Biomedical subjects

P Mulder

Publications and source records attributed to P Mulder.

At least 37 records · Page 2Linked to original sources

PubMed1998

Selective ETA receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure.

BACKGROUND: Left ventricular (LV) dilation, which is a predictor of survival in humans with chronic heart failure (CHF), is limited by a mixed endothelin ETA-ETB antagonist. Whether selective ETA receptor blockade influences LV dilation is unknown. We determined, in a rat model of CHF, the effects of the ETA receptor blocker LU 135,252 on LV remodeling. METHODS AND RESULTS: Rats were subjected to coronary artery ligation and treated for ten weeks with placebo or LU 135,252 (LU), at a dose of 10 or 30 mg kg-1 day-1. Systolic blood pressure and heart rate (plethysmography) were determined in conscious animals before and after four and ten weeks of treatment. At these time points, cardiac output and LV dimensions were measured in anesthetized rats by transthoracic echocardiography. LV hemodynamics were determined in anesthetized rats after ten weeks. Pressor responses to ET-1 (1 nmol/kg, i.v.) and sarafotoxin S6c (0.3 ng/kg, i.v.) were measured, to assess the efficacy of ET receptor antagonism and the lack of blockade of ETB receptor blockade, respectively. The pressor response to ET-1 was significantly reduced by LU (% change in systolic blood pressure: sham: 9 +/- 1; CHF: 5 +/- 1; CHF LU: 0 +/- 3 and -4 +/- 2% for the low and high dose, respectively). LU did not affect the response to sarafotoxin (CHF: -37 +/- 3; CHF LU: -29 +/- 3 and -28 +/- 2% for the low and high dose, respectively). Both doses of LU decreased systolic blood pressure, but only the high dose of LU reduced heart rate. Furthermore, LU restored cardiac output dose-dependently throughout the study. Both doses of LU limited LV dilatation and deterioration of LV fractional shortening to the same extent. After ten weeks, LU normalized LV end-diastolic- and central venous pressures, but did not affect LV dP/dtmax or dP/dtmin. LU did not prevent the development of cardiac hypertrophy, but reduced LV collagen density. CONCLUSIONS: In this rat model, the selective ETA receptor blocker LU, at the dose of 30 mg kg-1 day-1, reduced blood pressure and heart rate, limited progressive left ventricular remodeling and improved cardiac hemodynamics and function. These effects of LU might have important clinical relevance in the treatment of heart failure.

Animals↗

PubMed1998

Regional serum cholesterol differences in Belgium: do genetically determined cardiovascular risk factors contribute?

BACKGROUND: Differences in serum lipid distribution and mortality from ischaemic heart disease have repeatedly been reported between Belgian northerners and southerners. We investigated whether serum lipoprotein(a) (Lp(a)) and apolipoprotein (apo) E polymorphism were involved. METHODS: Fasting serum lipids, apo A-I and B, and Lp(a) levels were examined in randomly selected, 20-39 year old Belgian males and females from the north (Flanders) and the south (Wallonia) of Belgium (N = 900). Apo E phenotype distribution was investigated in random subsamples from either region (N = 249). RESULTS: Mean serum cholesterol, low density lipoprotein cholesterol (LDL-c), apo B and triglyceride levels were higher in Walloons compared to Flemings within each gender, the difference being significant in 30-39 year old males. Average high density lipoprotein cholesterol and apo A-I levels were significantly lower in 30-39 year old male southerners, compared to their northern counterparts. Median Lp(a) was 67 mg/l in northerners and 75 mg/l in southerners (NS). The apo E phenotype distribution was similar in both regions (chi2 = 7.213; d.f. = 5; P = 0.2053), whereas the average effects of the apo E alleles differed between the regions. In southerners the epsilon4 effect upon adjusted apo B and LDL-c levels was approximately+12% and the epsilon2 effect was approximately-15%; in northerners the epsilon4 and epsilon2 effects were approximately+5% and approximately-25%, respectively. The apo E polymorphism did not affect serum Lp(a) levels. CONCLUSIONS: Regional cholesterol differences between Flemings and Walloons cannot be explained by differences in serum Lp(a) or apo E phenotype distribution. The less favourable epsilon2 and epsilon4 effects in southerners compared to northerners reflect modulation of the apo E gene by particular environments.

Adult↗

PubMed1998

Different effects of calcium antagonists in a rat model of heart failure.

