Assignment of secondary structure from Cα coordinates

A multiple regression analysis has established a nonlinear relationship between the backbone dihedral angles and the C^α coordinates obtained from the x-ray crystal structures of 14 proteins. The regression equations have been applied to predict specific dihedral angles of each residue in the backbone of 24 proteins. Overall this method (Nonlinear Regression Distance Torsion) predicts values of ϕ and ψ within a ±45° window of those found in the x-ray structure with an accuracy of 94 and 91% and within a ±30° window of 88 and 81%. Two methods for the assignment of motif from C^α coordinates are reported. For the first method, motif is assigned from the dihedral angles predicted using the regression equations. By the second method, motif of the ith residue is assigned from the distance C^α_i-1 to C^α_i+2 (v₆) and torsional angle C^α_i-1, C^α_i, C^α_i+1, C^α_i+2 (v₁₃). For the 24 proteins, 23.7% of the residues by the former method and 19.6% by the latter method are assigned differently than in the Protein Data Bank. © 1997 John Wiley & Sons, Inc.     

Differential alteration of lipoxygenase and cyclooxygenase metabolism by rat peritoneal macrophages induced by endotoxin tolerance

Altered macrophage arachidonic acid metabolism may play a role in endotoxic shock and the phenomenon of endotoxin tolerance induced by repeated injections of endotoxin. Studies were initiated to characterize both lipoxygenase metabolite formation by endotoxin tolerant and non-tolerant macrophages in response to 4 different stimuli, i.e. endotoxin, glucan, zymosan, and the calcium ionophore A23187. In contrast to previous reports of decreased prostaglandin synthesis by tolerant macrophages, A23187-stimulated immunoreactive (i) leukotriene (LT)C₄/D₄ and prostaglandin (PG)E₂ production by tolerant cells was greater than that by non-tolerant controls (p<0.001). However, A23187-stimulated i-6-keto-PGF_1α levels were lower in tolerant macrophages compared to controls. Stimulation of prostaglandin and thromboxane (Tx)B₂ synthesis by endotoxin or glucam was significantly less in tolerant macrophages compaared to controls (p<0.05). iLTC₄/D₄ production was not significantly stimulated by endotoxin or glucan, but was stimulated by zymosan in the non-tolerant cells. Synthesis ofb iLTB₄ by control macrophages was stimulated by endotoxin (p<0.01). These results demonstrate that arachidonic acid metabolism via the lipoxygenase and cyclooxygenase pathways in macrophages is differentially altered by endotoxin tolerance.     

Prostaglandin levels in isolated brain microvessels and in normal and norepinephrine-stimulated cat brain homogenates

The levels of PGD₂, PGE₂, PGF_2α and 6-keto-PGF_1α (6KF_1α) produced from endogenous archidonic acid (AA) were quantitated in cat cerebral cortical homogenates and microvessels isolated from cat cerebral cortex using gas chromatography/mass spectrometry (GC/MS). There was a six-fold enrichment of 6KF_1α levels in isolated microvessels, compared to homogenates, suggesting that 6KF_1α is of vascular, rather than neuronal origin. In order to further understand any possible role that norepinephrine (NE)_might have on modulation of PG synthesis, we studied the effects of 0.5 mM NE on PG synthesis from endogenous AA and from ³H-PGG₂, the endoperoxide precursor of PGs. In cat cortical homogenates NE induced a 74% increase in PGD₂ and PGF_2α, a 62% increase in PGE₂, and a 36% increase in 6KF_1α, as measured by GC/MS. NE caused a twofold increase in the conversion of ³H-PGG₂ to ³h-PGG_2α, with a concomitant decrease in ³H-PGE₂ and ³H-6KF_1α formation, and no change in ³H-PGD₂ synthesis. NE had no effect on the total conversiob of ³H-PGG₂ to ³H-PGs, nor on the breakdown of ³H-PGG₂ in the absence of brain tissue. We conclude that NE stimulates extravascular synthesis of PGD₂, PGE₂ and PGF_2α by stimulation of the prostaglandin synthetase complex, in addition to NE's stimulatory effect on the conversion of PGG₂ to PGF_2α, and that the lack of effect of NE on 6KF_1α synthesis reflects either a failure to achieve an adequate concentration at the vascular tissue, or an absence of the mechanism whereby NE stimulates PG synthetase.     

