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A van der Laarse

Publications and source records attributed to A van der Laarse.

At least 19 recordsLinked to original sources
PubMed1998

Functional and metabolic evaluation of the athlete's heart by magnetic resonance imaging and dobutamine stress magnetic resonance spectroscopy.

BACKGROUND: The question of whether training-induced left ventricular hypertrophy in athletes is a physiological rather than a pathophysiological phenomenon remains unresolved. The purpose of the present study was to detect any abnormalities in cardiac function in hypertrophic hearts of elite cyclists and to examine the response of myocardial high-energy phosphate metabolism to high workloads induced by atropine-dobutamine stress. METHODS AND RESULTS: We studied 21 elite cyclists and 12 healthy control subjects. Left ventricular mass, volume, and function were determined by cine MRI. Myocardial high-energy phosphates were examined by 31P magnetic resonance spectroscopy. There were no significant differences between cyclists and control subjects for left ventricular ejection fraction (59+/-5% versus 61+/-4%), left ventricular cardiac index (3.4+/-0.4 versus 3.4+/-0.4 L x min(-1) x m[-2]), peak early filling rate (562+/-93 versus 535+/-81 mL/s), peak atrial filling rate (315+/-93 versus 333+/-65 mL/s), ratio of early and atrial filling volumes (3.0+/-1.0 versus 2.6+/-0.6), mean acceleration gradient of early filling (5.2+/-1.4 versus 5.8+/-1.9 L/s2), mean deceleration gradient of early filling(-3.1 +/- 0.9 versus -3.2 +/- 0.7 L/s2), mean acceleration gradient of atrial filling (3.6+/-1.8 versus 4.5+/-1.7 L/s2), and atrial filling fraction (0.23+/-0.06 versus 0.26+/-0.04, respectively). Cyclists and control subjects showed similar decreases in the ratio of myocardial phosphocreatine to ATP measured with 31P magnetic resonance spectroscopy during atropine-dobutamine stress (1.41+/-0.20 versus 1.41+/-0.18 at rest to 1.21+/-0.20 versus 1.16+/-0.13 during stress, both P=NS). CONCLUSIONS: Left ventricular hypertrophy in cyclists is not associated with significant abnormalities of cardiac function or metabolism as assessed by MRI and spectroscopy. These observations suggest that training-induced left ventricular hypertrophy in cyclists is predominantly a physiological phenomenon.

Adaptation, Physiological↗
PubMed1997

Metabolic response of normal human myocardium to high-dose atropine-dobutamine stress studied by 31P-MRS.

BACKGROUND: 31P-MRS during cardiac stress may provide (patho)physiological insights into the high-energy phosphate metabolism of the myocardium. Accordingly, the purpose of the present study was to determine the metabolic response of normal human myocardium to severe atropine-dobutamine (A-D) stress. To corroborate the results from the present in vivo study, a 31P-MRS experiment was performed with a moving phantom to simulate respiratory motion. METHODS AND RESULTS: The phantom experiment showed no relation (P=.371) between the intensity ratio of two separate phosphate peaks and amplitude of phantom excursions. The phosphocreatine (PCr) and ATP signal strength and the PCr/ATP ratio were determined from the left ventricular wall in 20 healthy subjects (posttest likelihood for coronary artery disease was <2.5%) with 31P-MRS at rest and during high-dose A-D stress (rate-pressure product increased threefold). Stress-induced changes were -21% for PCr (P<.001) and -9% for ATP (P<.05). The average PCr/ATP value at rest was 1.42+/-0.18 and decreased by 14% to 1.22+/-0.20 during stress (P<.001). CONCLUSIONS: The phantom experiment shows that the in vivo decrease of myocardial PCr/ATP due to high-dose A-D stress we observed is not a motion artifact. Consequently, this indicates that myocardial high-energy phosphate metabolism of the normal human heart is altered at high workloads.

Adenosine Triphosphate↗
PubMed1997

Detection and quantification of dysfunctional myocardium by magnetic resonance imaging. A new three-dimensional method for quantitative wall-thickening analysis.