Calcium antagonists have, to date, shown disappointing effect in chronic heart failure (CHF), possibly due to their cardiodepressant effects and/or reflex increases in sympathetic tone. Mibefradil is a new, selective T-channel calcium antagonist which has no relevant effects on cardiac contractility, sympathetic activity or neurohormonal levels. This study compares the effect of mibefradil with an angiotensin-converting enzyme (ACE) inhibitor on systemic and cardiac hemodynamics, cardiac structure and survival in a rat model of CHF. Rats underwent coronary artery ligation followed by 9 months treatment with mibefradil, cilazapril or no treatment. Both mibefradil and cilazapril increased survival rate to a similar extent over the study treatment period. Both periods reduced systolic blood pressure compared with untreated rats, although the reduction was slightly more marked with cilazapril than mibefradil. Both treatments decreased left ventricular (LV) end-diastolic and central venous pressures without any change in the first derivative LV pressure over time or heart rate. Mibefradil decreased LV weight without effecting right ventricular (RV) weight. Both drugs normalized LV collagen density. The data from this study show that long-term treatment with mibefradil results in a survival benefit comparable to that observed with an ACE inhibitor in a rat model of CHF. Mibefradil was also associated with improvements in cardiac hemodynamics, a reduction in LV weight and fibrosis. Mibefradil may be beneficial in the treatment of CHF.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling.

BACKGROUND: Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF. METHODS AND RESULTS: Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)). Bosentan 100 mg x kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg x kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival. CONCLUSIONS: Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.

Animals↗

PubMed1997

Early versus delayed angiotensin-converting enzyme inhibition in experimental chronic heart failure. Effects on survival, hemodynamics, and cardiovascular remodeling.

BACKGROUND: The efficacy of ACE inhibitors in congestive heart failure (CHF) might be affected by the pathophysiological status present at the onset of treatment. We compared in a rat model the effects of ACE inhibition (lisinopril, 10 mg.kg-1.d-1) initiated early (1 week) or late (3 months) after myocardial infarction (i.e., at time points corresponding to moderate or severe CHF without or with established cardiac remodeling). METHODS AND RESULTS: Survival was improved by early treatment at 3 months (from 76% to 95%) and by both early and delayed treatment at 9 months (placebo, 28%; early, 90%; delayed, 61%). Delayed treatment was initiated in a more severe pathophysiological context of CHF than early treatment, illustrated in untreated rats by higher left ventricular (LV) end-diastolic and central venous pressures and by increased LV weight and LV cavity circumference. After 9 months, early and delayed treatments reduced systolic, LV end-diastolic, and central venous pressures. Both treatments also similarly decreased LV weight, LV cavity circumference, and LV collagen density. CONCLUSIONS: In this rat model of CHF, early and delayed ACE inhibitor treatments both increase survival and exert similar beneficial effects on cardiac hemodynamics and remodeling. Although early treatment prevents the development of ventricular dysfunction and remodeling, delayed treatment is capable of reversing cardiac hypertrophy and remodeling, as well as ventricular dysfunction. Thus, ACE inhibitors exert marked beneficial effects even when treatment is initiated late into the evolution of heart failure (ie, at a time of established ventricular dysfunction and remodeling).

Analysis of Variance↗

PubMed1997

Increased survival after long-term treatment with mibefradil, a selective T-channel calcium antagonist, in heart failure.

OBJECTIVES: We sought to investigate the effects of mibefradil on survival, hemodynamic variables and cardiac remodeling in a rat model of chronic heart failure (HF) and to compare these effects with those of the angiotensin-converting enzyme (ACE) inhibitor cilazapril. BACKGROUND: The use of calcium channel blocking agents in chronic HF has been disappointing. Most studies have shown that these drugs have either no or even detrimental effects due in part to the negative inotropic effects they induce. Mibefradil is a calcium channel blocker that selectively blocks T channels and displays moderately negative inotropic properties only at high doses. Because T channels are upregulated in the hypertrophied heart and could mediate hypertrophic signals and increase arrhythmogenicity, blockade of these channels might be beneficial in chronic HF. METHODS: Rats were subjected to coronary artery ligation and 9 months of treatment with mibefradil (15 mg/kg body weight per day) or cilazapril (10 mg/kg per day) or no treatment. Survival and systolic blood pressure were assessed over the 9-month treatment period, after which cardiac hemodynamic variables and structure were determined. RESULTS: Mibefradil increased survival rate to the same extent as cilazapril (71% for mibefradil vs. 75% for cilazapril and 44% for no treatment). Mibefradil decreased systolic blood pressure, although to a lesser extent than cilazapril. Both treatments decreased left ventricular (LV) end-diastolic and central venous pressures, without any change in the first derivative of LV pressure over time or heart rate. Mibefradil decreased LV weight (although less than cilazapril) without affecting right ventricular weight. Finally, both drugs normalized LV collagen density. CONCLUSIONS: Mibefradil in a rat model improved survival to the same extent as an ACE inhibitor, without impairing LV function, and was associated with a reduction in LV weight and fibrosis. Thus, mibefradil might be beneficial in the treatment of chronic HF.

