[Endothelium and nitric oxide]. / Endotelis ir azoto oksidas.

Studied nature of the "blood vessels relaxing factor" derived from endothelium that was identified as nitric oxide caused intensive scientific research on nitric oxide regarding some aspects of its impact on human physiological and pathological processes. The objective of this short review is to discuss widely used (in the clinical practice) direct and indirect donors of nitric oxide and/or other agents, increasing nitric oxide concentration in human body, and their beneficial role for the prevention of atherosclerosis. Under physiological conditions, endothelium regulates the tone of blood vessels, homeostasis of which is maintained by endothelium-generated vasoconstrictors and vasodilators. The most important vasodilator and the main substance produced by the endothelium is nitric oxide. The failure of synthesis and/or the lost of nitric oxide bioavailability is the major feature of endothelial dysfunction and key factor initiating progression of atherosclerosis. The endothelial dysfunction initiates the series of events, which stimulate and aggravate the course of atherosclerosis by increasing endothelial permeability, platelet aggregation, and leukocyte adhesion, and cytokine expression. Further, the review deals with the mechanisms of action of statins, angiotensin-converting enzyme inhibitors, L-arginine, direct nitric oxide donors (nitroglycerin, isosorbide mononitrate and isosorbide dinitrate), and indirect nitric oxide donors (phosphodiesterase-V inhibitors, K(ATP) openers).

Effect of Low-Intensity Cavitation on the Isolated Human Thoracic Artery In Vitro.

Reported here are the results of an experimental study on the response to low-intensity cavitation induced by low-frequency (4-6 W/cm2, 20 kHz and 32.6 kHz) ultrasound of isolated human arterial samples taken during conventional myocardial revascularization operations. Studies have found that low-frequency ultrasound results in a significant (48%-54%) increase in isometric contraction force and does not depend on the number of exposures (10 or 20) or the time passed since the start of ultrasound (0, 10 and 20 min), but does depend on the frequency and location (internal or external) of the blood vessels for the application of ultrasound. Diltiazem (an inhibitor of slow calcium channels) and carbachol (an agonist of muscarinic receptors) used in a concentration-dependent manner did not modify the relaxation dynamics of smooth muscle affected by ultrasound. Thus, ultrasound conditioned to the augmentation of the isometric contraction force the smooth muscle of blood vessels and did not improve endothelial- and calcium channel blocker-dependent relaxation.

[The main determinants of endothelial dysfunction]. / Svarbiausi endotelio disfunkcijos determinantai.

Nitric oxide (NO) is produced from amino acid L-arginine via the catalytic action of NO synthases, which use dioxygen and NADH or NADPH as cofactor. This simple molecule acts at nanomolar concentrations and demonstrates a wide spectrum of physiological effects, a primary of which is vasodilatation. The production of NO in endothelium cells is induced by mechanical action (increased blood-vessels wall tension) and chemical agents (catecholamines, acetylcholine, bradykinin, histamine). The endothelium-released NO easily diffuses to the underlying smooth muscles and triggers their relaxation by increasing cyclic guanosine monophosphate level and subsequent opening of endothelial potassium channels (K(ATP), K(Ca)). NO on the endothelium surface inhibits adhesion and aggregation of platelets, regulates the main functions of myocardium, modulates the permeability of endothelium, and weakens the interaction of endothelium cells and leukocytes by reducing the expression of adhesion-stimulating proteins. Direct evidence suggests that free radicals and related reactive oxygen species mostly as O2-, HO-, ONOO-, ROO- are associated with an endothelium dysfunction, which manifests itself as an impairment of endothelium-dependent vasorelaxation. Though reactive oxygen species in a small amount are produced constantly, the decreased metabolic turnover of homocysteine, poor performance of antioxidants or high level of angiotensin II alters the balance between production of free radicals and their neutralization. Such events decrease NO bioavailability and thus condition the development of various diseases like arteriosclerosis, hypertension, diabetes, heart and renal failure. Agents increasing NO bioavailability and depressing the endothelial dysfunction would be the most useful for the treatment above-mentioned pathologies.

Antitumor activity of new substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and study of their effect on the cell cycle.

This paper reports the synthesis of a new series of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones which were tested as potential antitumor agents at the National Cancer Institute. Two derivatives are now under review by BEC (Biological Evaluation Committee of NCI). To investigate the mechanism of action, the effect on cell cycle progression was studied by monitoring them in colon adenocarcinoma HT-29: both were able to block HT-29 in mitosis. 3-[(2,6-Dimethylimidazo[2,1-b]thiazol-5-yl)methylene]-5-chloro-2-indolinone was the most active compound.

Synthesis and antitumor activity of 1,5,6-substituted E-3-(2-chloro-3-indolylmethylene)-1,3-dihydroindol-2-ones.

