Many natural coumarins and their chemically synthesized analogs and derivatives exert diverse properties, such as anticancer, antioxidant, anti-inflammatory, or anticoagulant, with the latter being of the utmost importance. The widely used warfarin, acenocoumarol, and phenprocoumon exert anticoagulant properties by inhibiting the vitamin K epoxide reductase complex. In this interdisciplinary review, we present biochemical principles of the coagulation processes and possible methods for their tuning based on the use of coumarins. We also summarize chemical methods of synthesis of coumarins and discuss structures and properties of those that have been used for a long time, as well as newly synthesized compounds. Brief information on the clinical use of coumarins and other anticoagulant drugs is given, including the severe effects of overdosing and methods for reversing their action.

Pulmonary arterial hypertension (PAH) still cannot be cured effectively, hence the search for novel treatments continues. The effects of sildenafil (25 mg/kg body weight) and fasudil (30 mg/kg body weight) given alone or in combination, on normalization of right ventricular pressure (RVP), right ventricle mass, as well as the levels of several biomarkers (HDL-C, BNP, VEGF-A), were assessed in a rat model of monocrotaline (MCT)-induced PAH. MCT (60 mg/kg body weight) induced clear PAH in male Wistar rats. After 21 days, a significant decrease in RVP accompanied by a reduction of right ventricular hypertrophy - a significant decrease in the right ventricle/left ventricle plus septum ratio - as a result of sildenafil or fasudil administration was assessed. The administration of fasudil and sildenafil alone or in combination caused a significant decrease in plasma BNP level as compared to MCT-treated rats. Fasudil alone or with sildenafil, but not sildenafil alone, significantly increased HDL-C level as compared to MCT-treated rats. Fasudil and sildenafil given alone or in combination caused a significant increase in plasma VEGF-A level as compared to rats exposed to MCT.

IntroductionIt remains controversial whether statins have a beneficial effect on pulmonary arterial hypertension (PAH). This study is intended to evaluate whether statin, co-administered with Rho-kinase inhibitor, could enhance its efficacy. Although Rho-kinase inhibitors, including fasudil, have been reported to improve pulmonary hypertension in experimental and clinical studies, the combination of these agents has not been tested in the treatment of pulmonary hypertension (PH).Material and methodsThe effects of such a regimen on hemodynamics, right ventricle hypertrophy, and Rho-associated protein kinase (ROCK) activity in experimental monocrotaline (MCT)-induced pulmonary hypertension were examined. Fourteen days after monocrotaline injection (60 mg/kg), male rats were treated orally for another 14 days with fasudil (15 mg/kg per day), or with a combination of fasudil + rosuvastatin (10 mg/kg per day).ResultsThe drug combination reversed the MCT-induced increase in right ventricle pressure (RVP) and reduced right ventricular hypertrophy (RV/LV + S ratio) more than Rho kinase inhibitor alone. The simultaneous administration of fasudil and rosuvastatin caused a further decrease of RhoA kinase activity in isolated lung tissues as compared to fasudil alone.ConclusionsThe results indicate that rosuvastatin intensifies the beneficial effects of Rho-kinase inhibitor on the Rho/Rho-kinase pathway and such a combination may represent an option for the treatment of pulmonary arterial hypertension.

IntroductionStatins and β1-adrenergic antagonists are well established in cardiovascular events therapy and prevention. The previous study showed that statins might impact on β-adrenergic signalling and blood pressure in a dose-dependent manner. The aim of the study was to evaluate the impact of 4-week administration of simvastatin given at different doses on the heart rate and blood pressure after injection of metoprolol in rats.Material and methodsThe experiments were performed in normocholesterolaemic and normotensive Wistar rats. Rats received simvastatin in doses of 1, 10 and 20 mg/kg body weight (bw) for 4 weeks. The control group received 0.2% methylcellulose. For the further estimation of the heart rate and blood pressure, metoprolol at 5 mg/kg bw or 0.9% NaCl was injected intraperitoneally.ResultsSimvastatin at doses of 1, 10 and 20 mg/kg bw did not influence the heart rate or blood pressure as compared to the control group. Metoprolol injection statistically significantly decreased the heart rate (439.29±14.03 min−1 vs. 374.41±13.32 min−1; p<0.05). In rats receiving simvastatin during the 4-week period after metoprolol injection, heart rate and blood pressure (mean, systolic, diastolic) were similar as compared to the group receiving metoprolol alone.ConclusionsSimvastatin administration during a 4-week period in different doses did not influence the heart rate or blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats.

The beneficial effects of statins have been discussed widely, and their preventative role has been confirmed in cardiovascular disorders, primary and secondary prevention settings, and in asymptomatic subjects with a high cardiovascular risk. Despite these benefits, discontinuation of statins is frequent in cardiac patients and might be associated with adverse outcomes in several conditions involving acute coronary syndromes or acute stroke. In this review, we focus on the mechanistic background of statins that might contribute to such negative changes and that extend beyond cholesterol-lowering effects, including the so-called pleiotropic statin activity. In particular, findings regarding the detrimental impact of statin withdrawal on endothelial function, inflammation, platelet activity or AT1 signaling are discussed, along with the possible clinical implications for statin safety.