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PubMed2003

[Chalcones (1,3-diarylpropen-1-ones) and their analogs as potential therapeutic agents in cardiovascular system diseases].

At the beginning of a new millennium, several important questions have come to the fore connected with the utilization of natural resources for the investigation of new medicaments (necessity of cooperation of both highly developed and developing countries in the protection of natural resources, necessity to justly evaluate and reward the contributions of the individual cultures in the case that a knowledge of traditional medicine was employed in the development of a new medicament, necessity to achieve the maximal chemical variety of real and virtual libraries of substances from which potential drugs are selected for screening tests). The research of chalcones and its analogues which are relatively easily available not only by isolation from natural material, but also by the methods of classical and combinatorial synthesis should not be substantially affected by the above-described changes. The present communication links up with previous papers (Opletalová, V., Sedivý, D.: Ces. slov. Farm. 48, 252 (1999); Opletalová, V.: Ces. slov. Farm. 49, 278 (2000); Opletalová, V. et al.: Folia Pharm. Univ. Carol. 25, 21 (2000)) and is devoted to the stabilizing action of chalcones on the vascular wall, vasodilating and anti-aggregating effects, and a favourable effect of their antioxidative activity on the functions of the cardiovascular system. The introduction also briefly discusses the nomenclature of this group of compounds.

Animals↗
PubMed1977

Responses of the cardiovascular system of the rat to noradrenaline infusions and their modification by adrenoceptor blocking agents.

1 The effects of noradrenaline upon the cardiovascular system of the rat, anaesthetized with pentobarbitone, have been investigated.2 Noradrenaline produces a dose-dependent increase in mean arterial blood pressure (MABP) which is due entirely to an increase in cardiac output; total peripheral vascular resistance (TPR) remains unchanged.3 Following beta-adrenoceptor blockade the pressor response to infused noradrenaline is enhanced and is now due mainly to an increase in TPR; the increment in cardiac output is reduced.4 After alpha-adrenoceptor blockade the pressor response is greatly reduced; the residual increase in MABP is due solely to an increase in cardiac output.5 After ganglion blockade resting cardiac output and TPR both fall, resulting in a reduction in MABP. The pressor response to noradrenaline is enhanced and is now due to increases in both TPR and in cardiac output.6 The cardiovascular response of the anaesthetized rat to noradrenaline can be explained in terms of classical alpha- and beta-adrenoceptor stimulation by the amine; the unusual form of the response may be due to an effective predominance of beta-adrenoceptor-mediated effects in this species.7 It is suggested that the failure of exogenous noradrenaline to produce a rise in TPR results from a balance between the alpha-adrenoceptor-mediated increase and beta-adrenoceptor-mediated decrease in this variable. However, this proposed balance is lost if resting vasoconstrictor tone is reduced by ganglion blockade.

Adrenergic alpha-Antagonists↗
PubMed1998

Gap junction channels in the cardiovascular system: pharmacological and physiological modulation.

Intercellular communication provides the basis for the intact functioning of tissue and for various organs and tissue types in an organism to work together. It is the crucial difference between isolated cells and intact tissue. Cells communicate in various ways with each other; these include the release of chemical transmitters, hormones and mediators as well as direct electrical and chemical intercellular communication via gap junction channels. The gap junction coupling is important for the organization of the tissue as an electrical syncytium and for accurate development. Pharmacological modulation of these channels could be important in the fields of arrhythmogenesis, vasomotion and cell differentiation. In this review, Stefan Dhein outlines the structure, synthesis and function of gap junction channels. Since their physiology and pharmacology are best investigated in the cardiovascular system, the second part of the article focuses on the role of gap junctions in the heart and vasculature, with special emphasis on the regulation of the channels by physiological stimuli such as ions, pH mediators and transjunctional voltage as well as their pharmacological modulation.

Animals↗
PubMed1983

The causes of perinatal death induced by prenatal exposure of rats to the pesticide, mirex. Part I: Pre-parturition observations of the cardiovascular system.