Animals↗

PubMed1997

Serum LP(a) levels in African aboriginal Pygmies and Bantus, compared with Caucasian and Asian population samples.

Serum lipoprotein(a) (Lp(a)) and its correlates were studied in African Aboriginal Pygmies (n = 146) and Bantus (n = 208) from Cameroon. Geometric mean Lp(a) levels were 274 and 289 mg/l in Bantu males and females, respectively, and 220 and 299 mg/l in Pygmy males and females, the gender difference being significant in Pygmies (p = 0.024). In Pygmies 41% and 52% of the males and females, respectively, had Lp(a) levels above 300 mg/l, compared with 47% and 55% in Bantus. Overall, Lp(a) levels did not significantly differ between Pygmies and Bantus, and did not correlate with age, body mass index (BMI), systolic and diastolic blood pressure. Compared with healthy Asian and Caucasian population samples, age- and BMI-adjusted geometric Lp(a) means were 2.3- to 5.0-fold higher in Pygmy and Bantu males, and 2.9- to 3.6-fold higher in Pygmy and Bantu females (p < or = 0.05). Across the population samples studied ethnicity predicted 12% and 17% of serum Lp(a) variance in males and females, respectively.

Adult↗

PubMed1997

Response of large and small vessels to alpha and beta adrenoceptor stimulation in heart failure: effect of angiotensin converting enzyme inhibition.

The increased sympathetic drive in chronic heart failure (CHF) might provoke vascular adrenoceptor desensitization, which, together with endothelial dysfunction, could contribute to the altered vasomotor tone seen in CHF. We investigated 1) whether CHF alters the responses mediated by alpha and beta adrenoceptors in small and large peripheral arteries, and 2) the effect of angiotensin-converting enzyme (ACE) inhibition. Rats with CHF (coronary artery ligation) were treated with placebo or the ACE inhibitor lisinopril (10 mg/kg/d) starting 7 days after ligation. Responses to phenylephrine (alpha 1 agonist), salbutamol (beta 2 agonist) as well as acetylcholine (endothelium-dependent), were assessed after 3 months in isolated and pressurized segments of the abdominal aorta, the femoral and the mesenteric arteries. In animals with hemodynamic signs of CHF, neither the vasoconstrictor responses to phenylephrine nor the vasodilator response to salbutamol were affected. In contrast, the dilator response to acetylcholine of both small arteries, but not that of the aorta, was impaired. Furthermore, CHF did not modify vessel structure. While lisinopril did not modify the responses to adrenergic agonists, it normalized the response to acetylcholine. Furthermore, ACE inhibition reduced vascular media cross sectional area and collagen density. Thus, the unchanged arterial responsiveness to adrenoceptor agonists does not indicate any vascular adrenoceptor desensitization, while endothelial dependent vasodilation of small arteries is impaired in CHF. ACE inhibition does not modify the response to adrenergic stimuli, prevents endothelial dysfunction and induces both cardiac and vascular remodeling, which probably contribute to the effect ACE inhibitors have on exercise tolerance and survival.

Acetylcholine↗

PubMed1997

Fluctuations in GAD65 antibodies after clinical diagnosis of IDDM in young children.