Effect of the thromboxane receptor antagonist EP 092 on endotoxin shock in the sheep

The thromboxane receptor antagonist EP 092 inhibits the acute pulmonary vascular response to endotoxin in the anaesthetized, closed-chest sheep. The increase in the TXB₂ level in arterial blood was not suppressed by EP 092. Intravenous infusion of the thromboxane mimetic 11,9-epoxymethano PGH₂, but not PGF_2α, raises pulmonary artery pressure and lowers arterial pO₂ similar to the endotoxin. Isolated strips of lobar pulmonary veins but not lobar arteries are contracted by low concentrations of 11,9-epoxymethano PGH₂ - the effects are potently inhibited by EP 092.     

Improved sensitivity of iodinated histamine-prostaglandin radioimmunoassay by prostaglandin methyl esters

Use of (¹²⁵I)-labeled histamine-prostaglandin tracer increases the sensitivity of the radioimmunoassays of prostaglandin derivatives. Six different antisera were produced for prostaglandins and their derivatives (prostaglandins E₁, E₂, F_1α, F_2α, 13,14-dihydro-15-ketoprostaglandin E₂, and 13,14-dihydro-15-ketoprostaglandin F_2α) and were investigated with the corresponding tritiated and lodinated tracers. Displacement of iodinated tracers by the methyl esters of the prostaglandin compounds resulted, in most cases, in a three- to fivefold increase in sensitivity compared to unesterified inhibitors. Esterification also caused some alteration in the specificities observed. Our results suggest that conformational changes in the esterified prostaglandins (tracer and inhibitor) could explain these charges.     

Transient cerebral ischemia and brain prostaglandins.

Prostaglandin levels were measured in gerbil brain during cerebral ischemia for up to 2 hours, and during reperfusion after various periods of transient ischemia. The levels of PGF_2α and its metabolite (13,14-dihydro-15-keto-PGF_2α) were low and did not change during ischemia. However, PGF_2α, 13,14-dihydro-15-keto-PGF_2α, PGE₂, and thromboxane B₂ increased during reperfusion after brief episodes of ischemia. Indomethacin or aspirin inhibited this increase. Animals pretreated with indomethacin recovered more rapidly and were more active during reperfusion than those without treatment.     

1α,25-dihydroxyvitamin D3 rapidly alters phospholipid metabolism in the nuclea envelope of osteoblasts

1α,25-Dihydroxyvitamin D₃ (1α, 25-(OH)₂D₃) has been shown to increase cytosolic calcium and inositol trophosphate levels in rat osteosarcoma cells (ROS 17/2.8) and to increase nuclear calcium in these cells. To determine the mechanism(s) of 1α, (OH)₂D₃-induced changes in the calcium, the effect of the hormone on phospholipid metabolism in isolated osteoblast nuclei wa assessed. 1α,25 (OH)₂D₃, 20 nM, increased inositol triphosphate levels in the nuclei after 5 min of treatment. The biologically inactive epimer, 1β,25-(OH)₂D₃, had no significant effect on inositol triphosphate levels. ATP, 1 mM, also increased inositol triphosphate levels in the isolated nuclei after 5 min. 1α,25-(OH)₂D₃, 20 nM, increased calcium in the isolated nuclei in the presence but not in the absence of extranuclear calcium with 5 min. Nuclear calcium was also increased within 5 min by ATP, 1 mM, and inositol triphosphate, 1 mM. The effects of ATP on nuclear calcium was not additive with 1α, 25-(OH)₂D₃, suggesting that these two agents increase nuclear calcium in these osteoblast-like cells by similar mechanisms. In summary, 1α,25-(OH)₂D₃ amd ATP rapidly increase inositol triphosphate levels in isolated from ROS 17/2.8 cells. The hormone, the nucleotide, and the inositol phospholipid nuclear calcium. Thus, the 1α,25-(OH)₂D₃ and ATP effects of nuclear calcium may be mediated by changes in phospholipid metabolism in the nuclei of these osteoblastlike cells. © Wiley-Liss, Inc.     