Prenatal exposure to mirex, a chlorinated hydrocarbon insecticide, induces a high rate of perinatal death, but only a low incidence of visible abnormalities which could help to account for these deaths. This study is an attempt to determine the cause of these deaths. Pregnant rats were intubated with a moderate dose of mirex, in oil, 6 mg/kg/day, on days 8 1/2-15 1/2 of gestation. Observations, on 78 control and 136 treated fetuses, were made on the morning before parturition was expected. Fetuses were sequentially exposed and electrocardiograms obtained with the fetus attached to the placenta and uterus. ECGs were evaluated for rate of beat, regularity of beat, PR intervals, and other features. Fetuses were examined for edema level and vitality. None of the controls were dead and none had abnormal ECGs. Of the treated group, 14% were dead, 16% had a first-degree heart block, and 2% had a second-degree heart block. Some (6%) had slow, feeble atrial beats only, possibly a third-degree block, and appeared to be dying. The severity of the symptoms was proportional to the degree of visible edema. Most of the fetuses with little or no visible edema had normal ECGs, but the majority of the moderate to severely edematous fetuses (i.e., with a layer of subcutaneous edema across the back of 0.5 mm or more) had abnormal ECGs and/or were either dead or dying. These data show that the effects of mirex on the fetal cardiovascular system are a major factor in inducing prenatal death.

Abnormalities, Drug-Induced↗
PubMed2003

Differentiation and genetic manipulation of human embryonic stem cells and the analysis of the cardiovascular system.

Human embryonic stem (ES) cells are pluripotent cells derived from blastocyst-stage embryos. The cells are characterized by their self-renewal capability and by their ability to differentiate into a wide range of cell types. In vivo, injection of the human ES cells into immune-deficient mice generates teratomas harboring derivatives of all three embryonic germ layers. In vitro, spontaneous aggregation of human ES cells results in the formation of embryoid bodies (EBs) comprised of differentiated cells from the three embryonic germ layers. Induced differentiation of ES cells into specific subsets of cells may be generated by treatment with several growth factors. Cardiomyocytes and endothelial cells were among the tissue types identified in vitro, and one of the most dramatic examples for the differentiation of human ES cells is the formation of rhythmic contractions of EBs containing pulsing cardiac muscle cells. Cells of the cardiovascular system were characterized by many molecular markers and by their structural and functional properties. The ability to genetically manipulate human ES cells now allows for the purification of specific cell types. Human ES cells have tremendous value as an in vitro model to study embryonic differentiation and as a source of cells for cellular transplantation in various pathologies among them cardiovascular diseases.

Animals↗
PubMed2002

Expression and developmental regulation of the NMDA receptor subunits in the kidney and cardiovascular system.

Antagonists to the N-methyl-D-aspartate (NMDA) receptor bind to various extraneuronal tissues. We therefore assessed the expression of the main NMDA subunit, NR1, in various tissues. We demonstrate that NR1 appears to be most abundant in the rat kidney and heart. NR1 is present in total rat kidney, cortex, and medulla. Of the NR2 subunits, only the NR2C subunit protein is present in the kidney. The abundance of the NR1 subunit protein increases with kidney development. Both NR1 and NR2C are present in opossum kidney, Madin-Darby canine kidney, and LLC-PK(1) cells. Immunohistochemistry studies show that the NR1 subunit is present in the renal proximal tubule. NR1 is abundant in the atrium and ventricle but is also expressed in the aorta and pulmonary artery. The NR2 subunits are not expressed in the heart. NR1 subunit protein expression is constant throughout heart development. Finally, the NR1 subunit protein is expressed in heart cells (H9c2) grown in culture. These studies reveal the presence of the NMDA receptor in the kidney and the cardiovascular system.

Aging↗
PubMed1999

Antioxidant function of the mitochondrial protein SP-22 in the cardiovascular system.

The mitochondrial protein SP-22 has recently been reported to be a member of the thioredoxin-dependent peroxide reductase family, suggesting that it may be one of the antioxidant systems in mitochondria, which are the major site of reactive oxygen intermediate generation. The aim of this study was to examine whether SP-22 is involved in mitochondrial antioxidant mechanisms and whether its expression is induced by oxidative stresses, particularly those in mitochondria. The expression of SP-22 protein was enhanced by about 1.5-4.6-fold when bovine aortic endothelial cells (BAEC) were exposed to various oxidative stresses, including mitochondrial respiratory inhibitors which increased the superoxide generation in BAEC mitochondria. The expression of SP-22 mRNA increased 2.0-3.5-fold with a peak at 3-6 h after exposure to Fe2+/dithiothreitol or a respiratory inhibitor, antimycin A. BAEC with an increased level of SP-22 protein caused by pretreatment with mild oxidative stress became tolerant to subsequent intense oxidative stress. On the other hand, BAEC that had been depleted of SP-22 with an antisense oligodeoxynucleotide against SP-22 mRNA became more labile to oxidative stress than control BAEC. The induction of SP-22 protein by oxidative stress in vivo was demonstrated in an experimental model of myocardial infarction in rat heart. These findings indicate that SP-22 functions as an antioxidant in mitochondria of the cardiovascular system.

