Protective Effects of Serotonin and its Derivatives, N-Feruloylserotonin and N-(p-Coumaroyl) Serotonin, Against Cisplatin-Induced Renal Damage in Mice.

This study examined whether serotonin and two of its derivatives, N -feruloylserotonin and N -( p -coumaroyl) serotonin, have a renoprotective effect in a mouse model of cisplatin-induced acute renal failure. Cisplatin (20 mg/kg body weight) was administered by intraperitoneal injection to male BALB/c mice that had received oral serotonin, N -feruloylserotonin or N -( p -coumaroyl) serotonin (7.5 mg/kg body weight per day) during the preceding 2 days. At 3 days after the cisplatin injection, serum and renal biochemical factors, oxidative stress, inflammation and apoptosis-related protein expression were evaluated, and histological examinations were performed. Cisplatin caused reduction in body weight and an increase in kidney weight; however, N -( p -coumaroyl) serotonin and N -feruloylserotonin attenuated these effects. Moreover, the serotonin derivatives significantly decreased serum urea nitrogen and creatinine levels. They also significantly reduced the level of reactive oxygen species and upregulated the expression of glutathione peroxidase in the kidney. Furthermore, the serotonin derivatives improved the abnormal expression of mitogen-activated protein kinases activation-dependent inflammation- and apoptosis-related protein and caused less renal damage. These results provide important evidence that N -( p -coumaroyl) serotonin and N -feruloylserotonin exert a pleiotropic effect on several parameters related to oxidative stress, inflammation and apoptosis. The derivatives also have a renoprotective effect in cisplatin-treated mice; however, this effect is higher with N -( p -coumaroyl) serotonin.

[Transcranial electrostimulation and serotonin laser phoresis in the athletes experiencing a combined effect of fatigue and psycho-emotional stress]. / Transkranial'naia élektrostimuliatsiia i lazeroforez serotonina u sportsmenov pri sochetanii utomleniia i psikhoémotsional'nogo stressa.

RATIONALE: At sports submaximal loads accompanied by muscle fatigue due to metabolic transformations, the conditions are created for the development of combined endogenous and exogenous emotional stresses. An important role in the development of stress is played by the state of adaptation mechanisms, in which sintoxic and catatoxic programs are involved, as well as the GABA-dopaminergic system. There is insufficient information on the possibilities for reducing the manifestations of stress. PURPOSE: The objective of the presser study was to estimate the possibilities for the prevention of the development of psycho-emotional stress with the use of transcranial electrostimulation in the combination with serotonin laser phoresis. METHODS: The assessment of the psychological status before and after transcranial electrostimulation in the combination with serotonin laser phoresis was performed in 96 athletes who were engaged in weightlifting and athletic gymnastics, as well as in 37 athletes comprising the control group in the state of sparing rest. Transcranial electrostimulation was carried out during 14 days. The laser phoresis of serotonin was conducted with the application of the Matrix device and transcranial electrostimulation with the use of the Magnon-DKS apparatus. The assessment of the psychological status was carried out based on the Hospital Anxiety and Depression Scale (HADS) and the results of the well-being-activity-mood (WAM) questionnaire and in accordance with the Hildebrandt index, and the Spielberger-Hanin test. RESULTS: The two-week course of exposure to transcranial electrostimulation and serotonin laser phoresis of the patients comprising the main group resulted in a faster stabilization of the psychological status than in the control group. This effect was due to the multi-component involvement of the athletes in the adaptation programs including the management of homeostasis and the influence on the GABA-dopaminergic system via the serotonin and opioidergic mechanisms. CONCLUSION: The results of this study give reason to recommend the proposed method of transcranial electrostimulation and serotonin laser phoresis for the use in sports medicine.

Serotonin enhances oxybuprocaine- and proxymetacaine-induced cutaneous analgesia in rats.

