Browsing by Author "Milojevic, Predrag (6602755452)"

The drug nicorandil is a vasodilator approved for the treatment of angina. In addition to its well-known effect on the opening of ATP-sensitive K +(K ATP) channels, nicorandil-induced vasorelaxation also involves the opening of Ca 2+-activated K + channels. The aim of this study was to investigate the effects of nicorandil on the isolated human internal mammary artery (HIMA) and the human saphenous vein (HSV) and to define the contribution of different K + channel subtypes in the nicorandil action on these arterial and venous grafts. Our results show that nicorandil induced a concentration-dependent relaxation of HSV and HIMA rings precontracted by phenylephrine. Glibenclamide, a selective K ATP channels inhibitor, partially inhibited the response to nicorandil in both HSV and HIMA. Iberiotoxin, a most selective blocker of large-conductance Ca 2+-activated K + (BK Ca) channels, partly antagonized relaxation of HIMA. A nonselective blocker of voltage-gated K + channels, 4-aminopyridine caused partial inhibition of the nicorandil-induced relaxation of HSV but did not antagonize relaxation of HIMA induced by nicorandil. Margatoxin, a potent inhibitor of K V1.3 channels, did not abolish the effect of nicorandil on HSV and HIMA. Our results showed that nicorandil induced strong endothelium-independent relaxation of HSV and HIMA contracted by phenylephrine. It seems that K ATP and 4-aminopyridine-sensitive K + channels located in the smooth muscle of HSV mediated relaxation induced by nicorandil. In addition, K ATP and BK Ca channels are probably involved in the nicorandil action on HIMA. © 2011 Lippincott Williams & Wilkins.

The drug nicorandil is a vasodilator approved for the treatment of angina. In addition to its well-known effect on the opening of ATP-sensitive K +(K ATP) channels, nicorandil-induced vasorelaxation also involves the opening of Ca 2+-activated K + channels. The aim of this study was to investigate the effects of nicorandil on the isolated human internal mammary artery (HIMA) and the human saphenous vein (HSV) and to define the contribution of different K + channel subtypes in the nicorandil action on these arterial and venous grafts. Our results show that nicorandil induced a concentration-dependent relaxation of HSV and HIMA rings precontracted by phenylephrine. Glibenclamide, a selective K ATP channels inhibitor, partially inhibited the response to nicorandil in both HSV and HIMA. Iberiotoxin, a most selective blocker of large-conductance Ca 2+-activated K + (BK Ca) channels, partly antagonized relaxation of HIMA. A nonselective blocker of voltage-gated K + channels, 4-aminopyridine caused partial inhibition of the nicorandil-induced relaxation of HSV but did not antagonize relaxation of HIMA induced by nicorandil. Margatoxin, a potent inhibitor of K V1.3 channels, did not abolish the effect of nicorandil on HSV and HIMA. Our results showed that nicorandil induced strong endothelium-independent relaxation of HSV and HIMA contracted by phenylephrine. It seems that K ATP and 4-aminopyridine-sensitive K + channels located in the smooth muscle of HSV mediated relaxation induced by nicorandil. In addition, K ATP and BK Ca channels are probably involved in the nicorandil action on HIMA. © 2011 Lippincott Williams & Wilkins.

Because there are so few data on the long-term effects on left ventricular systolic function and functional status in patients who electively undergo Bentall procedures, we established a retrospective study group of 90 consecutive patients. This group consisted of 71 male and 19 female patients (mean age, 54 ± 10 yr) who had undergone the Bentall procedure to correct aortic valve disease and aneurysm of the ascending aorta, from 1997 through 2003 in a single tertiary-care center. We monitored these patients for a mean period of 117 ± 41 months for death, left ventricular ejection fraction and volume indices, and functional capacity as determined by New York Heart Association (NYHA) class. There were no operative deaths. The survival rate was 73.3% during follow-up. There were 10 cardiac and 13 noncardiac deaths, and 1 death of unknown cause. Echocardiography was performed before the index procedure and again after 117 ± 41 months. In surviving patients, statistically significant improvement in left ventricular ejection fraction, in comparison with preoperative values (0.49 ± 0.11 vs 0.41 ± 0.11; P <0.0001), was noted at follow-up. Similarly, we observed statistically significant reductions in left ventricular endsystolic (39.24 ± 28.7 vs 48.77 ± 28.62 mL/m2) and end-diastolic volumes (54.63 ± 6.97 vs 59.17 ± 8.92 mL/m2; both P <0.0001). Most patients (53/66 [80.3%]) progressed from a higher to a lower NYHA class during the follow-up period. The Bentall procedure significantly improved long-term left ventricular systolic function and functional status in surviving patients who underwent operation on a nonemergency basis. © 2016 by the Texas Heart ® Institute, Houston.