Synthesis and antitumor activity of new E-3-(2-chloro-3-indolylmethylene)-1,3-dihydroindol-2-ones are described. All compounds prepared were active in the primary test (three human cell lines) and entered the second level (60 human cell lines). The most active antitumor derivatives bear the same substituents in the chloroindole ring and are not CDK1 inhibitors. A COMPARE analysis showed that they could act as tubulin binders. In most cell lines, E-3-(2-chloro-5-methoxy-6-methyl-3-indolylmethylene)-1,3-dihydroindol-2-one was a growth inhibitor more potent than vincristine.

Potential antitumor agents. 34.(1) Synthesis and antitumor activity of guanylhydrazones from imidazo[2,1-b]thiazoles and from diimidazo[1,2-a: 1,2-c] pyrimidine.

We report the synthesis of new guanylhydrazones from imidazo[2,1-b]thiazoles and of a bis-guanylhydrazone from diimidazo[1,2-a:1,2-c]pyrimidine. The compounds were tested as potential antitumor agents at the National Cancer Institute. Two derivatives are now under review by BEC: one of these was also subjected to a test for positive inotropic activity in view of a possible coanthracyclinic activity. Tyrosine kinase receptors may be involved as molecular targets in the mechanism of action of the guanylhydrazones described.

Action of calcium antagonists and agonists on isolated human thoracic arteries used for coronary artery bypass grafting.

BACKGROUND: The goal of this study was to investigate the modulation of the contraction-relaxation effects in isolated human thoracic artery samples of three calcium-channel antagonists, amlodipine (CAS [88150-42-9]), cerebrocrast (CAS [118790-71-9]) and diltiazem (CAS [42399-41-7]), and two calcium-channel agonists, CGP 28392 (CAS [89289-93-0]) and benzimidazole derivative. To estimate the endothelial function of the artery samples, carbachol, an agonist of muscarinic receptors, was used. METHODS: The experiments were conducted on isolated human thoracic artery samples, and their isometric contractions were recorded using an i-FOT10 force transducer. Cumulative concentration-contraction curves of the tested agents (10(-7) to 10(-4) M) were established. RESULTS: Carbachol at concentrations of 10(-7) to 10(-6) M did not cause any relaxation of artery rings precontracted by 10(-4) M phenylephrine, and at concentrations of 10(-5) and 10(-4) M, isometric contractions increased by 7% and 20%, respectively. In response to amlodipine, cerebrocrast and CGP28392, the contraction of artery samples increased significantly, whereas diltiazem and benzimidazole derivative caused their relaxation by ≈55%. CONCLUSION: The obtained data indicate that the endothelium of the thoracic artery, which is used for coronary artery bypass grafting, is damaged by and may have some influence on the inadequate response of 1,4-dihydropyrine type calcium-channel antagonists.

Effects of calcium antagonists and agonists on isolated human v. saphena magna used for coronary artery bypass grafting and guinea pig's papillary muscle.

BACKGROUND: The goal of this study was to investigate the movement of contraction-relaxation effects on isolated human blood vessel samples by the actions of amlodipine (CAS 88150-42-9), cerebrocrast (CAS 118790-71-9), diltiazem (CAS 42399-41-7), and a benzimidazole derivative. Additionally, their effects on isometric contraction force and the duration of the action potential (AP) were measured. METHODS: The experiments were carried out on isolated human v. saphena magna samples and papillary muscles of adult guinea pigs. Isometric contraction and the AP were recorded using a force transducer and standard microelectrode technique. RESULTS: Phenylephrine (10(-4) M) caused contractions of vein rings to 928 +/- 76.5 mg. All the tested agents at a concentration of 10(-7)-10(-4) M significantly relaxed the smooth muscle in a dose-dependent manner. The weakest response was shown by amlodipine. Pre-treatment with 50 microM of amlodipine, diltiazem and benzimidazole for 30 min significantly increased the magnitude of the contraction induced by phenylephrine in concentration-dependent (10(-6)-10(-4) M) fashion but only in the benzimidazole group versus other tested agents and the control. The benzimidazole derivative caused augmentation of isometric contraction of the papillary muscles and negligible lengthening of AP duration; the other agents tested showed opposite effects. CONCLUSION: These results show that agents possessing positive or negative inotropic action significantly relaxed the isolated vein samples precontracted with phenylephrine. These responses point to a different mechanism of action underlying both calcium antagonist and agonist effects even though their action ultimately resulted in vasodilatation.

Effect of 4-aryl-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylates on the guinea pig papillary muscle and isolated human vena saphena magna that is used for coronary artery bypass grafting.