The aim of the study was to investigate the analgesic effects of adding serotonin to oxybuprocaine or proxymetacaine preparations. We employed a rat model of the cutaneous trunci muscle reflex (CTMR) to conduct the dose-response curves and duration of drugs (oxybuprocaine, proxymetacaine, or serotonin) as an infiltrative anesthetic. The use of isobolographic methods to analyze the drug-drug interactions. We showed that oxybuprocaine and proxymetacaine, as well as serotonin produced dose-dependent skin antinociception. On the basis of 50% effective dose (ED50), the rank order of drug potency was serotonin [7.22 (6.45-8.09) µmol/kg] < oxybuprocaine [1.03 (0.93-1.15) µmol/kg] < proxymetacaine [0.59 (0.53-0.66) µmol/kg] (P < 0.01 for each comparison). The sensory block duration of serotonin was longer (P < 0.01) than that of oxybuprocaine or proxymetacaine at the equipotent doses (ED25, ED50, and ED75). The mixture of serotonin with oxybuprocaine or proxymetacaine produced a better analgesic effect than the drug itself. We have concluded that oxybuprocaine, proxymetacaine, or serotonin displays dose-related cutaneous analgesia. Oxybuprocaine or proxymetacaine is more potent and has a shorter duration of cutaneous analgesia than serotonin. Serotonin produces a synergistic antinociceptive interaction with oxybuprocaine or proxymetacaine.

Isobolographic analysis of the cutaneous antinociceptive interaction between bupivacaine co-injected with serotonin in rats.

BACKGROUND: The aim of this experiment was to investigate a long-lasting local anesthetic bupivacaine combined with serotonin at inducing cutaneous antinociception. METHODS: The skin antinociception, characterized by an inhibition of the cutaneous trunci muscle reflex (CTMR) following the pinprick on the dorsal skin of rats, was evaluated. The cutaneous antinociceptive effects of bupivacaine alone, serotonin alone, or bupivacaine co-injected with serotonin in a dose-dependent fashion were constructed, while the drug-drug interactions were evaluated by isobologram. RESULTS: Subcutaneous serotonin, as well as the local anesthetic bupivacaine provoked dose-related cutaneous antinociception. On an equipotent basis (50% effective dose [ED50]), the relative potency was bupivacaine (0.43 [0.37-0.50] µmol)>serotonin (1.27 [1.15-1.40] µmol) (p<0.01). At the equi-anesthetic doses (ED75, ED50 and ED25), the duration of bupivacaine was similar to that of serotonin at producing cutaneous antinociceptive effects. Co-administration of bupivacaine and serotonin displayed a synergistic antinociception. CONCLUSIONS: The preclinical data demonstrated that serotonin is less potent in eliciting cutaneous antinociceptive effects but has the similar duration of action, compared with bupivacaine. We also found a more significant depth of the sensory block with bupivacaine+serotonin than bupivacaine alone.

Serotonin modulates response properties of neurons in the dorsal cochlear nucleus of the mouse.

The neurochemical serotonin (5-hydroxytryptamine, 5-HT) is involved in a variety of behavioral functions including arousal, reward, and attention, and has a role in several complex disorders of the brain. In the auditory system, 5-HT fibers innervate a number of subcortical nuclei, yet the modulatory role of 5-HT in nearly all of these areas remains poorly understood. In this study, we examined spiking activity of neurons in the dorsal cochlear nucleus (DCN) following iontophoretic application of 5-HT. The DCN is an early site in the auditory pathway that receives dense 5-HT fiber input from the raphe nuclei and has been implicated in the generation of auditory disorders marked by neuronal hyperexcitability. Recordings from the DCN in awake mice demonstrated that iontophoretic application of 5-HT had heterogeneous effects on spiking rate, spike timing, and evoked spiking threshold. We found that 56% of neurons exhibited increases in spiking rate during 5-HT delivery, while 22% had decreases in rate and the remaining neurons had no change. These changes were similar for spontaneous and evoked spiking and were typically accompanied by changes in spike timing. Spiking increases were associated with lower first spike latencies and jitter, while decreases in spiking generally had opposing effects on spike timing. Cases in which 5-HT application resulted in increased spiking also exhibited lower thresholds compared to the control condition, while cases of decreased spiking had no threshold change. We also found that the 5-HT2 receptor subtype likely has a role in mediating increased excitability. Our results demonstrate that 5-HT can modulate activity in the DCN of awake animals and that it primarily acts to increase neuronal excitability, in contrast to other auditory regions where it largely has a suppressive role. Modulation of DCN function by 5-HT has implications for auditory processing in both normal hearing and disordered states.

