Endotel-zavisna relaksacija unutrašnje torakalne arterije prouzrokovana rezveratrolom

Resveratrol, a polyphenol present in wine, has been thought to be responsible for cardiovascular benefits associated with moderate wine consumption. It is also present in the plant Polygonum Cuspidatum. The mechanism of cardiovascular benefits probably includes vasorelaxation, antioxidant and anti-platelet effects of resveratrol. The mechanisms by which resveratrol causes vasodilatation are uncertain. The aim of this study was to investigate the mechanism(s) of resveratrol induced vasorelaxation in human internal mammary artery (HIMA) with endothelium. HIMA rings were precontracted by phenylephrine. Resveratrol induced relaxation of the HIMA rings with endothelium. LNAME, an inhibitor of NO synthase, and methylene blue, an inhibitor of guanylate cyclase, abolished relaxation of HIMA induced by resveratrol. Highly selective blocker of ATP-sensitive K channels, glibenclamide as well as a nonselective blocker of big Ca-sensitive K+ channels, charybdotoxin did not block resveratrol-induced relaxation of HIMA. 4-Aminopyridine and margatoxin, blockers of voltage-gated K+ (KV) channels, abolished endothelium-dependent relaxation of HIMA, induced by resveratrol. In conclusion, we have shown that resveratrol induces relaxation of HIMA with endothelium. It seems that NO and smooth muscle KV channels are included in this relaxation.Smatra se da rezveratrol kao jedna polifenolna komponenta prisutna u značajnim količinama u crnom vinu, smanjuje rizik od razvoja ateroskleroze i koronarne bolesti. U mehanizam kardioprotektivnog delovanja verovatno su uključ eni antioksidativno, antitrombocitno i vazodilatatorno delovanje rezveratrola. Mehanizam vazodilatacije još uvek nije poznat, pa je cilj ovog rada bio da se ispitaju efekti i mehanizam vazorelaksantnog delovanja rezveratrola na humanoj unutraš njoj torakalnoj arteriji sa endotelom. Unutrašnja torakalna arterija je prekontrahovana fenilefrinom. Rezveratrol je koncentracijski-zavisno relaksirao unutrašnju torakalnu arteriju čoveka. L-NAME, inhibitor NO sintaze, i metilensko plavo, inhibitor solubilne gvanilat ciklaze, su antagonizovali relaksaciju unutrašnje torakalne arterije sa intaktnim endotelom, prouzrokovanu rezveratrolom. Visoko selektivni blokator ATP-senzitivnih K+ kanala, glibenklamid, kao i neselektivni blokator velikih Ca-senzitivnih K+ kanala, karibdotoksin nisu antagonizovali rezveratrolom indukovanu relaksaciju unutrašnje torakalne arterije. 4-Aminopiridin i margatoksin, blokatori voltažnih K+ kanala su antagonizovali relaksaciju prouzrokovanu rezveratrolom. Na osnovu ovih činjenica se može zaključiti da je endotel-zavisna relaksacija unutrašnje torakalne arterije čoveka, prouzrokovana rezveratrolom, verovatno posredovana NO. Izgleda, da su 4-aminopiriin- i margatoksin-senzitivni K-kanali smešteni u membrani vaskularnih glatko-mišićnih ćelija humane unutrašnje torakalne arterije, uključeni u mehanizam endotel-zavisne relaksacije prouzrokovane rezveratrolom

Relaksacija aorte pacova indukovana novosintetisanim orto-hlornim derivatom propafenona

