Overview of pleiotropic effects of platelet P2Y12 receptor inhibitors.

Dual antiplatelet therapy consisting of one of the P2Y12 receptor inhibitors in conjunction with aspirin is the mainstay of treatment for patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary interventions (PCI). In recent years, multiple extra-platelet features of P2Y12 receptor antagonists have been reported in numerous clinical trials. The aim of this review is to summarise reported pleiotropic effects of clopidogrel, prasugrel, ticagrelor and other P2Y12 receptor blockers. We included observations made both in human and in animal models, together with proposed mechanisms of action for described features. If confirmed in randomised studies and properly applied to everyday practice, the observed extra-platelet actions could enable us to improve efficacy of ACS and post-PCI treatment, as well as to confine mortality and occurrence rate of cardiovascular events.

Imidazole-induced contractility of vascular smooth muscle cells in the presence of U-73122, ODQ, indomethacin and 7-nitroindazole.

The aim of the study was to assess the impact of modulating factors on vascular smooth muscle cells reactivity. Vascular resistance was induced by the administration of increasing concentrations of imidazole. The experiments were performed on isolated and perfused tail artery of Wistar rats (weight 250 g - 350 g). Rats were been narcotized by urethane (intraperitoneal injection) at a dose of 120 mg/kg, stunned and then sacrificed by cervical dislocation. In the following investigation classical pharmacometric methods were used. Relationships between concentration-response curves (CRCs) for imidazole observed in the presence of ODQ [(1H-(1,2,4)oxadiazolo-[4,3-a]quinoxalin-1-one)], 7-nitroindazole and indomethacin were analyzed. Imidazole-induced contractility of vascular smooth muscle cells was independent from alpha-adrenergic receptors and PLC activity. Reactivity of VSMCsinduced by imidazole, was significantly changed in the presence of ODQ and 7-nitroindazole.

Modulation of the reaction of vascular smooth muscle cells to angiotensin II induced by catalase and aminotriasol during ischemia-reperfusion.

BACKGROUND: We investigated the influence of catalase and aminotriasol on reactions of the smooth muscle cells induced by angiotensin II (ANG II) after ischemia-reperfusion (I/R). MATERIALS AND METHODS: Experiments were performed on perfused male Wistar rat tail arteries. Using classical pharmacometric methods we analyzed the influence of ANG II on vascular contraction, in the presence of catalase and aminotriazole, and after I/R. RESULTS: A reduction in maximal response and increased EC(5) value were observed after ischemia, while an increased maximal response and decrease EC(50) value were observed after reperfusion. Catalase decreased and aminotriasol increased maximal responses to ANG II. In the presence of catalase, reduction of the maximal response and increase in EC(50) value were observed after reperfusion. In the presence of aminotriasol, we observed increased maximal response and decreased EC(50) value after I/R. CONCLUSION: Ischemia reduced and reperfusion increased the responses of vascular smooth muscle cells to ANG II. Catalase decreased and aminotriasol increased hyperreactivity of arteries to ANG II after reperfusion. These results suggested that antioxidative system modulates reactions induced by ANG II. Reperfusion impairs the balance between antioxidants and the production of reactive oxygen species.

Guanylate cyclase activators influence reactivity of human mesenteric superior arteries retrieved and preserved in the same conditions as transplanted kidneys.

INTRODUCTION: This study sought to investigate the mechanisms of relaxation induced by the (nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulators 3-[5'-hydroxymethyl-2'-furyl]-1-benzylindazole (YC-1) in human mesenteric arteries relaxed and precontracted with 1 micromol/L 5-hydroxytryptamine (serotonin). MATERIAL AND METHODS: Human mesenteric arteries obtained during kidney retrieval were preserved in the same conditions as transplanted kidneys. All experiments were performed after reperfusion with Krebs buffer in 37 degrees C and 100% oxygen exposure. RESULTS: In endothelium-intact rings, YC-1 (0.001 to 30 mmol/L) caused concentration-dependent relaxation (pEC(50): 6.59 +/- 0.12), which shifted to the right in endothelium-denuded rings. The sGC inhibitor 1H- [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ 10 mmol/L) partially attenuated the maximal responses to YC-1 (E(max) = 51.30% +/- 3.70%; n = 6) and displaced its curve to the right in intact and denuded vessels. Both, the NO synthesis inhibitor N-nitro-L-arginine methyl ester (100 mmol/L) and the NO scavenger carboxy-2-[4-carboxyphenyl]-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (100 mmol/L) significantly reduced YC-1 relaxation. The sodium pump inhibitor ouabain (1 micromol/L) produced a greater decrease in the vasodilator response of YC-1 (E(max) = 18.7% +/- 4.55%; n = 9). ODQ (10 micromol/L) plus 1 mumol/L ouabain abolished the relaxant response of YC-1 (E(max) = 9.4% +/- 2.94%, n = 9). CONCLUSIONS: This study demonstrated that sodium pump stimulation by YC-1 as an additional mechanism of sGC activation independent of cGMP relaxed human mesenteric artery, including blockade of Ca(2+) influx. Furthermore, this study suggested an ability of NO to mediate relaxation of resistance-like arteries through the activation of soluble guanylate cyclase and K(+) channels.