BACKGROUND: Regional left ventricular dysfunction is a major consequence of myocardial ischemia, and its extent determines long-term prognosis. Accurate and reproducible analysis of left ventricular dysfunction is therefore useful for risk stratification and patient management. METHODS AND RESULTS: Short-axis cardiac cine magnetic resonance (MR) imaging was performed in 25 patients after anterior myocardial infarction at 21 +/- 2.1 days after the acute onset. The MR images were analyzed with the use of a dedicated analytical software package (MASS version 1.0), which includes a modified centerline method and a new three-dimensional analysis approach. A database of 48 healthy volunteers was constructed to objectively depict myocardial dysfunction in the patients; this database was compared with enzymatically determined infarct size. The mean (+/-SEM) quantity of dysfunctional myocardium and enzymatically calculated infarct size equaled 24.0 +/- 3.0 and 22.3 +/- 2.9 g, respectively (P = .69). Enzymatically determined infarct size correlated strongly with left ventricular dysfunction determined by cine MR imaging (y = 0.90x + .92. P < .0001). Segments related to the distribution of the left anterior descending coronary artery showed a significantly lower percentage wall thickening in patients than did corresponding segments of 48 normal subjects (46.0 +/- 8.22% versus 87.1 +/- mean SEM, respectively; P < .001). The mean (+/-SEM) end diastolic wall thickness of the infarcted segment did not differ from that of corresponding normal segments (7.4 +/- 0.33 versus 7.5 +/- 0.15 mm; P = .75). CONCLUSIONS: We conclude that the use of three-dimensional quantitative analysis of cine MR images accurately quantities the extent of regional left ventricular dysfunction in the infarcted heart. This method of analysis may be useful in assessing the effect of interventional therapies.

Adolescent↗
PubMed1997

Beneficial effect of enalapril on left ventricular remodelling in patients with a severe residual stenosis after acute anterior wall infarction.

OBJECTIVE: The present study was designed to evaluate the effects of early angiotensin converting enzyme (ACE) inhibition on left ventricular enlargement in patients with anterior wall infarction following reperfusion therapy. METHODS: Seventy-one consecutive patients with an anterior wall myocardial infarction were randomly allocated to enalapril (n = 36) or placebo (n = 35). All patients received either thrombolytic therapy (n = 46) or underwent primary coronary angioplasty (n = 25). Medication was started within 48 h admission to hospital and continued for 48 weeks. The process of left ventricular remodelling was assessed with two-dimensional echocardiography at 3 weeks and 1 year after the acute onset, and was related to the severity of the residual stenosis of the infarct-related artery. RESULTS: Baseline left ventricular ejection fraction was 39.2% +/- 8.7%. During the study period left ventricular end-diastolic volume index increased from 48.2 +/- 9.9 ml.m-2 to 54.6 +/- 12.2 ml.m-2 at 3 weeks, and to 59.4 +/- 17.0 ml.m-2 after 1 year I control patients (P < 0.001). In the enalapril-treated patients, left ventricular end-diastolic volume index increased from 50.0 +/- 16.1 to 57.7 +/- 19.3 ml.m-2 at 3 weeks, and to 61.9 +/- 22.7 ml.m-2 after 1 year (P < 0.001). Both at 3 weeks and after 1 year, no overall differences in left ventricular volumes were observed between the enalapril and the placebo group (both ns). However, patients with a residual stenosis severity of > or = 70% in the infarct-related artery (n = 43) showed significant attenuation of remodelling by enalapril (n = 22) when compared to placebo (n = 21). In patients on enalapril, left ventricular end-diastolic volume index increased from 47.0 +/- 13.0 to 53.7 +/- 17.7 ml.m-2 compared to 48.0 +/- 9.6 to 60.3 +/- 16.3 ml.m-2 in control patients (P < 0.03). Also diastolic filling parameters were significantly improved in patients with > or = 70% residual stenosis. CONCLUSION: In patients with an anterior wall infarction and a severe residual infarct-related coronary artery stenosis following reperfusion, treatment with enalapril prevents the process of left ventricular remodelling. As left ventricular dilatation is an early process we suggest that treatment with ACE inhibition should be started as soon as possible in this group of patients.

Aged↗
PubMed1997

Effect of 17 beta-estradiol on plasma lipids and LDL oxidation in postmenopausal women with type II diabetes mellitus.