Background: Prognostic value of concomitant aprtic regurgitation (AR) in patients operated for severe aortic stenosis (AS) is not clarified. The aim of this study was to prospectively examine the impact of presence and severity of concomitant AR in patients operated for severe AS on long-term functional capacity, left ventricular (LV) function and mortality.Methods: Study group consisted of 110 consecutive patients operated due to severe AS. The patients were divided into AS group (56 patients with AS without AR or with mild AR) and AS+AR group (54 patients with AS and moderate, severe or very severe AR). Follow-up included clinical examination, six minutes walk test (6MWT) and echocardiography 12 and 104 months after AVR.Results: Patients in AS group had lower LV volume indices throughout the study than patients in AS+AR group. Patients in AS group did not have postoperative decrease in LV volume indices, whereas patients in AS+AR group experienced decrease in LV volume indices at 12 and 104 months. Unlike LV volume indices, LV mass index was significantly lower in both groups after 12 and 104 months as compared to preoperative values. Mean LVEF remained unchanged in both groups throughout the study. NYHA class was improved in both groups at 12 months, but at 104 months remained improved only in patients with AS. On the other hand, distance covered during 6MWT was longer at 104 months as compared to 12 months only in AS+AR group (p = 0,013), but patients in AS group walked longer at 12 months than patients in AS+AR group (p = 0,002). There were 30 deaths during study period, of which 13 (10 due to cardiovascular causes) in AS group and 17 (12 due to cardiovascular causes) in AS+AR group. Kaplan-Meier analysis showed that the survival probability was similar between the groups. Multivariate analysis identified diabetes mellitus (beta 1.78, p = 0.038) and LVEF < 45% (beta 1.92, p = 0.049) as the only independent predictor of long-term mortality.Conclusion: Our data indicate that the preoperative presence and severity of concomitant AR has no influence on long-term postoperative outcome, LV function and functional capacity in patients undergoing AVR for severe AS. © 2011 Catovic et al; licensee BioMed Central Ltd.

Background: Changes in K+ channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K+ channels. Their involvement in hydrogen sulfide (H2S)-mediated vasorelaxation is still unclear, and data about human vessels are limited. Objective: To determine the role of K+ channel subtypes in the vasorelaxant mechanism of H2S donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA). Results: NaHS (1 × 10−6–3 × 10−3 mol/L) induced a concentration-dependent relaxation of HIMA pre-contracted by phenylephrine and high K+. Among K+ channel blockers, iberiotoxin, glibenclamide, 4-aminopyridine (4-AP), and margatoxin significantly inhibited NaHS-induced relaxation of phenylephrine-contracted HIMA (P < 0.01), whereas in the presence of apamin/1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) combination, the HIMA relaxation was partially reduced (P < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L-NAME and KT5823, and by cyclo-oxygenase inhibitor, indomethacin (P < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM-34 and glibenclamide caused further decrease in NaHS-induced vasorelaxation (P < 0.01), while iberiotoxin, 4-AP, and margatoxin were without additional effect (P > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (P < 0.01). Conclusion: Our results demonstrated that H2S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H2S included direct or indirect opening of different K+ channel subtypes, KATP, BKCa, SKCa/IKCa, and KV (subtype KV1.3), in addition to NO pathway activation and interference with extracellular Ca2+ influx. © 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

Background: Changes in K+ channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K+ channels. Their involvement in hydrogen sulfide (H2S)-mediated vasorelaxation is still unclear, and data about human vessels are limited. Objective: To determine the role of K+ channel subtypes in the vasorelaxant mechanism of H2S donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA). Results: NaHS (1 × 10−6–3 × 10−3 mol/L) induced a concentration-dependent relaxation of HIMA pre-contracted by phenylephrine and high K+. Among K+ channel blockers, iberiotoxin, glibenclamide, 4-aminopyridine (4-AP), and margatoxin significantly inhibited NaHS-induced relaxation of phenylephrine-contracted HIMA (P < 0.01), whereas in the presence of apamin/1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) combination, the HIMA relaxation was partially reduced (P < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L-NAME and KT5823, and by cyclo-oxygenase inhibitor, indomethacin (P < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM-34 and glibenclamide caused further decrease in NaHS-induced vasorelaxation (P < 0.01), while iberiotoxin, 4-AP, and margatoxin were without additional effect (P > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (P < 0.01). Conclusion: Our results demonstrated that H2S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H2S included direct or indirect opening of different K+ channel subtypes, KATP, BKCa, SKCa/IKCa, and KV (subtype KV1.3), in addition to NO pathway activation and interference with extracellular Ca2+ influx. © 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

