Donors of H2S may be beneficial in treating cardiovascular diseases where the plasma levels of H2S are decreased. Therefore, we investigated the mechanisms involved in relaxation of small arteries induced by GYY4137 [(4-methoxyphenyl)-morpholin-4-yl-sulfanylidene-sulfido-λ5-phosphane;morpholin-4-ium], which is considered a slow-releasing H2S donor. Sulfides were measured by use of 5,5′-dithiobis-(2-nitro benzoic acid), and small rat mesenteric arteries with internal diameters of 200–250 µm were mounted in microvascular myographs for isometric tension recordings. GYY4137 produced similar low levels of sulfides in the absence and the presence of arteries. In U46619-contracted small mesenteric arteries, GYY4137 (10−6–10–3 M) induced concentration-dependent relaxations, while a synthetic, sulfur-free, GYY4137 did not change the vascular tone. L-cysteine (10−6–10–3 M) induced only small relaxations reaching 24 ± 6% at 10–3 M. Premixing L-cysteine (10–3 M) with Na2S and GYY4137 decreased Na2S relaxation and abolished GYY4137 relaxation, an effect prevented by an nitric oxide (NO) synthase inhibitor, L-NAME (Nω-nitro-L-arginine methyl ester). In arteries without endothelium or in the presence of L-NAME, relaxation curves for GYY4137 were rightward shifted. High extracellular K+ concentrations decreased Na2S and abolished GYY4137 relaxation suggesting potassium channel-independent mechanisms are also involved Na2S relaxation while potassium channel activation is pivotal for GYY4137 relaxation in small arteries. Blockers of large-conductance calcium-activated (BKCa) and voltage-gated type 7 (KV7) potassium channels also inhibited GYY4137 relaxations. The present findings suggest that L-cysteine by reaction with Na2S and GYY4137 and formation of sulfides, inhibits relaxations by these compounds. The low rate of release of H2S species from GYY4137 is reflected by the different sensitivity of these relaxations towards high K+ concentration and potassium channel blockers compared with Na2S. The perspective is that the rate of release of sulfides plays an important for the effects of H2S salt vs. donors in small arteries, and hence for a beneficial effect of GYY4137 for treatment of cardiovascular disease.

BackgroundApproximately 30% of patients treated with cardiac resynchronization therapy (CRT) do not achieve favourable response. The purpose of the present study was to identify echocardiographic and clinical predictors of a positive response to CRT.MethodsThe study included 82 consecutive heart failure (HF) patients in New York Heart Association (NYHA) functional class III or IV with left bundle branch block (LBBB), QRS duration ≥ 120 ms and left ventricular ejection fraction (LVEF) ≤ 35%. Statistical analysis was performed using IBM SPSS statistical software (SPSS v.21.0 for Mac OS X). A p value < 0.05 was considered statistically significant.ResultsEchocardiographic response was established in 81.6% and clinical response was achieved in 82.9% of patients. Significant univariate predictors of favourable echocardiographic response after 12 months were smaller left ventricular end-diastolic diameter (LVEDD) (odds ratio [OR] 0.89; 95% confidence interval [CI] 0.82 - 0.97, p = 0.01), and smaller left ventricular end-systolic diameter (LVESD) (OR 0.91; 95% CI 0.85 - 0.98, p = 0.01). Lower uric acid concentration was associated with better echocardiographic response (OR 0.99; 95% CI 0.99 - 1.0, p = 0.01). Non-ischemic HF etiology (OR 4.89; 95% CI 1.39 - 17.15, p = 0.01) independently predicted positive clinical response. Multiple stepwise regression analysis demonstrated that LVEDD lower than 75 mm (OR 5.60; 95% confidence interval [CI] 1.36 - 18.61, p = 0.01) was the strongest independent predictor of favourable echocardiographic response.ConclusionsSmaller left ventricular end-diastolic and end-systolic diameters and lower serum uric acid concentration were associated with better response to CRT. Left ventricular end-diastolic diameter and non-ischemic heart failure etiology were the strongest independent predictors of positive response to CRT.

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In this research we present that Carthamus Tinctorius L. (gen. Asteraceae, otherwise known as Safflower) (Fig. 1) may contain agents active in Cryptococcal infections, malaria and Leishmaniasis, as treatment options are becoming scarce due to drug resistance development. Phytochemistry and pharmacological activities (antimicrobial, antimalarial, antileishmanial) of C. tinctorius L. were analyzed. The composition of volatile oil of safflower dried flowers was analyzed by gas chromatography-mass spectrophotometry with flame ionization detector (GC-FID) and in vitro sensitivity assays were performed to assess biological activity. 8 known and 3 unknown compounds were detected in the extract (Fig. 1). Then the Safflower ointment was manufactured and its acute toxicity study on rats was tested. The volatile oil of C. tinctorius L exhibited activity against Cryptococcus neoformans, Plasmodium falciparum and Leishmania donovani. Safflower volatile oil has anticryptococcal, antimalarial and antileishmanial effects. The prepared ointment had an excellent acute toxicity safety profile.