In type II diabetes mellitus the altered hormonal state after menopause may represent an additional cardiovascular risk factor. Estrogen replacement therapy (ERT) is associated with a decreased cardiovascular risk, at least in nondiabetic postmenopausal women. We studied the effect of ERT on plasma lipids and lipoproteins and on LDL oxidation in 40 postmenopausal women with type II diabetes but with minimal vascular complications in a randomized placebo-controlled trial. Twenty patients were treated orally with 2 mg/d micronized 17 beta-estradiol and 20 patients with placebo for 6 weeks. Plasma total cholesterol (-6%, P = .04), LDL cholesterol (-16%, P = .0001), and apoB (-11%, P = .001) levels decreased and HDL cholesterol (20%, P = .0001) and apoA-I (14%, P = .0001) levels increased after ERT compared with placebo. Glycated hemoglobin (HbA1c) decreased significantly after ERT (-3%, P = .03), the cholesterol content of the LDL particles decreased (-5%, P = .006), triglyceride content increased (16%, P = .01), and LDL particle size did not change significantly. ERT had no effect on parameters of LDL oxidation. We conclude that plasma levels of HDL cholesterol, apoA-I, LDL cholesterol, apoB, and glycated hemoglobin are improved in postmenopausal women with type II diabetes mellitus after treatment with 17 beta-estradiol, indicative of a better metabolic control, and that ERT has no effect on LDL oxidizability.

Aged↗
PubMed1997

Comparison of in vivo cardiac function with ex vivo cardiac performance of the rat heart after thoracic irradiation.

The aim of the study was to compare in vivo cardiac function with ex vivo cardiac performance after local heart irradiation in the same rat. Left ventricular ejection fraction (LVEF) was measured in vivo by radionuclide ventriculography in Sprague-Dawley rats up to 16 months after a single dose of 20 Gy. Four days after in vivo measurements, cardiac performance was determined ex vivo, using the isolated working rat heart preparation. After irradiation, cardiac performance measured ex vivo deteriorated more rapidly than the in vivo measured LVEF. Within 4 months post-treatment, ex vivo cardiac output and stroke volume started to decrease and declined continuously throughout the observation period of 16 months. The reduction in stroke volume was already significant (p < 0.04) at 4 months post-treatment, whereas the decline in cardiac output was significant (p < 0.05) at 12 months post-treatment. In vivo, no change in LVEF was observed during the first 12 months post-treatment. Thereafter, LVEF decreased rapidly from 65 +/- 2% to 46 +/- 8% (p < 0.01), at 16 months post-treatment. Up to 12 months post-irradiation, LVEF was not correlated to ex vivo cardiac output. At 16 months post-treatment, when clinical symptoms of heart failure become evident, a positive relation between both parameters was found. The lack of correlation between the in vivo and ex vivo measurements of cardiac function during the first 12 months post-treatment might be explained by the involvement of compensatory mechanisms being operative in vivo to maintain sufficient cardiac output.

Animals↗
PubMed1997

Lipolysis of very low density lipoproteins by heparan sulfate proteoglycan-bound lipoprotein lipase.

An in vitro assay to study lipolysis of very low density lipoproteins (VLDL) by heparan sulfate proteoglycan (HSPG-bound lipoprotein lipase (LPL) was developed. Optimal conditions for VLDL lipolysis by HSPG-bound LPL were obtained by incubating plastic wells with 0.5 microg HSPG and 1.5 microg LPL, subsequently. Control experiments with heparinase indicate that at least 90% of the LPL activity is derived from LPL bound to heparan sulfate chains. For HSPG-LPL-mediated lipolysis, the apparent Km and Vmax values were 0.36 +/- 0.11 mM VLDL-triglycerides and 1.2 +/- 0.1 microM free fatty acids/min x ng LPL, respectively. The mean intra-assay and inter-assay coefficients of variance were 5% and 8%, respectively.

Animals↗
PubMed1996

Eicosapentaenoic acid incorporation in membrane phospholipids modulates receptor-mediated phospholipase C and membrane fluidity in rat ventricular myocytes in culture.