Amino Acid Sequence↗
PubMed2005

Functional evidence that in the cardiovascular system AT1 angiotensin II receptors are AT1B prejunctionally and AT1A postjunctionally.

Numerous studies have shown that angiotensin II causes vasoconstriction both by a direct action on smooth muscle cells (postjunctional effect) and indirectly through the facilitation of noradrenaline release from postganglionic sympathetic neurons (prejunctional effect). The receptors through which angiotensin II exerts its actions were first divided into AT1 and AT2 subtypes. A further subdivision of AT1 receptors into AT1A and AT1B subtypes was based on cloning and receptor binding studies: AT1A showed a high affinity for losartan, but low affinity for PD123319, while AT1B receptors showed nearly 100-fold lower affinity for losartan and 10,000-fold higher affinity for PD123319 relative to AT1 sites. The present review deals with functional evidence supporting the existence of AT1A and AT1B subtypes in the cardiovascular system. Taken together, all the functional results obtained in vivo and in vitro-in a wide variety of vascular tissues from different species-allow one to conclude that angiotensin II AT1 receptors are different pre- and postjunctionally and also that prejunctional and postjunctional angiotensin II receptors most probably belong to AT1B and AT1A subtypes, respectively.

Angiotensin II↗
PubMedDate not supplied

A search for ultrasonic cavitation within the canine cardiovascular system.

Resonant bubble detectors (RBD) were used to search for both pre-existing bubbles and bubbles created by cavitation within the cardiovascular system of 22 dogs. No pre-existing bubbles of 3.8 micron diam or larger were found, nor were any created by exposing the left ventricle to 0.51-1.61 MHz ultrasound of up to 16 W/cm2 spatial-peak intensity. Bubbles introduced into the arterial system by high speed injection were readily detected and could be held in the heart by 1 MHz ultrasound at 1-2 W/cm2 or above. A surprising observation was that gas bubbles of resonant size injected into the left ventricle and held by ultrasound did not multiply continuously as happens in saline or water in vitro. This in vivo system was designed to assess the potential for cavitation bioeffects and the essentially negative results obtained may limit the expected or potential risk of this mechanism in regard to medical applications of ultrasound.

Animals↗
PubMed2002

[Tolerance of moderate hypothermic therapy: it's effect on the neonatal cardiovascular system and particularly pulmonary and intestinal circulation].

We present a study in which we investigated the safety of therapeutic mild hypothermia on the neonatal cardiovascular system. In an attempt to mimic the state of affairs that may follow an hypoxic-ischemic insult, the effect of moderate hypothermia was studied under conditions where cardiovascular integrity was impaired. Newborn piglets where randomized to either receive a thromboxane A2 mimetic or an hypoxic inspiratory gas mixture. Periods of hypothermia (5 degrees C below normothermic level) preceded or were combined with those agents in a random manner. Isolated hypothermia decreased cardiac output by 25%, and increased pulmonary vascular resistance by 48%. Mesenteric blood flow and cerebral blood flow decreased by a similar magnitude (21 and 18% respectively). When hypothermia was combined with alveolar hypoxia or thromboxane, the increase in pulmonary vascular resistance (103 and 292% respectively) exceeded the increase produced by the sum of each individual component. In contrast neither hypoxia nor thromboxane potentiates the hypothermia induced decrease in mesenteric blood flow. Ileal mucosal blood flow remained stable for all conditions. We conclude that mild therapeutic hypothermia may be safe in conditions where cardiac function is impaired, but may be more hazardous when severe pulmonary hypertension is present.

Animals↗
PubMed2002

Mineralocorticoid receptors and pathophysiological roles for aldosterone in the cardiovascular system.

For almost 40 years since its discovery in 1953, the mineralocorticoid hormone, aldosterone, was considered to affect blood volume, and thus blood pressure, by its action to retain sodium at epithelial tissues. Over the past decade, direct effects of aldosterone on the heart and blood vessels, and on the cerebral control of blood pressure, have been established in experimental animals. Simultaneously, the incidence of primary aldosteronism in essential hypertension is now acknowledged to be 10-20%, rather than <or= 1%, underscoring a previously unrecognized role for aldosterone in hypertension. The 30% improvement in mortality (and 35% in morbidity) seen in the RALES trial with the addition of low-dose spironolactone to best practice therapy in moderate to severe heart failure, similarly points to an unrecognized role for aldosterone in the pathophysiology of heart failure. Currently, both experimental and clinical studies are directed towards establishing the mechanisms involved in these pathophysiological effects of aldosterone in the cardiovascular system, and of the role of mineralocorticoid receptor antagonists in offsetting or blocking such effects. A brief account of the current state of these mechanisms in at a cellular and tissue level forms the basis of this review.