Hydrogen sulfide (H2S) represents the third and the youngest member of the gaseous transmitters family. The dominant effect of H2S on isolated vessels is vasodilation. As the mechanism of H2S-induced relaxation in human vessels remains unclear, the present study aimed to investigate the effects of H2S donor, sodium hydrosulfide (NaHS), on isolated human saphenous vein (HSV) and to determine the mechanism of action. Our results showed that NaHS (1 µM–3 mM) induced a concentration-dependent relaxation of endothelium-intact HSV rings pre-contracted by phenylephrine. Pre-treatment with L-NAME, ODQ and KT5823 significantly inhibited NaHS-induced relaxation, while indomethacin induced partial inhibition. Among K+ channel blockers, the combination of apamin and TRAM-34 significantly affected the relaxation produced by NaHS, while iberiotoxin and glibenclamide only reduced maximal relaxation of HSV. NaHS partially relaxed endothelium-intact rings pre-contracted by high K+, as well as phenylephrine-contracted rings in the presence of nifedipine. Additionally, the incubation of HSV rings with NaHS increased NO production. These results demonstrate that NaHS produces the concentration- and endothelium-dependent relaxation of isolated HSV. Vasorelaxation to NaHS probably involves activation of NO/cGMP/PKG pathway and partially prostacyclin. In addition, different K+ channels subtypes, especially SKCa and IKCa, as well as BKCa and KATP channels in high concentrations of NaHS, probably participate in the NaHS-induced vasorelaxation. © 2021 Société Française de Pharmacologie et de Thérapeutique

Hydrogen sulfide (H2S) represents the third and the youngest member of the gaseous transmitters family. The dominant effect of H2S on isolated vessels is vasodilation. As the mechanism of H2S-induced relaxation in human vessels remains unclear, the present study aimed to investigate the effects of H2S donor, sodium hydrosulfide (NaHS), on isolated human saphenous vein (HSV) and to determine the mechanism of action. Our results showed that NaHS (1 µM–3 mM) induced a concentration-dependent relaxation of endothelium-intact HSV rings pre-contracted by phenylephrine. Pre-treatment with L-NAME, ODQ and KT5823 significantly inhibited NaHS-induced relaxation, while indomethacin induced partial inhibition. Among K+ channel blockers, the combination of apamin and TRAM-34 significantly affected the relaxation produced by NaHS, while iberiotoxin and glibenclamide only reduced maximal relaxation of HSV. NaHS partially relaxed endothelium-intact rings pre-contracted by high K+, as well as phenylephrine-contracted rings in the presence of nifedipine. Additionally, the incubation of HSV rings with NaHS increased NO production. These results demonstrate that NaHS produces the concentration- and endothelium-dependent relaxation of isolated HSV. Vasorelaxation to NaHS probably involves activation of NO/cGMP/PKG pathway and partially prostacyclin. In addition, different K+ channels subtypes, especially SKCa and IKCa, as well as BKCa and KATP channels in high concentrations of NaHS, probably participate in the NaHS-induced vasorelaxation. © 2021 Société Française de Pharmacologie et de Thérapeutique

Anticoagulants are effective agents for the prevention and treatment of thrombosis and thromboembolic complications, which represent a common cause of morbidity and mortality. Despite their clinical efficiency, traditional anticoagulants are all associated with significant drawbacks. As a result, modulation of the coagulation process represents an important target in the development of new oral and parenteral anticoagulants today. The new oral anticoagulants selectively target thrombin (ximelagatran, dabigatran etexilate) or factor Xa (rivaroxaban, apixaban, edoxaban). Unlike the traditional anticoagulants, vitamin K antagonists, these drugs have rapid onset of action and a relatively wide therapeutic range, do not require routine prothrombin time (PT) monitoring and have low potential for food and drug interaction. The new parenteral anticoagulants achieve their effects through indirect (semuloparin, idrabiotaparinux) or direct inhibition of factor Xa (otamixaban), as well as through inhibition of coagulation factor IXa (RB006). The main characteristics of these agents are a rapid onset of action and a predictable anticoagulant effect, whereby the most of them can be rapidly neutralized by an adequate antidote.

Background: There is ongoing debate regarding the efficacy of the radial artery (RA) as an aortocoronary conduit, with few solid data regarding long-term clinical results. We sought to determine if the use of the RA as the second arterial conduit, beside left internal thoracic artery (LITA), would improve long-term clinical outcome after CABG as compared to saphenous vein graft (SVG). Methods: Between March 2001 and November 2003, 200 patients underwent isolated CABG and were randomized in 1:1 fashion to receive either LITA and RA grafts or LITA and SVGs. The primary end point was composite of cardiovascular mortality, non-fatal myocardial infarction and need for repeat myocardial revascularization (either surgical or percutaneous). Results: There was no significant difference in absolute survival, with 12 deaths in each group during the study period (log rank = 0.01, p = 0.979). There were 3 and 2 cardiac deaths in RA and SVG groups, respectively. There was no difference in long-term clinical outcome between the groups (log rank = 0.450, p = 0.509). Eleven patients in RA group had one or more non-fatal events; 7 patients suffered a myocardial infarction, 9 patients underwent percutaneous coronary angioplasty, and 1 patient required redo coronary surgery. Likewise, 13 patients in SVG group had non-fatal event; 7 patients had myocardial infarction, 13 patients had percutaneous coronary intervention and 3 patients required redo coronary surgery. Angiograms were performed in 23 patients in RA group (patency rate 92%) and 24 in SVG group (patency rate 86%) (p = 0.67). Conclusion: In this small randomised study our data indicate that there is no difference in the 8year clinical outcomes in relatively young patients between those having a RA or a saphenous vein graft used as a second conduit, beside LITA, for surgical myocardial revascularisation. © 2015 Petrovic et al.