BACKGROUND: The goal of this study was to estimate: (i) the action of 5-nitro-substituted 1,4-dihydropyridines as well as Bay K 8644 (CAS [71145-03-4]) and CGP 28392 (CAS [89289-93-0]) on cardiac action potential duration (APD) and isometric contraction in the isolated guinea pig papillary muscles; (ii) whether the effects of 2-propoxyethyl 4-(2-difluoromethoxyphe-nyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate on the lengthening of cardiac APD were related to certain potassium channels (e.g., I(K1), K(ATP) and I(K)); and (iii) the modulation of the contraction-relaxation effects on isolated human vena saphena magna samples using three 5-nitro-substituted 1,4-dihydropyridine derivatives, displaying the positive inotropic and AP duration effects. METHODS: The experiments were conducted on isolated human vena saphena magna samples and papillary muscles from adult guinea pigs. Isometric contractions and APs were recorded using a force transducer and microelectrode technique, respectively. RESULTS: 2-Propoxyethyl 4-(2-difluoromethoxyphenyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate significantly increased APD and isometric contractions in a concentration-dependent manner. Its effects were suppressed by dl-sotalol. Other derivatives tested, such as Bay K 8644 and CGP 28392, showed either negligible effects or increased the contraction force but did not influence the APD. Compounds possessing positive inotropic properties at a concentration of 10(-7) to 10(-4) M significantly relaxed the isolated vessel samples pre-contracted with phenylephrine (10(-4) M). The weakest response was shown by 2-propoxyethyl 4-(2-difluoromethoxyphenyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate. CONCLUSION: These results show that 5-nitro-substituted 1,4-dihydropyridine derivatives with positive inotropic action significantly relaxed isolated vein samples that were pre-contracted with phenylephrine in a dose-dependent manner. 2-Propoxyethyl 4-(2-difluoromethoxyphenyl)-2-methyl-5-nitro-1,4-dihydropyridine-3-carboxylate prolongs the cardiac APD, which could be determined by the rapid component I(Kr) of the delayed potassium current I(K) blocker.

Effect of 1-acyl-5,6-dialkoxy-2-alkylthiobenzo[d] imidazoles on the action potential duration and isometric contraction in guinea pig atrium activated by carbachol and in guinea pig heart papillary muscles.

BACKGROUND: Studies have shown that some benzo[d]imidazole derivatives (1-(5,6-dimethoxy-2-methylthio-1H-benzo[d]imidazol-1-yl)-1-ethanone (1), 1-(6-ethylthio-5H[1,31dioxolo[4',5':4,5] benzo[d]imidazol-5-yl)-1-propanone (2), 1-(2-ethylthio-6,7-dihydro-1H[1,4]dioxino [2:3':4,5]benzo[d]imidazol-1-yl)-1-pro-panone (3) and 2,3,9,10-tetrahydro-8H [1,4]dioxino[2' 3":4',5']benzo[4,5]imid-azo[2,1-b][1,3]thiazin-10-one (4)) possess strong cardiotonic activity. The goal of this study was to investigate the effect of compounds 1-4 on the action potential (AP) duration and contractile force in guinea pig atrium activated by carbachol and in guinea pig heart papillary muscles. METHODS: The experiments were carried out on the guinea pig papillary muscles and atrium. Isometric contraction and transmembrane potential were recorded using a force transducer and standard microelectrode technique. RESULTS: Compounds 1-4 exerted a positive inotropic effect in a dose-dependent manner on the electrically driven left atrium and papillary muscles, more pronounced in atrium. In response to 1 micromol/L carbachol the AP duration at a 90 % repolarization in atrium shortened more than 70 %, the isometric contraction decreased to the similar level as well. Compounds 1 and 4 significantly antagonized the shortening of the AP duration induced by carbachol and increased it. Compound 1 abolished the reduction of isometric contraction as well. Derivative 3 significantly lengthened (31 ms) the AP duration at a 90 % repolarization in papillary muscles, while 1 and 4 failed to affect this index. The selective blockade of the rapid component of the delayed rectifier potassium current (Ikr) by dl-sotalol (1 micromol/L) did not show the substantial influence on benzimidazole effects. CONCLUSION: These findings support the hypothesis that the tested benzo[d] imidazole derivatives abolish the influence of carbachol on AP and the isometric contraction by inhibition of acetylcholine-activated potassium current (KACh) in guinea pig atrial myocytes and therefore may be beneficial for the prognosis of patients with advanced heart failure and atrial fibrillation.

Substituted E-3-(2-Chloro-3-indolylmethylene)1,3-dihydroindol-2-ones with antitumor activity.

The synthesis and antitumor activity of a new series of E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones is described. Several compounds were active on the primary test (three human cell lines) and entered the second level (60 human cell lines). All of them were potent growth inhibitors with GI(50) ranging from -5.32 to -7.27. Four are now under review by BEC (Biological Evaluation Committee of the NCI). The most potent antitumor derivatives were also evaluated as cardiotonic agents (in view of a possible coanthracyclinic activity). In order to find a possible mechanism of action their effects on cell cycle progression in an adenocarcinoma cell line (HT29) were tested, evidencing that these molecules are able to block HT29 in mitosis. The introduction of new substituents in the indolinone moiety while maintaining the same chloroindole portion generated interesting derivatives. 3-(2-Chloro-5-methoxy-6-methyl-3-indolylmethylene)5-hydroxy-1,3-dihydroindol-2-one was the most active of the whole series. It was more potent than vincristine against seven of the nine tumors considered. Moreover it was selective towards some cell lines such as MDA-MB-435 (breast), OVCAR-3 (ovarian) and SK-MEL-28 (melanoma). Even the introduction of a benzyl ring at the nitrogen of the chloroindole portion, gave rise to potent compounds.