The influence of increased incorporation of linoleic acid (18:2n-6) and eicosapentaenoic acid (20:5n-3) in membrane phospholipids on receptor-mediated phospholipase C beta (PLC-beta) activity in cultured rat ventricular myocytes was investigated. For this purpose, cells were grown for 4 days in control, stearic acid (18:0)/oleic acid (18:1n-9), 18:2n-6 and 20:5n-3 enriched media, and subsequently assayed for the basal- and phenylephrine- or endothelin-1-induced total inositol phosphate formation. The various fatty acid treatments resulted in the expected alterations of fatty acid composition of membrane phospholipids. In 18:2n-6-treated cells, the incorporation of this 18:2n-6 in the phospholipids increased from 17.1 mol % in control cells to 38.9 mol %. In 20:5n-3-treated cells, incorporation of 20:5n-3 and docosapentaenoic acid (22:5n-3) in the phospholipids increased from 0.5 and 2.7 mol % in control cells to 23.2 and 9.7 mol %, respectively. When 20:5n-3-treated cells were stimulated with phenylephrine or endothelin-1, the inositolphosphate production decreased by 33.2% and increased by 43.4%, respectively, as compared to cells grown in control medium. No effects were seen in 18:2n-6-treated cells. When 18:0/18:1n-9-treated cells were stimulated with endothelin-1, inositolphosphate formation increased by 26.4%, whereas phenylephrine-stimulated inositolphosphate formation was not affected. In saponin-permeabilized cells, that were pre-treated with 20:5n-3, the formation of total inositolphosphates after stimulation with GTP gamma S, in the presence of Ca2+, was inhibited 19.3%. This suggests that the 20:5n-3 effect on intact cardiomyocytes could be exerted either on the level of agonist-receptor, receptor-GTP-binding-protein coupling or GTP-binding-protein-PLC-beta interaction. Investigation of the time course of saponin-induced permeabilization of the cardiomyocytes, measured by the release of lactate dehydrogenase, unmasked a slight decrease in the rate of permeabilization by 20:5n-3 pretreatment, indicating a protective effect. This led the authors to measure the cholesterol/phospholipid molar ratio, the double bond index of membrane phospholipids, and the membrane fluidity; the latter by using a diphenylhexatriene probe. In 20:5n-3-pretreated cells, a strong increase in the cholesterol/phospholipid molar ratio (from 0.23 to 0.39), a marked increase in the double bond index (from 1.76 to 2.33), and a slight decrease in fluidity (steady-state anisotropy rss of the diphenylhexatriene probe increased from 0.196 to 0.217) were observed. Thus, treatment of cardiomyocytes for 4 days with 20:5n-3, but not with 18:2n-6, causes alterations of receptor-mediated phospholipase C beta activity. A causal relationship may exist between the 20:5n-3 causes alterations of the physicochemical properties in the bilayer and of the agonist-stimulated phosphatidylinositol cycle activity.

Adrenergic alpha-Agonists↗
PubMed1996

Changes in cardiac performance and sympathetic stimulation during and after fractionated radiotherapy in a rat model.

The consequences of fractionated irradiation on the number of cardiac alpha- and beta-adrenergic receptors, myocardial norepinephrine concentration and in vitro assessed heart function were studied in Sprague-Dawley rats. Animals were locally irradiated on the thorax with a total dose of 50 Gy, in 5 weeks, using two different fractionation schemes (5 x 2.0 Gy/week and 3 x 3.3 Gy/week). Functional and biochemical assays were performed during treatment and at 6 months after initiation of treatment. During fractionated irradiation, the numbers of alpha- and beta-adrenergic receptors tended to rise. During this period, myocardial norepinephrine concentration remained fairly constant and no decrease in cardiac output was observed. At 6 months, a significant increase of the numbers of alpha- and beta-adrenergic receptors was observed in the 3.3 Gy/fraction group compared to age-matched controls, p = 0.012 and p = 0.02, respectively. At this time point, the myocardial norepinephrine concentration had decreased below control levels (p = 0.008 for the 3.3. Gy/fraction schedule, and p = 0.03 for the 2.0 Gy/fraction schedule). At 6 months, the cardiac output declined to 61% (p = 0.009) and 69% (p = 0.04) of control values for the 3.3 and 2.0 Gy/fraction schedules, respectively. The present data clearly show development of late cardiac sequelae caused by fractionated thorax irradiation with a total dose of 50 Gy. Moreover, this study lends support to the importance of fraction size with regard to the severity of the radiation-induced cardiac damage.