Analgesic and anti-inflammatory actions on bradykinin route of a polysulfated fraction from alga Ulva lactuca.

We investigated structural features of polysaccharides from Ulva lactuca and their effects on the classical models of nociception and inflammation. Crude extract was obtained by enzymatic digestion and isolated by ion exchange chromatography on DEAE-cellulose. The fraction with higher yield was used in the tests (SP-Ul). Swiss mice received SP-Ul (1, 3 or 9mg/kg; i.v.), 30min prior to injection of 0.8%-acetic acid or 1%-formalin or prior to a thermal stimulus. At same doses, SP-Ul was tested on Wistar rats on paw edema elicited by different irritants (carrageenan, dextran, bradykinin, histamine or serotonin). The results of infrared characterization indicated the presence of hydroxyl groups, sulfate, uronic acid and glycosidic linkages in all SP fractions spectrums. SP-Ul decreased significantly the antinociception in response to acetic acid or formalin (second phase), but not in the hot-plate test, suggesting that its analgesia occurs through a peripheral mechanism. SP-Ul did not reduce carrageenan-induced paw edema as supported by both histological and myeloperoxidase activity assessments. However, SP-Ul (1mg/kg; s.c.) reduced dextran-elicited edema, showing vascular anti-inflammatory effect, with bradykinin as major target because it did not reduce histamine- and serotonin-induced paw edemas. Therefore, SP-Ul acts on bradykinin pathway in its antinociceptive and anti-inflammatory responses.

Possible Parkinson's Disease Induced by Chronic Manganese Supplement Ingestion.

OBJECTIVE: The objective is to report a case of possible neurotoxicity resulting from an incorrect dietary supplement for osteoporosis taken at a toxic dose. SUMMARY: The case study examined here is a 37-year-old African-American female who consumed excessive manganese over a period of years, resulting in Parkinson's disease (PD). This patient was referred to the pharmacist pharmacotherapy service by a neurology physician. PD has been shown in the medical literature to be caused by chronic exposure to high levels of manganese. It may be concluded that daily doses of manganese well above the upper limit of 9 mg per day were taken by this patient for an extended period of time, possibly causing PD via manganism. CONCLUSION: This case illustrates the unknown risks taken by patients who use excessive amounts of over-the-counter herbals and supplements and how pharmacists can assist patients and physicians in the proper use of these popular products. ABBREVIATIONS: AI = Adequate intake, EMS = Eosinophilia myalgia syndrome, MTM = Medication therapy management, UL = Tolerable upper limit.

Effect of different doses of transmitters on the mechanisms of adaptation.

We studied the responses of the organism to administration of autonomic transmitters in different doses: epinephrine (from 0.0000001 to 300 µg per 100 g body weight), serotonin (25, 50, 250, and 500 µg), and their combinations. The concentrations of biogenic amines in the blood and hypothalamus and parameters of oxidative and antioxidant systems, immune status, and blood coagulation and anticoagulation systems were analyzed. Cyclic dose-dependent variations in the levels of transmitters were revealed that dynamically changed their properties of syntoxins and catatoxins.

Hypothalamic neuropeptide Y (NPY) gene expression is not affected by central serotonin in the rainbow trout (Oncorhynchus mykiss).

Mammalian studies have shown a link between serotonin (5-HT) and neuropeptide Y (NPY) in the acute regulation of feeding and energy homeostasis. Taking into account that the actions of 5-HT and NPY on food intake in fish are similar to those observed in mammals, the objective of this study was to characterize a possible short-term interaction between hypothalamic 5-HT and NPY, by examining whether 5-HT regulates NPY gene expression, to help clarify the mechanism underlying the observed anorexigenic action of central 5-HT in the rainbow trout. We used qRT-PCR to determine the levels of NPY mRNA in the hypothalamus-preoptic area (HPA) of rainbow trout after intraperitoneal (i.p.) injection of a single dose of dexfenfluramine (dFF, 3mgkg(-1); 24h-fasted and fed fish) or intracerebroventricular (i.c.v.) administration of 5-HT (100µgkg(-1); 24h-fasted fish). Significant suppression of food intake was observed after administration of 5-HT and dFF. No significant changes in NPY gene expression were obtained 150min after administration of 5-HT or dFF. However, administration of the 5HT1B receptor agonist anpirtoline did not have any significant effect on food intake in rainbow trout. The results suggest that in fish, unlike in mammals, neither the NPY neurons of the HPA nor the 5-HT1B receptor subtype participate in the neural circuitry involved in the inhibition of food intake induced by central serotoninergic activation.

