Leposava Grbovic

Characterization of adenosine action in isolated rat renal artery: Possible role of adenosine A2A receptors

Adenosine (0.1-300 microM) induced concentration- and endothelium-dependent relaxation of rat renal artery (RRA). N(G)-Nitro-L-arginine (L-NOARG, 10 microM) significantly reduced adenosine-elicited dilatation, but not the application of indomethacin (10 microM), ouabain (100 microM) or tetraethylammonium (TEA, 500 microM). In the presence of high concentration of K(+) (100 mM) or glibenclamide (1 microM), adenosine-evoked relaxation was almost abolished. 8-(3-Chlorostyril)caffeine (CSC, 0.3-3 microM), a selective A(2A)-antagonist, significantly reduced adenosine-evoked dilatation in a concentration-dependent manner (pA(2)=7.29). Conversely, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10 nM), an A(1)-antagonist, did not alter adenosine-induced relaxation. These results indicate that adenosine produces endothelium-dependent relaxation of isolated RRA. Dilatation evoked by adenosine is mediated by predominant releasing of endothelium-derived hiperpolarizing factor (EDHF) and also in one part of nitric oxide (NO) from endothelial cells. The obtained results also suggest that RRA response to adenosine is most likely initiated by activation of endothelial adenosine A(2A) receptors.

Altered response of human umbilical artery to 5-HT in gestational diabetic pregnancy

The aim of this investigation was to evaluate serotonin (5-HT) action on isolated human umbilical arteries (HUA) from normal and gestational diabetes mellitus (GDM) pregnancies. 5-HT caused HUA contraction in a concentration-dependent manner in both investigated groups but with lower efficacy in GDM. After endothelial denudation or in the presence of indomethacin (cyclooxygenase inhibitor), the 5-HT-evoked response was comparably augmented, but only in arteries from uncomplicated pregnancies. 5-HT contractions were unchanged by L-NOARG (NO-synthase inhibitor) or glibenclamide (K(ATP) channel blocker) in both investigated groups. Whereas nifedipine (Ca(2+) channel blocker) reduced the contractile effect of 5-HT and was more potent in GDM, ouabain (Na(+)/K(+)-ATPase inhibitor) caused the contraction of HUA prior to 5-HT addition in both groups, but with a significantly reduced effect in GDM. In vascular rings from GDM, methiothepin (a 5-HT(1)/5-HT(2) receptor antagonist) significantly reduced 5-HT-induced contraction to a similar extent as compared to uncomplicated pregnancies. Ketanserin (a 5-HT(2A) receptor antagonist) produced a concentration-dependent inhibition of the 5-HT effect in GDM. In conclusion, in normal pregnancies, 5-HT produced a concentration- and endothelium-dependent contraction of HUA, most probably via endothelial prostacyclin. In contrast, the contractile effect of 5-HT in GDM was reduced with apparent endothelial dysfunction. In both normal and diabetic pregnancies, voltage-gated Ca(2+) channels and Na(+)/K(+)-ATPase contribute to the 5-HT-evoked contraction, as well to the regulation of basal vascular tone, but those actions were notably impaired in GDM. In uncomplicated and diabetic pregnancies, the transduction mechanism of 5-HT involves activation of mixed population of 5-HT(1) and 5-HT(2A) receptors in the HUA.

Functional characterization of the muscarinic receptors involved in endothelium‐dependent relaxation in isolated canine uterine artery

Acetylcholine interacts with endothelial muscarinic receptors releasing nitric oxide and causing vasodilatation. To identify the receptor subtype responsible for acetylcholine-induced relaxation in canine uterine artery, the usual organ bath method for in vitro investigation on isolated blood vessels was applied. Using a range of muscarinic receptor antagonists such as atropine (nonselective), pirenzepine (M(1)-selective), methoctramine (M(2)-selective) and p-fluoro-hexahydro-sila-difenidol (p-FHHSiD) (M(1)/M(3)) and determining pA2 value of those antagonists through Shild analysis, we aimed at establishing a precise receptor mechanism underlying acetylcholine-induced relaxation in isolated canine uterine artery. The relaxation of uterine arterial rings in response to acetylcholine in the presence or absence of selective muscarinic receptors antagonists was calculated using concentration response curves. Acetylcholine induced concentration-dependent and endothelium-dependent relaxation of arterial rings precontracted with phenylephrine (pEC(50) = 6.90 +/- 0.02). Muscarinic receptors antagonists atropine, pirenzepine, methoctramine and p-FHHSiD competitively antagonized the response to acetylcholine and obtained pA(2) values were 9.91 +/- 0.06, 6.60 +/- 0.04, 6.21 +/- 0.08 and 8.05 +/- 0.1, respectively. This study showed that acetylcholine induced endothelium-dependent relaxation of canine uterine artery by stimulation of muscarinic receptors localized on the endothelial cells. On the basis of differential antagonist affinity, we suggest that the muscarinic receptors involved in the acetylcholine-induced relaxation of canine uterine artery are predominantly of M(3) subtype.