Dose-dependent effects of a pyridoquinazoline thromboxane synthetase inhibitor on arachidonic acid metabolites and hemodynamics during E. Coli endotoxemia in anesthetized sheep

We investigated the effects of a new pyridoquinazoline thromboxane synthetase inhibitor infused before administering endotoxin into 18 anesthetized sheep with lung lymph fistulas. In normal sheep increasing plasma Ro 23-3423 concentrations were associated with increased plasma levels of 6-keto-PGF_1α, a reduced systemic vascular resistance (SVR, r = −0.80) and systemic arterial pressure (SAP, r = −0.92), the mean SAP falling from 80 to 50 mm Hg at the 20 and 30 mg/kg doses. Endotoxin infused into normal sheep caused transient pulmonary vasoconstriction associated with increased TxB₂ and 6-keto-PGF_1α levels while vasoconstriction and TxB₂ increase were significantly inhibited by pretreatment with Ro 23-3423 in a dose-dependent manner. When compared to controls, plasma and lymph levels of 6-keto-PGF_1α, PGF_2α and PGE₂ after endotoxin infusion were increased several-fold by administering Ro 23-3423 up to plasma levels of 10 μg/ml. Doses over 30 mg/kg with blood levels above 10 μg/ml reduced plasma and lymph levels of 6-keto-PGF_1α, PGF_2α and PGE₂, suggesting cyclooxygenase blockade at this dose. The peak 6-keto-PGF_1α levels at 60 min after endotoxin infusion in sheep with Ro-23-3423 levels below 10 μg/ml were associated with the greatest systemic hypotension due to a reduced SVR (r = −0.86). After endotoxin infusion the leukotrienes B₄, C₄, D₄ and E₄ in lung lymph were assayed by radioimmunoassay and high pressure liquid chromatography and remained at baseline values.     

Novel naftopidil derivatives containing methyl phenylacetate and their blocking effects on α1D/1A-adrenoreceptor subtypes

α₁-Adrenoceptor (α₁-AR) antagonists are considered to be the most effective monotherapy agents for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we synthesized compounds 2–17, which are novel piperazine derivatives that contain methyl phenylacetate. We then evaluated the vasodilatory activities of these compounds. Among them, we found that compounds 2, 7, 12, which contain 2-OCH₃, 2-CH₃ or 2, 5-CH₃, respectively, exhibited potent α₁-blocking activity similar to protype drug naftopidil (1). The antagonistic effects of 2, 7, and 12 on the (?)-noradrenaline-induced contractile response of isolated rat prostatic vas deferens (α_1A), spleen (α_1B) and thoracic aorta (α_1D) were further characterized to assess the sub receptor selectivity. Compared with naftopidil (1) and terazosin, compound 12 showed the most desirable α_1D/1A subtype selectivity, especially improved α_1A subtype selectivity, and the ratios pA₂ (α_1D)/pA₂ (α_1B) and pA₂ (α_1A)/pA₂ (α_1B) were 17.0- and 19.5-fold, respectively, indicating less cardiovascular side effects when used to treat LUTS/BPH. Finally, we investigated the chiral pharmacology of 12. We found, however, that the activity of enantiomers (R)-12 and (S)-12 are not significantly different from that of rac-12.     

Regulation of inositol phosphate levels by prostaglandins in cultured endometrial cells

Stimulation of cultured rabbit endometrial cells by one of the rabbit endometrial cell culture proliferation factors, prostaglandin F_2α (PGF_2α), resulted in a very rapid increase in the intracellular levels of [³H]-inositol triphosphate (IP₃), [³H]-inositol biphosphate (IP₂), and [³H]-inositol monophosphate (IP₁) in cells prelabeled with [³H]-inositol. These increases in inositol phosphate levels were detected in periods of stimulation as short as 30 seconds, reached a maximum by 1 1/2?2 min and declined to control levels by 6–10 min. The stimulation was dose-dependent with maximal increases observed near 10^?6 M PGF_2α. The cholinergic agent, carbachol, also led to time and dose-independent increases in IP₃. Lithium, cadmium, silver, copper, and zinc ions had no effect either on the breakdown of IP₃ or on the accumulation of IP₁. In contrast, vanadate at 10^?6 or 10^?5 M did lead to a decrease in the breakdown of IP₁ and a concomitant increase in IP₁, IP₂, and IP₃. PGF_2α was found previously to induce an increase in rabbit endometrial cell DNA synthesis which was inhibited by concomitant or prior addition of prostaglandin E₁ (PGE₁). PGE₁, in a dose-dependent manner, was found to inhibit the observed IP₃ increase by PGF_2α at 1 1/2 min of stimulation. PGF_2α treated and control cultures did not differ in cAMP or cGMP levels, cellular ⁴⁵Ca uptake, nor cellular ²²Na uptake. We propose that IP₃ may be one of the intracellular messenger(s) synthesized following the treatment of rabbit endometrial cell cultures with the proliferation agent PGF_2α and that it may play a crucial role with cAMP in growth regulation.     