The anorexigenic effect of serotonin is mediated by the generation of NADPH oxidase-dependent ROS.

Serotonin (5-HT) is a central inhibitor of food intake in mammals. Thus far, the intracellular mechanisms for the effect of serotonin on appetite regulation remain unclear. It has been recently demonstrated that reactive oxygen species (ROS) in the hypothalamus are a crucial integrative target for the regulation of food intake. To investigate the role of ROS in the serotonin-induced anorexigenic effects, conscious mice were treated with 5-HT alone or combination with Trolox (a ROS scavenger) or Apocynin (an NADPH oxidase inhibitor) by acute intracerebroventricular injection. Both Trolox and Apocynin reversed the anorexigenic action of 5-HT and the 5-HT-induced hypothalamic ROS elevation. The mRNA and protein expression levels of pro-opiomelanocortin (POMC) were dramatically increased after ICV injection with 5-HT. The anorexigenic action of 5-HT was accompanied by markedly elevated hypothalamic MDA levels and GSH-Px activity, while the SOD activity was decreased. Moreover, 5-HT significantly increased the mRNA expression of UCP-2 but reduced the levels of UCP-3. Both Trolox and Apocynin could block the 5-HT-induced changes in UCP-2 and UCP-3 gene expression. Our study demonstrates for the first time that the anorexigenic effect of 5-HT is mediated by the generation of ROS in the hypothalamus through an NADPH oxidase-dependent pathway.

Effects of an Atractylodes lancea rhizome extract and a volatile component ß-eudesmol on gastrointestinal motility in mice.

AIM OF THE STUDY: The rhizomes of Atractylodes lancea DC (Compositae) are used clinically to treat gastrointestinal symptoms, including functional dyspepsia and gastroparesis, in China and Japan, but their influence and mechanism on gastrointestinal motility are not yet proven in detail. MATERIALS AND METHODS: This study examined the effects of an Atractylodes lancea extract, and isolated ß-eudesmol, on gastric emptying and small intestinal motility in atropine-, dopamine-, and 5-hydroxytryptamine (5-HT)-treated mice. RESULTS AND CONCLUSIONS: The extract (500 or 1000mg/kg) and ß-eudesmol (50 or 100mg/kg), as well as itopride hydrochloride (a dopamine D(2) receptor antagonist, 10 or 50mg/kg), stimulated small intestinal motility in normal mice. They inhibited reductions in gastric emptying and gastrointestinal motility induced by dopamine (1mg/kg, intraperitoneal injection, ip). The extract (1000mg/kg) and ß-eudesmol (100mg/kg) inhibited the atropine-induced decrease in small intestinal motility, but not gastric emptying. Furthermore, the extract (500 or 1000mg/kg) and ß-eudesmol (25, 50, or 100mg/kg) inhibited reductions in gastric emptying and small intestinal motility caused by 5-HT (4mg/kg, ip) or the 5-HT(3) receptor agonist 1-(3-chlorophenyl) biguanide (0.5mg/kg, ip), but not a 5-HT(2C) receptor agonist. These findings suggest that the extract of Atractylodes lancea and ß-eudesmol may stimulate gastric emptying or small intestinal motility by inhibiting the dopamine D(2) receptor and 5-HT(3) receptor.

Differences between human wild-type and C23S variant 5-HT2C receptors in inverse agonist-induced resensitization.