Aldosterone↗
PubMed1998

A study on possible modulating and direct effects of gamma2-MSH and ACTH-(1-24) on the cardiovascular system of the rat.

In conscious rats, gamma2-melanocyte-stimulating hormone (gamma2-MSH) dose-dependently increases blood pressure and heart rate, whereas adrenocorticotropin-(1-24) [ACTH-(1-24)] dose-dependently decreases blood pressure, an effect which was accompanied by a reflectory tachycardia. As the exact mechanism involved in these cardiovascular effects of the two melanocortins is as yet not known, we undertook a series of experiments to investigate the possibility that these peptides have modulating or direct effect on the cardiovascular system of the rat. In pithed rats gamma2-MSH, administered intravenously (i.v.) in doses of 5-200 nmol/kg, had no significant effect on systolic and diastolic blood pressure and on heart rate, whereas ACTH-(1-24), 5-500 nmol/kg, i.v., dose-dependently decreased blood pressure and increased heart rate. Infusion of gamma2-MSH, 10(-8) M, or ACTH-(1-24), 10(-6) M, in the isolated perfused rat heart did not significantly affect left ventricular pressure or coronary flow. Pretreatment with either gamma2-MSH or ACTH-(1-24) did not modify the responsiveness of the myocardium and coronary vasculature to salbutamol and phenylephrine. Neither gamma2-MSH nor ACTH-(1-24) did affect the vascular contractile machinery of skinned vascular smooth muscles of the rabbit with respect to Ca2+ handling in the cell, as measured by its sensitivity to exogenously applied Ca2+. Gamma2-MSH had no effect on blood pressure and heart rate in pithed rats in which postganglionic sympathetic outflow was stimulated by 1,1-dimethyl-4-phenylpiperazinium (DMPP), nor in pithed rats in which preganglionic sympathetic outflow was stimulated electrically. A dose of 15 nmol/kg ACTH-(1-24) had no significant influence on preganglionic outflow to the cardiac and vascular structures in pithed rats. These data show that gamma2-MSH does not exert its cardiovascular effects via a peripheral site of action at the level of the vascular system and the heart, nor directly on pre- or postganglionic sympathetic outflow. These results are in support for the notion that the peptide acts via a brain region localised outside the blood-brain barrier. The acute depressor effect of ACTH-(1-24), however, seems to be due to a direct effect on the vasculature in the periphery.

Animals↗
PubMedDate not supplied

[The restoration of cardiovascular system function in patients with chronic glomerulonephritis after the use in staged medical rehabilitation of measured therapeutic physical exercise].

As many as 195 patients were studied presenting with mixed, nephrotic, and hematuric varieties of chronic glomerulonephritis (ChG), aged 6-15 years, including 118 children from the test-groups who were given a combined therapy involving differentiated rest-and-movement regimens (DRMR) and graded therapeutical physical training (GTPT) and 77 controls who received none of the above treatments. The examination involved clinical as well as functional tests (the unit "Cardiocid"-aided ECG, EchoCG on the "Combison-420-5"), with the renal function being evaluated as recommended by Ota Shiuk. Commonly seen in those being admitted into hospital was nephrogenous hypertension as were abnormal changes in myocardium associated with automatism malfunction, inadequate conductivity, and impaired myocardial contractile ability. Clinical and functional tests as a whole suggested to us a latent cardiac insufficiency in those children presenting with faulty kidney function. Use of DRMR and GTPT in a complex of therapeutic and rehabilitative measures in a continuous staged medical rehabilitation project makes for improvement of the function of the cardiovascular system in all of the varieties of the condition particularly so in hematuric and nephrotic forms of ChG, as evidenced by ECG and EchoCG in a 5-yr follow-up.

Adolescent↗
PubMed1982

[Pharmacological Characterization of novel pyridazines Part 3: Testing on the cardiovascular system and the isolated smooth-muscle organ (author's transl)].