Effect of endotoxin administration in pregnant camels

Intravenous administration of Escherichia coli endotoxin at a dose of 0.05 μg/kg bodyweight to pregnant camels resulted in abortion. The injection of endotoxin caused significant increases in the plasma concentration of 13,14-dihydro-15-prostaglandin F_2α, the metabolite of prostaglandin F_2α (PG F_2α) and cortisol and a significant decrease in the concentration of progesterone. It is suggested that endotoxin caused abortion in camels was a consequence of endotoxin induced PG F_2α secretion resulting in luteal regression and decreased progesterone concentration.     

Measurement of Prostaglandins in the Cerebrospinal Fluid in Cat, Dog, and Man

Prostaglandins are involved in the modulation of various central functions (neurotransmitters and hypothalamic hormone release, thermoregulation, cerebro-vascular tone) and their levels increase in pathological situations [subarachnoid hemorrhage (SAH), stroke, convulsive disorders, etc.]. This study, using sensitive and specific antibodies, examined levels of four eicosanoids, Prostaglandins E₂ and F_2α(PGE₂, PGF_2α); and the metabolites of PGI₂, 6-keto-prostaglandin F_1α (6-keto-PGF1_α) and of thromboxane A₂, thromboxane B₂ (TxB₂), in the cerebrospinal fluid (CSF) obtained atraumatically from three species (human, canine, and feline). An assessment of the methodologic procedures (extraction and radioimmunoassay) was carried out. Human lumbar cerebrospinal fluid was shown to contain PGF_2α (15–44 pg/ml), 6-keto-PGF_1α (undetectable to 39 pg/ml), and TxB₂ (un-detectable to 28 pg/ml), whereas PGE₂ was undetectable (>18 pg) in all cases. In both animals species the eico-sanoid concentrations were 3-to 30-fold higher than humans for every prostaglandin examined. Although the prostaglandin profile for a given species remained constant (cat, PGE₂:6-keto-PGF_1α:TxB₂:PGF_2α; dog, TxB₂:PGE₂:6-keto-PGF_1α:PGF_2α), the absolute levels were found to be lower in the pentobarbital-anesthetized animals than in conscious cats. The correspondence of the prostaglandin profiles found in cerebrospinal fluid with the profiles reported in the literature in brain homogenates for the same species supports the hypothesis that cerebrospinal fluid levels of prostaglandins reflect the relative rates of synthesis in neural tissue.     

Comitogenicity of eicosanoids and the peroxisome proliferator ciprofibrate in cultured rat hepatocytes