Animals↗
PubMed1995

Glutathione disulfide as an index of oxidative stress during postischemic reperfusion in isolated rat hearts.

The objectives of this study were to determine 1) whether reactive oxygen species generated upon postischemic reperfusion lead to oxidative stress in rat hearts, and 2) whether an exogenous prooxidant present in the early phase of reperfusion causes additional injury. Isolated buffer-perfused rat hearts were subjected to 30 min of hypothermic no-flow ischemia followed by 30 min of reperfusion. Increased myocardial content of glutathione disulfide (GSSG) and increased active transport of GSSG were used as indices of oxidative stress. To impose a prooxidant load, cumene hydroperoxide (20 microM) was administered during the first 10 min of reperfusion to a separate group of postischemic hearts. Reperfusion after 30 min of hypothermic ischemia resulted in a recovery of myocardial ATP from 28% at end-ischemia to 50-60%, a release of 5% of total myocardial LDH, and an almost complete recovery of both coronary flow rate and left ventricular developed pressure. After 5 and 30 min of reperfusion, neither myocardial content of GSSG nor active transport of GSSG were increased. These indices were increased, however, if cumene hydroperoxide was administered during early reperfusion. After stopping the administration of cumene hydroperoxide, myocardial GSSG content returned to control values and GSH content increased, indicating an unimpaired glutathione reductase reaction. Despite the induction of oxidative stress, reperfusion with cumene hydroperoxide did not cause additional metabolic, structural, or functional injury when compared to reperfusion without cumene hydroperoxide. We conclude that reactive oxygen species generated upon postischemic reperfusion did not lead to oxidative stress in isolated rat hearts. Moreover, even a superimposed prooxidant load during early reperfusion did not cause additional injury.

Adenine Nucleotides↗
PubMed1995

Quantitative analysis of regional left ventricular function after myocardial infarction in the pig assessed with cine magnetic resonance imaging.

To assess the accuracy of quantitative analysis of global and regional wall motion and wall thickening of the left ventricle with cine magnetic resonance (MR), images obtained in eight pigs before and after myocardial infarction were compared with those obtained using gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA)-enhanced multislice spin-echo MR imaging and determination of pathology. The region with abnormal wall motion and wall thickening, as determined with cine MR imaging, identified the same region of infarction as indicated by Gd-DTPA-enhanced spin-echo MR imaging and pathology. Within the infarcted region wall motion and wall thickening analyzed with the centerline method were significantly reduced. We conclude that the use of quantitative analysis of cine MR images accurately determines localization and extent of regional left ventricular dysfunction in the infarcted heart in vivo. This analysis using dedicated software including the centerline method allows sequential assessment of regional left ventricular function in normal and infarcted hearts.

Animals↗
PubMed1995

Alpha-adrenergic agonist and endothelin-1 induced intracellular Ca2+ response in the presence of a Ca2+ entry blocker in cultured rat ventricular myocytes.

Previously we demonstrated that stimulation of cultured neonatal rat ventricular myocytes by either alpha 1-adrenergic agonist or endothelin-1 resulted in a rapid formation of total inositolphosphates, although the levels of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate did not rise significantly. The aim of this study was to examine whether stimulation by alpha 1-adrenergic agonist and endothelin-1 could still elicit phosphatidylinositol cycle mediated intracellular Ca2+ mobilization in these cells. The intracellular free Ca2+ concentration ([Ca2+]i) was measured by single cell imaging dual wavelength fluorescence microscopy in Fura-2-loaded cardiomyocytes. The interference of agonist induced [Ca2+]i responses by the beat to beat variation of [Ca2+]i was prevented by arresting the cells with the Ca2+ entry blocker diltiazem (10 microM). The [Ca2+]i response (expressed as % of baseline ratio of fluorescence intensities of Fura-2 at 340 nm and 380 nm excitation wavelength), induced by phenylephrine (10(-4) M) and endothelin-1 (10(-8) M) was small, up to 20% of baseline after 9-20 min. In contrast, Ca(2+)-influx induced by incubation in Na(+)-free buffer caused a steep increase of [Ca2+]i up to 150% of baseline after 30 s. Analysis of single cells following stimulation with phenylephrine or endothelin-1 showed heterogeneity with respect to a rise in [Ca2+]i. However, if rapid Ca(2+)-influx was induced by incubation in Na(+)-free buffer, [Ca2+]i responses in individual myocytes occurred homogeneously. It is concluded that the alpha 1-adrenergic agonist and endothelin-1 induced [Ca2+]i responses are delayed in time, small and quite heterogeneous among cells. The findings are in agreement with earlier observations which revealed no detectable overall increase of the Ca2+ releasing inositolphosphates under these conditions and suggest that other second messengers, such as 1,2-diacylglycerol, are involved in the agonist mediated Ca2+ signals.