17 newly synthetized pyridazines were tested for activity on the cardiovascular system. Two of them caused a dose dependent fall in blood when applied intravenously. Intravascular administration of one of these two compounds, the hypotensively active hydrazinopyridazine, to the "perfused hind extremities of the rat" gave rise to an increase in flow. All the 17 compounds under investigation were inactive on the isolated ileum preparation. From these results it is concluded that the hypotensive effect of the active pyridazines is attributable to a prominent action on the peripheral vascular system. As all these compounds are regarded as relatively weak, closer examination of their mechanism of action is not planned.

Animals↗
PubMed2000

A role for smad6 in development and homeostasis of the cardiovascular system.

Smad proteins are intracellular mediators of signalling initiated by Tgf-betasuperfamily ligands (Tgf-betas, activins and bone morphogenetic proteins (Bmps)). Smads 1, 2, 3, 5 and 8 are activated upon phosphorylation by specific type I receptors, and associate with the common partner Smad4 to trigger transcriptional responses. The inhibitory Smads (6 and 7) are transcriptionally induced in cultured cells treated with Tgf-beta superfamily ligands, and downregulate signalling in in vitro assays. Gene disruption in mice has begun to reveal specific developmental and physiological functions of the signal-transducing Smads. Here we explore the role of an inhibitory Smad in vivo by targeted mutation of Madh6 (which encodes the Smad6 protein). Targeted insertion of a LacZ reporter demonstrated that Smad6 expression is largely restricted to the heart and blood vessels, and that Madh6 mutants have multiple cardiovascular abnormalities. Hyperplasia of the cardiac valves and outflow tract septation defects indicate a function for Smad6 in the regulation of endocardial cushion transformation. The role of Smad6 in the homeostasis of the adult cardiovascular system is indicated by the development of aortic ossification and elevated blood pressure in viable mutants. These defects highlight the importance of Smad6 in the tissue-specific modulation of Tgf-beta superfamily signalling pathways in vivo.

Animals↗
PubMed1992

[Molecular pharmacology of endothelin in the cardiovascular system].

Endothelin-1 (ET-1), ET-2 and ET-3 are 21-amino acid peptides that act to stimulate contraction of many smooth muscle tissues including blood vessels, uterus, bladder, and intestine. In the case of each ET, the 21-amino acid bioactive form is produced from each precursor (referred to as big ET) via specific conversion between Trp-Val (ET-1, ET-2) or Trp-Ile (ET-3). Northern blot analysis of the mRNA for the ET isoform as well as determination of the peptide itself revealed that they are independently expressed in various tissues, indicating that each isoform may play separate physiological or pathophysiological roles. However, the vascular endothelial cells appear to produce only ET-1. Since ET-1 was first discovered, the majority of investigations so far reported have been concerned with this particular peptide. This review will focus on ET-1 with respect to the regulation of its biosynthesis in endothelial cells and its precise pharmacological actions on the cardiovascular system including the cerebral, coronary and renal circulations. Sub-classification of ET receptors was made from molecular biological, biochemical as well as pharmacological points of view. The signal transduction for mechanisms of action was also explained in detail.

Animals↗
PubMed1992

Effects of flunoxaprofen, a non-steroidal anti-inflammatory agent, on the cardiovascular system.

The effects of flunoxaprofen (FL) were investigated using anesthetized normotensive and spontaneously hypertensive (SHR) young and old rats. The animals were divided into two groups. One group received a non-steroidal anti-inflammatory agent at doses significantly inhibiting prostaglandin (PG)-cyclooxygenase; the other received no non-steroidal anti-inflammatory drugs. Oral pretreatment of anesthetized rats with flunoxaprofen (6.6, 11.5, and 19.9 mg/kg/day in the feed for 560 days) significantly increased the following responses: occlusion of the common carotid arteries, and reactivity to L-noradrenaline (NA) (i.v.), and angiotensin II (Ang) (i.v.). Pressor responses also increased in normotensive and in SHR rats treated with FL (20 mg/kg/day for seven days). The effects were more intense in the SHR rats. Moreover, oral pretreatment of normotensive rats with FL (20 mg/kg/day for seven days) partially yet significantly reduced the antihypertensive activity of etozolin (ET), a diuretic and antihypertensive drug. Our data confirm the important role of prostaglandins in the regulation of the cardiovascular system, and an increase in arachidonic acid metabolite biosynthesis with vasodilatory effects being part of the mechanism of action of some antihypertensive drugs.

Administration, Oral↗