The aim of this study was to analyze functional properties of the naturally occurring C23S variant of the human 5-HT2C receptor. In HEK293 cells transiently expressing the unedited forms of the variant receptor (VR) or the wild-type receptor (WTR), surface expression was determined by [3H]mesulergine binding to membrane fragments. Function was examined by an aequorin luminescence-based Ca2+ assay. Surface expression of the VR was 116% of that of the WTR. The 5-HT-induced increase in cytosolic Ca2+ ([Ca2+]i), and its inhibition by the inverse agonist SB 206553 did not differ between VR- or WTR-expressing cells. Preexposure of VR- or WTR-expressing cells to 0.5 µM 5-HT (3 min-4.5 h) led to a practically identical time course and extent in the reduction of the 5-HT-induced increase in [Ca2+]i. In contrast, prolonged preexposure to the inverse agonist SB 206553 (1 µM) elevated the 5-HT-induced increase in [Ca2+]i for both isoreceptors. A preexposure time of 4.5 h was necessary to significantly elevate the Ca2+ response of the WTR, but the VR produced this elevation within 1 h with virtually no further effect after 4.5 h of preexposure. In conclusion, prolonged preexposure to 5-HT caused equally rapid and strong desensitization of both isoreceptors. The different time course of SB 206553-induced resensitization of the two isoreceptors might be therapeutically relevant for drugs exhibiting inverse agonist properties at 5-HT2C receptors, such as atypical antipsychotics and certain antidepressants.

Bronchospasm potentiating effect of methanolic extract of Ficus religiosa fruits in guinea pigs.

ETHNOPHARMACOLOGICAL RELEVANCE: The sacred tree Peepal (Ficus religiosa family: Moraceae) has numerous therapeutic utility in folk medicine. AIM OF THE STUDY: It has been reported to be used in ethno medical treatment of asthma and also in epilepsy due to its high serotonin content, which has been implicated in pathophysiology of asthma, this led us to carry out the present study. MATERIALS AND METHODS: The in vivo studies of histamine induced bronchospasm in guinea pigs and in vitro isolated guinea pig tracheal chain and ileum preparation. RESULTS: Pre-treatment of guinea pigs with ketotifen (1 mg/kg, p.o.) has significantly delayed the onset of histamine aerosol induced pre-convulsive dyspnea, compared with vehicle control (281.8(a)±11.7 vs. 112.2±9.8). The administration of methanolic extract (125, 250 and 500 mg/kg, p.o.) did not produced any significant effect on latency to develop histamine induced pre-convulsive dyspnea. On the other hand, methanolic extract of the fruits at the doses employed (i.e., 0.5, 1 and 2 mg/ml) has significantly potentiate the EC(50) doses of both histamine and acetylcholine in isolated guinea pig tracheal chain and ileum preparation. In addition, HPLC analysis of the methanolic extract showed the presence of high amounts of serotonin (2.89%, w/w). CONCLUSIONS: On the basis of data, it may be concluded that Ficus religiosa fruits have been found to be ineffective against histamine induced bronchospasm in guinea pigs. In addition, methanolic extract of the fruits have shown to potentiate the bronchoconstriction induced by both histamine and acetylcholine on guinea pig tracheal chain preparation.

Long-term consumption of fish oil-enriched diet impairs serotonin hypophagia in rats.

Hypothalamic serotonin inhibits food intake and stimulates energy expenditure. High-fat feeding is obesogenic, but the role of polyunsaturated fats is not well understood. This study examined the influence of different high-PUFA diets on serotonin-induced hypophagia, hypothalamic serotonin turnover, and hypothalamic protein levels of serotonin transporter (ST), and SR-1B and SR-2C receptors. Male Wistar rats received for 9 weeks from weaning a diet high in either soy oil or fish oil or low fat (control diet). Throughout 9 weeks, daily intake of fat diets decreased such that energy intake was similar to that of the control diet. However, the fish group developed heavier retroperitoneal and epididymal fat depots. After 12 h of either 200 or 300 µg intracerebroventricular serotonin, food intake was significantly inhibited in control group (21-25%) and soy group (37-39%) but not in the fish group. Serotonin turnover was significantly lower in the fish group than in both the control group (-13%) and the soy group (-18%). SR-2C levels of fish group were lower than those of control group (50%, P = 0.02) and soy group (37%, P = 0.09). ST levels tended to decrease in the fish group in comparison to the control group (16%, P = 0.339) and the soy group (21%, P = 0.161). Thus, unlike the soy-oil diet, the fish-oil diet decreased hypothalamic serotonin turnover and SR-2C levels and abolished serotonin-induced hypophagia. Fish-diet rats were potentially hypophagic, suggesting that, at least up to this point in its course, the serotonergic impairment was either compensated by other factors or not of a sufficient extent to affect feeding. That fat pad weight increased in the absence of hyperphagia indicates that energy expenditure was affected by the serotonergic hypofunction.