The information on the inhibitory effect of propafenone in vascular smooth muscle is sparse. Propafenone acts through blockage of voltage-dependent cardiac Na+ channels, L-type Ca2+ channels, voltage-sensitive K+ (Kv) channels, as well as β-adrenergic receptors in the heart. The introduction of different chemical groups in the benzyl moiety of propafenone influences pharmacological properties of newly developed derivate of propafenone. Here we investigated the effect of new ortho-chloro derivate of propafenone (5OCl) on the vascular tone of precontracted rat aorta. 5OCl produced endothelium-independent relaxation of rat aorta. In order to test the involvement of different ion channels in 5OCl mechanism of action, antagonist of Na+, lidocaine, KV channels, 4-aminopyiridine (4-AP) and L-type Ca2+ channels, nifedipine were used. All tested antagonists of ion channels did not influence the relaxation of rat aorta induced by high a concentration of 5OCl (≥10 μM), but antagonized the relaxation induced by low concentrations of this propafenone derivate. Thus, 5OCl derivate has comparable potency and efficacy as propafenone. According to its interaction with lidocaine, 4-AP and nifedipine it seems that 5OCl partly shares the mechanism of action with propafenone. The mechanism of vasodilatation induced by high micromolar concentration of 5OCl is not defined and further investigations are necessary.Informacije o efektima propafenona na vaskularne glatke mišiće su oskudne. Propafenon blokira voltažno-zavisne Na+ kanale, Ca2+ kanale L-tipa, voltažno-senzitivne K+ (Kv) kanale i β-adrenergičke receptore u srcu. Uvođenje različitih hemijskih grupa u benzilni deo molekula propafenona utiče na promenu njegovih farmakoloških osobina. U ovoj studiji je ispitivan uticaj novog orto-hloro derivata (5OCl) propafenona na vaskularni tonus prekontrahovane aorte pacova. Orto hlorni derivat (5OCl) je izazvao endotel-nezavisnu relaksaciju aortnih prstenova. Da bi se ispitala uloga različitih jonskih kanala u ovoj relaksaciji, korišćeni su lidokain, (antagonist Na+ kanala), 4-aminopiridin (antagonist Kv kanala) i nifedipin (antagonist Ca2+ kanala L-tipa). Testirani antagonisti jonskih kanala nisu uticali na relaksaciju aorte pacova izazvanu visokom koncentracijom 5OCl (≥10 μM), ali su zato antagonizovali relaksaciju aorte koncentracijama 5OCl koje su bile manje od 10 μM. Prema tome, 5OCl derivat ima sličnu jačinu i efikasnost kao propafenon. Prema njegovoj interakciji sa lidokainom, 4-AP i nifedipinom može se reći da je mehanizam dejstva 5OCl sličan propafenonu. Mehanizam vazodilatacije 5OCl derivata u koncentracijama većim od 10 μM nije definisan i za to su potrebna dalja istraživanja

Nosocomial infections in the departments of orthopedics and traumatology

Aim. To determine the incidence and the localization of nosocomial infections (NI) in the departments of orthopedics and traumatology. Methods. A prospective cohort study carried out between February 1 and July 31, 2002 included all of the surgical patients who were hospitalized longer than 48 hours, as well as 30 days after the discharge. The patients were examined and their diagnoses made according to the definition of NI, that was based on the clinical and/or laboratory findings. Results. Out of 277 hospitalized patients, 78 had a total of 91 NIs. Sixty seven (85.8%) of the patients had 1 registered NI each, 9 (11.6%) of the patient had 2 NIs each, while only the 2 (2.6%) were with 3 NIs. The incidence of the patients with HAI was 28.2% (95% IP = 22.9-33.5), while the incidence of HAI was 32.8%. The patients who developed a NI were hospitalized almost twice as long as the patients who did not (t test = 6.0, DF = 275, p < 0.001). In regard to the duration of hospitalization, the incidence of NI was 12.3 per 1000 patient-hospital days. The patients operated on most frequently had the surgical-site infections (69.2%). Of 63 infections of the surgical site, 3 patients (4.8%) were diagnosed as having the NI at that localization following the discharge, and then the urinary tract infections, 25.3% (23/91), and sepsis, 5.5% (5/91). Conclusion. Epidemiological surveillance was the first step towards the prevention and the eradication of NI. The results of this study could be of use in planning of the adequate measures for the prevention of NI in the departments of orthopedic surgery

Fractures of the humerus during arm wrestling

Background/Aim. Humeral shaft fractures may occur as a result of arm wrestling. The aim of this study was to present our treatment of humerus fracture sustained during arm wrestling. Methods. A total of six patients, aged 22 to 48, were treated at our department form January 2008 to January 2010 with open reduction and internal fixation and with hanging arm casts. A review of all the relevant literature on the subject was also presented. Results. In all the cases, the fractures healed and function returned to normal. No patient had any neural or vascular compromise. Conclusion. Closed and operative treatments were equally successful in all reported cases. [Projekat Ministarstva nauke Republike Srbije, br. 175-095