Several hypolipidemic drugs and environmental contaminants induce hepatic peroxisome proliferation and hepatic tumors when administered to rodents. These chemicals increase the expression of the peroxisomal β-oxidation pathway and the cytochrome P-450 4A family, which metabolize lipids, including eicosanoids and their precursor fatty acids. We previously found that the peroxisome proliferator ciprofibrate decreases the level of eicosanoids in the liver and in cultured hepatocytes. In this study, we examined the effect of prostaglandins E₂ and F_2α (PGE₂ and PGF_2α), leukotriene C₄ (LTC₄) and the peroxisome proliferator ciprofibrate on DNA synthesis in cultured hepatocytes. Primary rat hepatocytes were cultured on collagen gels in serum-free L-15 medium with varying concentrations of eicosanoids and ciprofibrate, and the absence or presence of growth factors. Ciprofibrate lowered hepatocyte eicosanoid concentrations; the addition of eicosanoids restored their levels. After a 48-h exposure with [³H]-thymidine, DNA synthesis was determined by measuring [³H]-thymidine incorporation into DNA. The addition of PGE₂, PGF_2α, and LTC₄ to cultures along with ciprofibrate increased DNA synthesis, whereas treatment with ciprofibrate or eicosanoids alone resulted in a much smaller increase. The addition of epidermal growth factor (EGF) to the eicosanoid-ciprofibrate combination increased DNA synthesis more than EGF or the eicosanoid-ciprofibrate combination alone. The PGF_2α-ciprofibrate combination also was comitogenic with transforming growth factor-α and hepatocyte growth factor. The addition of both ciprofibrate and prostaglandins also blocked the growth inhibitory effect of transforming growth factor-β on DNA synthesis induced by EGF. These results show that the eicosanoids PGE₂, PGF_2α, and LTC₄ are comitogenic with the peroxisome proliferator ciprofibrate in cultured rat hepatocytes. © 1996 Wiley-Liss, Inc.     

Melanocyte-Stimulating Properties of Arachidonic Acid Metabolites: Possible Role in Postinflammatory Pigmentation

Normal human epidermal melanocytes became swollen and more dendritic with an increase in the amount of tyrosinase and immunoreactive b-locus protein when they were cultured for 2 days with the following arachidonic acid metabolites: prostaglandin (PG) D₂, leukotriene (LT) B₄, LTC₄, LTD₄, LTE₄, thromboxane (TX) B₂ and 12-hydroxy eicosatetraenoic acid (12-HETE). The effect of LTC₄ was particularly strong compared to that of PGE₂, about which we have previously reported. On the other hand, PGE₁, PGF_2α and 6-ketoPGF_1α did not show any significant stimulatory effect. These data suggest that arachidonate-derived chemical mediators, especially LTC₄, may be responsible for the induction of post-inflammatory hyperpigmentation of the skin.     

Determination of cyclooxygenase products and prostaglandin metabolites using high-pressure liquid chromatography and radioimmunoassay.

A method is described for measurement of the cyclooxygenase products, thromboxane,prostacyclin, and prostaglandins (PG), and several prostaglandin metabolites. The procedure involves separation of the compounds by high-pressure liquid chromatography combined with identification and estimation by serologic analysis. These combined procedures have been used to identify and estimate five such products, PGE₂, PGE₁ PGF2α, PGF_1α, and 6-keto-PGF_1α, in the culture fluids of dog kidney cells stimulated by a tumor-promoting phorbol diester. The prostaglandin metabolites, 13,14-dihydro-15-keto-PGE₂, 13,14-dihydro-15-keto-PF2_2α, 13,14-dihydro-PGE₂, and 13,14-dihydro-PGF_2α, were not found in these culture fluids.     

Prostaglandin levels in BL6 melanoma cells cultured in vitro: the effect of vitamin E succinate supplementation

Malignant murine melanoma (BL6-F10) cells convert arachidonic acid primarily to PGD₂, PGF_2α, PGE₂, PGI₂ in descending order of magnitude. Supplementation with 1–10 μg/ml vitamin E succinate resulted in a significant (P ≤ 0.05) decrease in PGD₂ levels at vitamin concentrations of 3,5,7 and 10 μg/ml respectively, while PGF_2α levels were significantly decreased at 1,3,5 (P ≤ 0.05), 7 and 10 μg/ml (P ≤ 0.01) vitamin E succinate. BL6-F10 cells supplemented with 7 and 10 μg/ml vitamin E succinate showed a marked increase in PGE₂ levels with a significant increase occurring at 10 μg/ml (P ≤ 0.025). PGI₂ levels followed a similar trend to PGE₂ with a significant increase (P ≤ 0.05) occurring at 10 μg/ml.     