Evaluation of antiulcer and antisecretory potential of Linum usitatissimum fixed oil and possible mechanism of action.

The aim of the study was to evaluate the antiulcer activity of Linum usitatissimum fixed oil against aspirin-, indomethacin-, ethanol-, reserpine-, serotonin- and stress-induced gastric ulceration in rats and histamine-induced gastric ulceration in guinea pigs. Attempts were also made to evaluate the in vitro anticholinergic and antihistaminic activity and in vivo antisecretary and antiulcer activity of oil following pylorus ligation in rats. L. usitatissimum fixed oil exhibited significant antiulcer activity against different ulcerogens in experimental animal models. The fixed oil significantly inhibited acetylcholine- and histamine-induced contraction of guinea pig and rat ileums, respectively, suggesting its anticholinergic and antihistaminic activity. The oil also exhibited significant inhibitory effect on gastric secretion/total acidity and aspirin-induced gastric ulceration in pylorus-ligated rats. The lipoxygenase inhibitory, histamine antagonistic and antisecretory (anticholinergic) effects of the oil could probably have contributed towards antiulcer activity. L. usitatissimum fixed oil may be considered to be a drug of natural origin which possesses significant antiulcer activity. The present observation is the first experimental data showing antiulcer activity of L. usitatissimum fixed oil.

Body distribution of infused serotonin in rats.

1. Our goal was to investigate the body distribution of serotonin (5-hydroxytryptamine; 5-HT) in rats infused with 5-HT (25 microg/kg per min) for 7 days and the contribution of the 5-HT transporter (SERT) for 5-HT uptake into the tissues. 2. Mini-osmotic pumps containing 5-HT or vehicle were implanted in rats knocked out for SERT (SERT-KO) or in wild-type (WT) rats. On the 8th day, tissues were harvested for measurements of 5-HT by high-performance liquid chromatography (HPLC). The 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA) was also measured by HPLC, because an increase in 5-HIAA in tissues from rats receiving 5-HT reflects 5-HT uptake followed by metabolism. 3. In WT rats infused with 5-HT, an increase in 5-HT or 5-HIAA was observed in the heart, pancreas, thyroid, adrenal gland, kidney, seminal vesicle, bladder, prostate, liver, oesophagus, stomach, femur, trachea, lung and spleen compared with vehicle-infused rats. An increase in 5-HT and 5-HIAA was not observed in aorta, vena cava and jejunum. In tissues from SERT-KO rats infused with 5-HT, the content of 5-HT or 5-HIAA was decreased in most of the tissues studied compared with 5-HT-infused WT rats. Although 5-HT uptake in the kidney, seminal vesicle, prostate, jejunum and trachea is SERT dependent, it is SERT independent in the pancreas. The remaining tissues display SERT-dependent and -independent mechanisms for 5-HT uptake. 4. Altogether, tissues from different systems, such as the cardiovascular, endocrine, genitourinary and gastrointestinal, accumulate 5-HT mainly via SERT and, thus, these systems are potential targets for drugs that interfere with 5-HT homeostasis.

Effect of dopamine on vascular reactivity in near-term lamb carotids: role of the endothelium.

Many neonates are diagnosed with hypotension in the first 24 hr of life. Those with severe hypotension are often given high doses of dopamine at 10 to 20 microg/kg/min. This study examined the hypothesis that dopamine, a vasoactive drug commonly used in the neonatal intensive care unit, alters vascular reactivity. Vascular reactivity was measured by comparing 5HT dose-response characteristics in untreated near-term lamb common carotid arteries and arteries treated with 15 microg/kg/min of dopamine. The authors found that dopamine pretreatment for 60 min significantly potentiated 5HT-induced contractile tone by approximately 100% ( p < .05). This observed increase in tone was accompanied by a significant decrease in the affinity of 5HT to its receptor ( p < .05), suggesting an activation of a separate contractile pathway, or a mechanism downstream from agonist-receptor binding. Interestingly, an increase in contractility was observed only in endothelium-intact arteries. In arteries with denuded endothelium, dopamine pretreatment resulted in a small but significant decrease in tone compared to control arteries ( p < .05), suggesting a vasodilatory mechanism unmasked by endothelium removal. Although multiple mechanisms can increase vascular resistance, these data described the in vitro effects of high doses of dopamine on vascular tone as well as the role of the endothelium in dopaminemediated vasoconstriction.