Adrenergic alpha-Agonists↗
PubMed1995

Combining salicylate and enalapril in patients with coronary artery disease and heart failure.

OBJECTIVE: To study the effects of adding a salicylate to the angiotensin converting enzyme inhibitor enalapril in patients with heart failure due to coronary artery disease. DESIGN: Double blind, crossover study for three days in hospital followed by an extended similar study outside hospital over two months of once daily enalapril plus salicylate and enalapril plus placebo. SETTING: Tertiary referral centre. PATIENTS: 20 patients with heart failure due to myocardial infarction (New York Heart Association class II or III) and an ejection fraction less than 0.40. Twelve patients completed the two parts of the study. MAIN OUTCOME MEASURES: Blood pressure, plasma converting enzyme activity; plasma angiotensin II and noradrenaline concentrations; excretion of metabolites of renal and systemic prostanoids. RESULTS: The unloading effect of first and second dose of enalapril in the morning lasted only during the day; in the extended study it lasted 24 hours because of the drug's accumulation. Converting enzyme inhibitors attenuate the breakdown of bradykinin and therefore enhance prostaglandin E2 synthesis mediated by bradykinin. Evidence was found of such a prostaglandin E2 mediated contribution to ventricular unloading by enalapril, which was blocked by salicylate. The contribution, however, was small and variable, and salicylate addition had on average no significant de-unloading effect during the day. Unloading was abolished in only three of the 20 patients in the short term study and in one of the 12 in the extended study. At night, when other effects of enalapril on blood pressure had waned and the bradykinin induced effect persisted, salicylate significantly reduced the remaining small unloading effect. No effect was seen of salicylate addition on reversal of remodelling. Enalapril reduced angiotensin II induced synthesis of systemic and renal prostaglandin I2 and thromboxane A2, initially only during the day, but later also at night. It thereby masked suppression of thromboxane A2 synthesis by salicylate, which is the effect to which reinfarct prevention by salicylate is attributed. CONCLUSION: The risk is low that salicylate will substantially reduce the benefit of enalapril in patients with heart failure by de-unloading the ventricle. Like other effects induced by bradykinin significant de-unloading occurs in only a minority of the patients. In the presence of enalapril, however, salicylate will probably not be as effective as expected in reducing reinfarction risk, because enalapril already reduces thromboxane A2 synthesis effectively in patients with heart failure and no further reduction by salicylate was found.

Adult↗
PubMed1995

Supplementation with low doses of vitamin E protects LDL from lipid peroxidation in men and women.

There is accumulating evidence that oxidative modification of LDL is an important step in the process of atherogenesis and that antioxidants may protect LDL from oxidation. We and others have previously shown that ingestion of pharmacological doses of the antioxidant D,L-alpha-tocopherol (vitamin E), far above the recommended daily intake (ie, 12 to 15 IU/d for adults), increases the oxidation resistance of LDL. In this study, we ascertained the minimal supplementary dose of vitamin E necessary to protect LDL against oxidation in vitro. Twenty healthy volunteers (10 men and 10 women, aged 21 to 31 years) ingested consecutively 25, 50, 100, 200, 400, and 800 IU/d, D,L-alpha-tocopherol acetate during six 2-week periods. No changes were observed in LDL triglyceride content, fatty acid composition of LDL, or LDL size during the intervention. Concentrations of alpha-tocopherol in plasma and LDL were both 1.2 times the baseline values after the first period (25 IU/d) and 2.6 and 2.2 times, respectively, after the last period (800 IU/d). There was a linear increase in LDL alpha-tocopherol levels up to an intake of 800 IU/d (r = .79, P < .0001) and a good correlation between alpha-tocopherol in plasma and LDL (r = .66, P < .0001). Simultaneously, the resistance of LDL to oxidation was elevated dose-dependently (+28% after the last period) and differed significantly from the baseline resistance time even after ingestion of only 25 IU/d.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