Prostaglandin-stimulated second messenger signaling in bone-derived endothelial cells is dependent on confluency in culture

New bone formation is associated with an increase in blood flow by the invasion of capillaries. Endothelial cells that line the capillaries can produce paracrine factors that affect bone growth and development, and in turn, could be affected by products produced by bone cells, in particular the osteoblasts. Since osteoblasts produce prostaglandins E₂ and F_2α (PGE₂, PGF_2α), it was investigated if these PGs were agonists to bone-derived endothelial cells (BBE) by assessing changes in cAMP and free cytosolic calcium concentration ([Ca²⁺]i) second messenger generation. We found that confluent cultures of BBE cells, a clonal endothelial cell line derived from bovine sternal bone, responded to 1 μM PGE₂ by an increase in cAMP. PGF_2α at the same concentration was less potent in stimulating an increase in cAMP production in confluent BBE cells. Subconfluent cells with a morphology similar to that of fibroblastic cells were not as sensitive to PGE₂-stimulated cAMP generation. PGF_2α failed to elicit any cAMP production in subconfluent cultures. PGE₂ and PGF_2α both stimulated an increase in [Ca²⁺]i concentration in a dose-dependent manner. The potency of PGE₂ was similar to that of PGF_2α in stimulating an increase in [Ca²⁺]i. The Ca²⁺ response was mostly independent of extracellular Ca⁺, was unchanged even with prior indomethacin treatment, was unaffected by caffeine pretreatment, but was abolished subsequent to thapsigargin pretreatment. The PG-induced increase in [Ca²⁺]i was also dependent on the confluency of the cells. In a subconfluent state, the responses to PGE₂ or PGF_2α were either negligible, or only small increases in [Ca²⁺]i were noted with high concentrations of these two PGs. Consistent, dose-dependent increases in [Ca²⁺]i were stimulated by these PGs only when the cells were confluent and had a cobblestoned appearance. Since it was previously demonstrated that BBE cells respond to parathyroid hormone (PTH) by the production of cAMP, we tested if bovine PTH(1-34) amide bPTH(1—34) also increased [Ca²⁺]i in these cells. No change in [Ca²⁺]i was found in response to bPTH (1—34), although bPTH (1—34) stimulated a nine to tenfold increase in cAMP. We conclude that BBE cells respond to PGE₂ and PGF_2α but not to bPTH(1—34) by an increase in [Ca²⁺]i probably secondary to stimulation of phospholipase C and that the cAMP and [Ca²⁺]i second messenger responses in BBE cells are dependent on the state of confluency of the cells. © 1994 Wiley-Liss, Inc.     

Evidence for 6-keto-PGF1α in adrenal cortex of the rat and effects of 6-keto-PGF1α and PGI2 on adrenal cAMP levels and steroidogenesis

Both intact cortical tissue and isolated cortical cells from the adrenal gland of the rat were analyzed for 6-keto-PGF_1α, the hydrolysis metabolite of PGI₂, using high-performance liquid chromatography and gas chromatography-mass spectrometry. 6-Keto-PGF_1α was present in both incubations of intact tissue and isolated cells of the adrenal cortex, at higher concentrations than either PGF_2α or PGE₂. Thus, the cortex does not depend upon vascular components for the synthesis of the PGI₂ metabolite. Studies $\text{in vitro}$, using isolated cortical cells exposed to 6-keto-PGF_1α (10^?6-10^?4M), show that this PG does not alter cAMP levels or steroidogenesis. Cells exposed to PGI₂ (10^?6-10^?4M), however, show a concentration-dependent increase of up to 4-fold in the levels of cAMP without altering corticosterone production. ACTH (5–200 μU/ml) increased cAMP levels up to 14-fold, and corticosterone levels up to 6-fold, in isolated cells. ACTH plus PGI₂ produced an additive increase in levels of cAMP, however, the steroidogenic response was equal to that elicited by ACTH alone. Adrenal glands of the rat perfused $\text{in situ}$ with PGI₂ showed a small decrease in corticosterone production, whereas ACTH greatly stimulated steroid release. Thus, while 6-keto-PGF_1α is present in the rat adrenal cortex, its precursor, PGI₂, is not a steroidogenic agent in this tissue although it does stimulate the accumulation of cAMP.     

Design,synthesis and cardiovascular evaluation of some aminoisopropanoloxy derivatives of xanthone

A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α₁-(compound 2 and 8), β-(compounds 1, 3, 4, 7), α₁/β-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.