[Postexposure prophylaxis against hepatitis B, hepatitis C and human immunodeficiency virus infection in healthcare workers].

nema PR Projekat Ministarstva nauke Republike Srbije, br. 175024: Filogenetski pristup analizi molekularne evolucije visokovarijabilnih virusa: ko-infekcije, interakcija virusa i domacina

Safety of antiretrovirals in pregnacy

nema PR Projekat Ministarstva nauke Republike Srbije, br. 175024: Filogenetski pristup analizi molekularne evolucije visokovarijabilnih virusa - ko-infekcije, interakcija virusa i domacina

Characterization of receptors involved in serotonin contractions of isolated human umbilical artery in uncomplicated pregnancy

Background Serotonin (5-HT), is a vasoactive substance involved in physiological functioning of fetoplacental blood flow and continuous modulation of smooth muscle tone in umbilical vein and arteries. Since umbilical blood vessels have been shown to be deficient in autonomic innervation, the action of local autocrine vasoactive substances (including serotonin) is of considerable importance. Although seven main groups of 5-HT receptors (5-HT1-7) have been characterized, it has been established that only several 5-HT receptor subtypes may be involved in vascular effects of this biogenic amine. Therefore, the aim of this study was to characterize receptors involved in serotonin-induced effect on isolated human umbilical artery (HUA) in uncomplicated pregnancy.

Contribution of potassium channels in human umbilical artery contractions

Bradykinin (BK) and serotonin (5-HT) are vasoactive agents that significantly contribute to the normal functioning of fetoplacental blood flow, including modulation of smooth muscle tone in umbilical vein and arteries. Accordingly, umbilical artery is a crucial component of fetoplacental circulation with the vital function of providing suitable perfusion and nutrition for placenta. The aim of this study was to investigate the effect of potassium channel blockers, namely glibenclamide (an ATP-sensitive K+ channel blocker), tetraethylammonium (a non-selective K+ channel blocker), Ba2+ (an inwardly rectifying K+ channel blocker) and apamin (a small conductance Ca2+-activated K+ channel blocker) in BK- and 5-HT-induced actions on isolated human umbilical artery (HUA) in normal pregnancy. The experiments were performed on vascular rings of HUA isolated from umbilical cords that were obtained immediately after vaginal delivery in women with uncomplicated pregnancy. Only the remnant tissue, which would have been otherwise disposed of, has been utilized. Isometric tension of suspended artery rings was continuously recorded. BK (1 nM – 1 μM) and 5-HT (1 nM – 30 μM) produced concentration-dependent contractions of HUA. Control contractions produced by BK were notably (p < 0.05) enhanced only in the presence of apamin (20 μM), while unaltered by other inhibitors. 5-HT-induced effect was not influenced by any of applied blockers. Our results suggest that small conductance Ca2+-activated potassium channels contribute to the fine regulation of maximal BK-induced contraction of HUA in normal pregnancy. On the other hand, potassium channels do not seem to be involved in 5-HT-evoked contractile response of umbilical artery.

[New bearings in pharmacotherapeutic strategies: pharmacogenetics and gene therapy].

Slicno drugim, novim terapijskim konceptima i genska terapija je puno obecavala, ali za sada je jos u razvoju. Glavni izazov ostaje unosenje pravog gena na pravo mesto, u pravu celiju i obezbeđenje adekvatne ekspresije, uz minimalna neželjena dejstva. Iako se najvise radi na virusnim vektorima, smatra se da buducnost genske terapije cine znatno bezbedniji nevirusni sistemi. Bilo je izvesnih promasaja u genskoj terapiji, sto je dovelo do sumnje i zabrinutosti u siroj populaciji. Međutim, razvoj genske terapije je realnost, kao i cinjenica da ona ima svoje mesto u medicini. Važno je istaci da genskoj terapiji treba pristupati sa izuzetno visokim stepenom naucne, strucne i eticke odgovornosti, jer se ne može iskljuciti mogucnost genetskih manipulacija opasnih za ljudsko zdravlje.