Percutaneous coronary intervention triggers a systemic inflammatory response in patients treated for in-stent restenosis -- comparison with stable and unstable angina.

OBJECTIVE AND DESIGN: It is believed that the magnitude of the systemic inflammatory response induced by percutaneous coronary intervention (PCI) impacts on the long-term outcomes in patients with stable angina (SA) and unstable angina (UA). We aimed to determine whether an inflammatory response appears in in-stent restenosis (ISR) patients undergoing balloon angioplasty and to assess its pattern and magnitude in relation to SA and UA subjects. SUBJECTS: 80 patients (59 with SA, 10 with UA, 11 with ISR) were enrolled into the prospective study. TREATMENT: SA and UA patients undergoing single vessel coronary balloon angioplasty followed by stenting versus ISR subjects in whom only balloon angioplasty was performed. METHODS: C-reactive protein (CRP), serum amyloid A (SAA), tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10) were measured in blood samples collected before and 6, 24 h and 1 month after the procedure. RESULTS: A comparable pattern of inflammatory response in terms of CRP and SAA concentrations in subjects undergoing PCI due to ISR and SA was discovered while in unstable patients its magnitude was substantially higher. CRP and SAA levels increased significantly in each group with the peak value at 24 h and the baseline levels remarkably correlated with the highest markers' concentrations. In contrast, preprocedural TNF-alpha concentrations were higher in ISR group when compared with SA and UA patients. Additionally, in ISR group a twofold increase in their values of borderline significance at 6 h was noted. SA and UA subjects were found to have significantly lower TNF-alpha levels at 6 and 24 h after the intervention though the marker concentrations markedly increased with peak values at 1 month. The levels of IL-10 did not differ at any time point between the groups. CONCLUSIONS: We suggest that PCI triggers a systemic inflammatory response in patients with ISR and considerable differences in its pattern when compared with SA and UA patients were demonstrated. Moreover, a high preprocedural TNF-alpha level and its increase provoked by PCI in the ISR group warrant the need for further investigation of its possible involvement in the restenosis process.

[Evaluation of some selected structural and functional parameters of red blood cells as oxidative stress markers in elderly people]. / Ocena wybranych parametrów strukturalnych i czynnosciowych krwinek czerwonych jako markerów stresu oksydacyjnego u osób w wieku podeszlym.

UNLABELLED: The ageing process induces age-related involutionary changes and leads to increased occurrence of many diseases. One of the most important theories of ageing and development of many pathologies is the free radical theory, which assumes that ageing process leads to lost of oxidative balance. THE AIM: of the research was to evaluate the degree of membrane lipid peroxidation, internal microviscosity, activity of membrane ATPase, both total and Na(+)K(+)-dependent, and markers of oxidative damage in erythrocyte membrane protein in elderly people. MATERIAL: The examination was performed on 35 people. The examined group (15 persons, mean age 71,3) consisted of healthy elderly people. The reference group was formed with younger healthy people (20 persons, mean age 55). RESULTS: Erythrocyte membrane lipid peroxidation was found stronger in the group of elderly people. Erythrocyte internal microviscosity was significantly higher in the elderly. The activity of ATPase, both total and Na(+)K(+)-dependent, appeared remarkably greater in the group of younger people. Stronger membrane lipid damage was observed in older age group, which may be implied by lower--SH group concentration, and higher W/S parameter value. CONCLUSION: The obtained results reveal that in elderly people the intensification of oxidative stress in the entire body occurs, which may be confirmed by structural and functional oxidative erythrocyte damage. This conclusion may be significant for pathogenesis of many diseases in this period of life.

Pharmacometric analysis of alpha1-adrenoceptor function in rat tail artery pretreated with lipopolysaccharides.

The inhibitory effect of lipopolysaccharides (LPS) on contraction evoked by alpha-adrenergic stimulation is quite well-known, but molecular mechanism of this inhibition is unclear. In the present study, an interaction between alpha-adrenoceptor response and LPS in rat tail artery was investigated using chemical stimulation. In the presence of LPS noradrenaline and phenylephrine, concentration-response curves were shifted to the right with a change in maximal responses. The K(A) and K(B) values calculated in the presence and absence of LPS did not differ significantly. The results strongly suggest that LPS did not change the affinity of alpha-adrenoceptors. Changes in the plot showing relationship between agonist-evoked responses and receptor occupancy in the presence of LPS and reduction of K(A)/ED50 value suggest reduction of alpha-adrenoceptor reserve. In the experiments performed on arteries without endothelium, the inhibitory effect of LPS was still present. In the presence of atropine, antazoline and indomethacin, the reduction of alpha-adrenoceptor reserve was noted, but in the presence of N-omega-nitro-L-arginine methyl ester (L-NAME), the inhibitory effect of LPS was not significant. Moreover, in LPS-pretreated arteries, in the presence of L-NAME, the increase in the receptor reserve was observed. It suggests that inhibitory effect of LPS is partially reversible. The results strongly indicate that in early endotoxemia, main inhibitory effect of LPS is connected with releasing nitric oxide and decreasing coupling between alpha1-adrenoceptor and signal induction.