Antivazokonstriktorni efekt pinacidila na izolovanoj radijalnoj arteriji

Pinacidil, a previously studied potassium channel opener (PCO), is a potent antihypertensive agent in animals and humans. Its mechanism of action is not completly defined. The aim of our study was to investigate the antivasoconstricting effect of pinacidil on the isolated RA and to study whether this effect is endothelium-dependent. Contractions of isolated RA rings with intact endothelium were provoked by electrical field stimulation (EFS, 20 Hz) or exogenously applied noradrenaline (NA, 10 μM). Pinacidil (10 nM-0.1 mM) produced a concentration-dependent inhibition of both EFS- and NA-evoked contractions (p>0.05). NO synthesis inhibitor, L-NAME (10 μM) and the guanylate cyclase inhibitor, methylene blue (10 μM) did partly antagonize NA-evoked contractions and were without effect on EFSinduced contractions. Thus, the antivasoconstrictor effect of pinacidil on RA is partly endothelium-dependent and probably mediated via cGMP-dependent NO-pathway.Pinacidil je 'otvarač' kalijumovih kanala (OKK) koji ima snažno antihipertenzivno dejstvo na životinjama i ljudima. Mehanizam dejstva pinacidila još uvek nije u potpunosti definisan. Zato je cilj naše studije bio da ispitamo da li je antivazokonstriktorno dejstvo pinacidila na izolovanoj radijalnoj arteriji (RA) čoveka endotel zavisno. Kontrakcije prstenova RA sa očuvanim endotelom su prouzrokovane električnom stimulacijom (EFS, 20 Hz) ili spolja dodatim noradrenalinom (NA, 10 μM). Pinacidil (10 nM - 0.1 mM) je prouzrokovao koncentracijski-zavisnu inhibiciju EFS- i NA-kontrakcija bez značajne razlike u senzitivnosti (p>0.05). Inhibitor sinteze NO-a, L-NAME (10 μM) i inhibitor gvanilat ciklaze, metilensko plavo (10 μM) su delimično antagonizovali inhibitorni efekt pinacidila na NA-kontrakcije. Nasuprot ovome, oni nisu uticali na efekt pinacidila na EFS-kontrakcije. Možemo da zaključimo da pinacidil ima antivazokonstriktorni efekt na RA kada su kontrakcije izazvane električnom strujom ili noradrenalinom. Ovaj efekt pinacidila je delom endotel zavisan, ali samo kada su kontrakcije izazvane spolja dodatim noradrenalinom

Plasminogen activator inhibitor-1 in the evolution of stroke

Fibrinolytic activity in the acute stroke was examined by monitoring the level of plasminogen activator inhibitor-1 (PAI-1), as one of the indicators of fibrinolytic activity. Given the role of PAI-1 in the processes of atherogenesis and thrombogenesis, plasma PAI-1 level was measured in 59 patients (up to 50 years of age) with atherothrombotic stroke (verified by computed tomography scanning or magnetic resonance imaging of brain) in the period from 12 to 24 hours (I analysis) and 30 days after the onset of stroke (II analysis); then, it was correlated with plasma PAI-1 level in the control group (57 healthy subjects), which was 2.86±0.70 U/ml. It was found that PAI-1 level was significantly higher in the acute stroke (I analysis: PAI-1 =4.10±1.40 U/ml, p<0.001; II analysis: PAI-1 =3.64+0.90 U/ml, p<0.001), while fibrinolytic activity was lower, especially on the first day from the stroke that was not completely increased even after 30 days. There was no difference in PAI-1 levels between the subgroups of patients with infarction and lacunar cerebral ischemia (p>0.05), as well as between females and males (p>0.05). Along with significantly increased fibrinogen level (4.65±1 g/l, in the controls - 2.83±0.64 g/l, p<0.001), significantly higher triglycerides (2.04±0.76 mmol/l, in the controls - 1.38+0.54 mmol/l, p<0.001) and lipoproteins(a) (0.405±0.29 g/l, in the controls -0.172±0.14 g/l, p<0.001) were found, correlating with higher plasma PAI-1 level in these patients. The increased plasma level of PAI-1 pointed to possibility of decreased fibrinolytic activity in pathogenesis of ischemie stroke, as well as, risk of reinsult, which had been the greatest after the onset of stroke and declined gradually within several weeks

Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt

Metformin is an antidiabetic drug with anticancer properties, which mainly acts through induction of AMP-activated protein kinase (AMPK). In the present study we investigated the influence of metformin on the in vitro anticancer activity of the well-known chemotherapeutic agent cisplatin. Cell viability was determined by MTT and LDH release assay, oxidative stress and apoptosis (caspase activation, DNA fragmentation, and phosphatidylserine exposure) were assessed by flow cytometry, while activation of AMPK and Akt was analyzed by immunoblotting. Although metformin reduced the number of tumour cells when applied alone, it surprisingly antagonized the cytotoxicity of cisplatin towards U251 human glioma, C6 rat glioma, SHSY5Y human neuroblastoma, L929 mouse fibrosarcoma and HL-60 human leukemia cell lines. Only in B16 mouse melanoma cells metformin augmented the cytotoxicity of cisplatin. In U251 glioma cells metformin suppressed cisplatin-induced apoptotic cell death through inhibition of oxidative stress and caspase activation. The observed cytoprotection was apparently AMPK-independent, as metformin did not further increase cisplatin-induced AMPK activation in U251 cells and other pharmacological AMPK activators failed to block cisplatin-mediated apoptosis. On the other hand, metformin induced Akt activation in cisplatin-treated cells and Akt inhibitor 10-DEBC hydrochloride or phosphoinositide 3-kinase/Akt inhibitor LY294002 abolished metformin-mediated antioxidant and antiapoptotic effects. In conclusion, the antidiabetic drug metformin reduces cisplatin in vitro anticancer activity through AMPK-independent upregulation of Akt survival pathway. These data warrant caution when considering metformin for treatment of diabetic cancer patients receiving cisplatin or as a potential adjuvant in cisplatin-based chemotherapeutic regimens. (c) 2010 Published by Elsevier B.V