cGMP and nitric oxide modulate thrombin-induced endothelial permeability. Regulation via different pathways in human aortic and umbilical vein endothelial cells.

Previous studies have demonstrated that cGMP and cAMP reduce the endothelial permeability for fluids and macromolecules when the endothelial permeability is increased by thrombin. In this study, we have investigated the mechanism by which cGMP improves the endothelial barrier function and examined whether nitric oxide (NO) can serve as an endogenous modulator of endothelial barrier function. Thrombin increased the passage of macromolecules through human umbilical vein and human aortic endothelial cell monolayers and concomitantly increased [Ca]2+ in vitro. Inhibition of these increases by the intracellular Ca2+ chelator BAPTA indicated that cytoplasmic Ca2+ elevation contributes to the thrombin-induced increase in endothelial permeability. The cGMP-dependent protein kinase activators 8-bromo-cGMP (8-Br-cGMP) and 8-(4-chlorophenylthio)cGMP (8-PCPT-cGMP) decreased the thrombin-induced passage of macromolecules. Two pathways accounted for this observation. Activation of cGMP-dependent protein kinase by 8-PCPT-cGMP decreased the accumulation of cytoplasmic Ca2+ in aortic endothelial cells and hence reduced the thrombin-induced increase in permeability. On the other hand, in umbilical vein endothelial cells, cGMP-inhibited phosphodiesterase (PDE III) activity was mainly responsible for the cGMP-dependent reduction of endothelial permeability. The PDE III inhibitors Indolidan (LY195115) and SKF94120 decreased the thrombin-induced increase in permeability by 50% in these cells. Thrombin treatment increased cGMP formation in the majority of, but not all, cell cultures. Inhibition of NO production by NG-nitro-L-arginine methyl ester (L-NAME) enhanced the thrombin-induced increase in permeability, which was restricted to those cell cultures that displayed an increased cGMP formation after addition of thrombin. Simultaneous elevation of the endothelial cGMP concentration by atrial natriuretic factor, sodium nitroprusside, or 8-Br-cGMP prevented the additional increase in permeability induced by L-NAME. These data indicate that cGMP reduces thrombin-induced endothelial permeability by inhibition of the thrombin-induced Ca2+ accumulation and/or by inhibition of cAMP degradation by PDE III. The relative contribution of these mechanisms differs in aortic and umbilical vein endothelial cells. NO can act in vitro as an endogenous permeability-counteracting agent by raising cGMP in endothelial cells of large vessels.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

Polyploidy of myocyte nuclei in pressure overloaded human hearts: a flow cytometric study in left and right ventricular myocardium.

Increased heart weight is known to be associated with polyploidy of myocardial nuclei. However, the relation between polyploidy and myocardial hypertrophy at a cellular level, i.e. myocyte hypertrophy, has not yet been investigated. The present study was conducted to reveal this relation in different regions in the heart using two recently developed techniques, i.e. flow cytometry to measure polyploidy and microscopic morphometry to measure myocyte dimensions in fixed tissue sections. We investigated the effect of pressure overload induced hypertrophy in subendocardial and subepicardial regions of 43 human left ventricles and transmural samples from 47 human right ventricles. In all regions the degree of polyploidy correlated well with myocyte volume indexed for body surface area. At equal extent of myocyte hypertrophy, the degree of polyploidy was higher in left ventricular samples than in right ventricular samples. In conclusion, pressure overload induced myocyte hypertrophy is associated with polyploidy, which is more pronounced in the left ventricle than in the right ventricle.

Cell Nucleus↗