Relation of coronary hypersensitivity to serotonin in cardiac transplant recipients to vessel wall morphology and effect of vitamin C.

Coronary hypersensitivity to serotonin promotes platelet aggregation, entailing the progression of the atherosclerotic process. This abnormality is a common finding in cardiac transplant recipients and may be triggered by reactive oxygen species, which plays a main role in the inflammatory process. Hence, this study aimed to determine the influence of intimal hyperplasia on this abnormality and its reversibility after acute supplementation with the superoxide anion scavenger vitamin C. Therefore, intracoronary injections of serotonin (3 microg), bradykinin (600 ng), and nitroglycerin (isosorbide dinitrate 200 microg) were administered to 21 cardiac transplant recipients (1 year after transplantation) with normal coronary angiographic results; the serotonin injections were repeated after intracoronary vitamin C supplementation (40 mg/min for 14 minutes). In the segments in which serotonin effects were the most pronounced, the diameter changes were measured by quantitative angiography, and vessel wall morphology was studied by intravascular ultrasound (IVUS). The IVUS examination revealed moderate to severe intimal thickening (total area - luminal area/total area) in 9 patients (group 1) of 25 +/- 2%, compatible with the early stage of graft vasculopathy. In this group, hypersensitivity to serotonin remained unchanged after intracoronary vitamin C supplementation, from -21 +/- 3% (percentage from baseline) to -25 +/- 3%, whereas in the other 12 patients with mild intimal thickening (9 +/- 1%; group 2), hypersensitivity to serotonin was attenuated from -20 +/- 5% to -4 +/- 6% (p <0.01). In contrast, the responses to bradykinin and isosorbide dinitrate were similar in the 2 groups. In group 1, plasma levels of high-sensitivity C-reactive protein and proinflammatory cytokines (interleukin-6 and -8) were significantly enhanced. For all the patients studied, the effect of vitamin C on the response to serotonin was significantly correlated with the intimal thickening. In conclusion, at 1 year after transplantation, morphologic changes compatible with the early stage of the graft vasculopathy are accompanied by hypersensitivity to serotonin unresponsive to vitamin C, despite a relatively preserved endothelial function (unaltered response to bradykinin).

Influence of several Styrian wines on bovine coronary artery contractions induced by endogenous agents.

In the current study, seven Styrian white wine varieties, as well as their corresponding grape skin extracts (GSE), were tested for possible antagonistic effects on several endogenous vasoconstrictors known to be involved in the pathogenesis of cardiovascular diseases via tissue contraction experiments. Results were compared to those of Zweigelt, the most cultivated Styrian red wine. Bovine coronary artery strips were attached to a force transducer connected to a bridge amplifier, and isometric force was recorded on a multipen recorder. Preincubation of the vessels with the dealcoholized wines (DAW; 330 microl/ml) inhibited the constrictions to histamine and serotonin (5-HT) NO-dependently in the range of 5-80% and 30-90%, respectively (Zweigelt 47% and 90%, respectively). The corresponding GSE (20 mg/ml) inhibited the coronary constrictions to histamine in the range of 40% to 80% (Zweigelt 80%). Additionally, all DAW antagonized the contractile responses to the thromboxane-mimetic U46619 and the isoprostane 8-iso-PGF2alpha, indicating a nonspecific inhibition. To characterize the vasoactive component(s), the Traminer GSE was separated representatively using ultrafiltration, solid phase extraction (SPE) on Isolute C18(EC), and Isolute SCX-2, as well as column chromatography (CC) on polyamide. The resulting fractions were subsequently bioassayed for vasorelaxing activity. Preliminary results refer to a very hydrophilic, nonpolyphenolic basic compound with a MW<1000 Da. Our findings demonstrate that certain Styrian wines have remarkable antagonistic effects on several endogenous agonists in vitro, and that also nonpolyphenolic components in grapes may contribute to cardiovascular protection. Further separation steps as well as phytochemical and pharmacological investigations are in progress.