressure was measured in conscious rats, using the tail-cuff method. Twenty four hours after the last administration of enalapril, quinapril, losartan or 1% solution of methylcellulose, the rats received a single dose of LPS (ip; 0.1 mg/kg). After 2 h, the rats were anesthetized with ether and the blood samples were collected by heart puncture. Serum TNF-alpha, IL-1 beta and IL-6 concentrations were measured with enzyme-linked immunosorbent assay kits. Additionally, total cholesterol and high density lipoprotein (HDL) cholesterol were evaluated. Enalapril, quinapril and losartan significantly decreased LPS-stimulated TNF-alpha and IL-1 beta level after 21 days. Three-week administration of quinapril lowered IL-6 serum concentration after LPS stimulation. Enalapril and losartan did not affect the IL-6 level. The results were accompanied by a statistically significant decrease in systolic, diastolic and mean blood pressure. Hypotensive drugs also showed no effect on lipid level. The latest data indicate additional properties of hypotensive drugs. However, further studies are necessary to elucidate precisely the role of proinflammatory cytokines in arterial hypertension.

Influence of amlodipine and atenolol on lipopolysaccharide (LPS)-induced serum concentrations of TNF-alpha, IL-1, IL-6 in spontaneously hypertensive rats (SHR).

An increasing body of evidence suggests that cytokines may play a role in the pathogenesis of cardiovascular diseases. Immunopharmacological studies provide new information on immunomodulating activity of some drugs, including their effect on the level of pro-inflammatory cytokines. The aim of the present study was to find out whether amlodipine and atenolol, drugs applied in the treatment of arterial hypertension, can modulate lipopolysaccharide (LPS)-induced pro-inflammatory cytokine level (TNF-alpha, IL-1, IL-6) in spontaneously hypertensive rats (SHR). The experiments were performed on 4 groups of animals as follows: WKY + MET(control Wistar-Kyoto normotensive rats), SHR + MET(control hypertensive rats), SHR + AML(hypertensive rats receiving amlodipine), SHR + AT (hypertensive rats receiving atenolol). Control rats received 1% solution of methylcellulose (1 ml/kg) by a gavage. Amlodipine and atenolol were administered by a gavage at doses of 15 mg/kg and 25 mg/kg, respectively. Arterial blood pressure was measured in conscious rats, using the tail-cuff method. Serum tumor necrosis factor alpha (TNF)-alpha, interleukin (IL)-1 and IL-6 concentrations were measured with enzyme-linked immunosorbent assay kits. Additionally, lipid levels were evaluated. The present data provide the evidence that amlodipine and atenolol act as immunomodulators of pro-inflammatory cytokines in SHR. Amlodipine decreased TNF-alpha, increased IL-6 and did not affect IL-1 level. Atenolol did not influence TNF-alpha and IL-1, but raised IL-6 in SHR. Additionally, amlodipine decreased total cholesterol level without changing HDL cholesterol level whereas atenolol did not influence lipid levels. The identification of additional immunomodulating properties of hypotensive drugs may be important for better understanding of their mechanisms of action.

[Drugs used in cardiovascular diseases and cytokines]. / Leki stosowane w chorobach ukladu krazenia a cytokiny.

Immunopharmacological studies show that medicines used in cardiovascular diseases (atherosclerosis, ischaemic heart disease, heart failure) can exert immunomodulatory effects on proinflammatory cytokines. In the paper the influence of statins, fibrates, angiotensin converting enzyme inhibitors (ACEI), beta-blockers, calcium channel blockers and phosphodiesterase inhibitors on the activity of cytokines was introduced.

Interaction of mianserin and some hypotensive drugs in Wistar rats.

Mianserin is thought to exert little effect on the cardiovascular system. In fact its safety in comparison with tricyclic drugs is high. Various experiments gave varying results as for the influence of the drug on arterial blood pressure in people and animals. Therefore, a study was undertaken in Wistar rats to evaluate interactions of mianserin administered intraperitoneally as a single dose, and for 21 days with 3 hypotensive drugs showing different mechanism of action (propranolol, enalapril, prazosine). The systolic, diastolic and mean blood pressure was measured with a LETICA apparatus. The results of the study revealed that administration of mianserin in normotensive rats leads to a short-term decrease in blood pressure and significantly enhanced the hypotensive effect of prazosine. Repeated doses of mianserin lead to a temporary increase in blood pressure after 2 weeks of administration. Single and repeated administration of mianserin did not change the hypotensive effect of propranolol and enalapril. Three-week therapy with mianserin significantly enhanced the hypotensive effect of prazosine.