OBJECTIVE: To investigate whether the presence of GAD antibodies at onset of IDDM correlates to a more aggressive rate of beta-cell destruction after clinical onset. RESEARCH DESIGN AND METHODS: We studied GAD antibodies at onset of disease, after 1 year, and after 6 years in 33 consecutively referred children (mean age 8.08, range 1.7-16.3). In a subset of 11 patients, GAD antibodies were studied very frequently. The correlation between GAD antibodies and clinical parameters, including glycosylated hemoglobin, residual insulin secretion, and insulin dosage, was evaluated. RESULTS: GAD antibody titers were highly variable. Four patients became GAD antibody positive weeks to years after clinical onset. Other patients switched between testing positive and negative for GAD antibodies shortly after clinical onset. No correlation was found between the presence of GAD antibodies and the rate of beta-cell destruction, but patients with high GAD antibody indexes at onset had significantly higher glycosylated hemoglobin levels. CONCLUSIONS: GAD antibodies at clinical onset do not predict the rate of beta-cell destruction in young children with newly diagnosed IDDM. The highly variable GAD antibody levels suggest variation of the autoimmune process.

Autoantibodies↗

PubMed1997

Significance of various parameters derived from biological variability of lipoprotein(a), homocysteine, cysteine, and total antioxidant status.

Analytical and biological components of variability and various derived indices have been determined for lipoprotein(a) [Lp(a)], homocysteine (Hcy), cysteine (Cys), and total antioxidant status (TAOS) in ostensibly healthy adult Caucasians and in stable outpatients with an increased serum Lp(a). In healthy Caucasians, average intraindividual biological CVs (CVb) were 20.0% for Lp(a), 9.4% for Hcy, 5.9% for Cys, and 2.8% for TAOS, CVbs being similar in men and women. In the outpatient group, CVbs were comparable for Hcy, Cys, and TAOS, but significantly lower for Lp(a) (7.5% vs 20.0%; P <0.0001). Moreover, a significant inverse relation between both biological and analytical CVs (CVa) and serum Lp(a) concentrations was demonstrated. We conclude that average CVa and CVb values, and hence average derived indices, are adequate for Hcy, Cys, and TAOS, whereas individual values should be used for Lp(a).

Adult↗

PubMed1997

[Endothelial dysfunction in cardial failure: potential mechanisms].

From the vascular point of view, cardiac failure is characterised by increased systemic resistances secondary to an increased concentration of a number of vasoconstrictor substances and also to decreased endothelium dependent vasodilatation. Endothelial dysfunction has been described both in man and in animal models, but its causes are not well understood. Such dysfunction could be due to a decrease in the production of nitric oxide, a decrease in its vasodilator effect due to an increased degradation or an increased vasoconstrictor tone. Recent data suggests an improvement or prevention of this endothelial dysfunction observed in cardiac failure by physical training and by chronic treatment with an angiotensin converting enzyme inhibitor. The improvement or preservation of endothelial function induced by exercise or ACE inhibitor could explain some of the benefits of these treatments in terms of tissue perfusion and haemodynamic conditions.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Polychlorinated Biphenyls, Dibenzo-p-dioxins, and Dibenzofurans in Harbor Porpoises (Phocoena phocoena) Stranded on the Dutch Coast Between 1990 and 1993

Congener-specific polychlorinated biphenyl (PCB) concentrations were determined in the blubber, kidney, and liver tissues of 22 harbor porpoises (Phocoena phocoena) stranded on the Dutch coast. For comparison, the PCB concentrations in blubber and liver samples of four porpoises from the vicinity of Greenland were investigated. In ten blubber samples, the non-ortho PCB concentrations were determined, while in four of these the levels of chlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) were analyzed. It is shown that the PCB level increases with age in males, whereas in mature females the levels remain relatively constant. A comparison with earlier data indicates a slight decrease over the last 20 years in the PCB burden of porpoises living near the Dutch coast. The amount of the most prominent and persistent congener, PCB 153, can be related to the feeding pattern of male porpoises; it appears to be completely retained in this species. Bioaccumulation of non-ortho PCBs and PCDD/Fs does not take place. The overall toxicity, expressed as 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents (TEQ), is mostly covered by di-ortho and mono-ortho PCBs, depending on age and sex, whereas the contribution of the notorious toxic PCDDs and PCDFs to the overall TEQ is at most 0.5%.

Journal Article↗

PubMed1996

Fixed-dose combination of perindopril with indapamide in spontaneously hypertensive rats: haemodynamic, biological and structural effects.

OBJECTIVE: The present study was designed to test the effects of chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor (perindopril) and of the diuretic indapamide in spontaneously hypertensive rats (SHR). METHODS: Adult SHR were treated with placebo or increasing doses of the combination of the drugs (0.3, 1 and 3 mg/kg per day; ratio of doses 0.32). In a separate set of experiments, the effects of the drugs combined (1 mg/kg per day) was compared with those induced by each drug alone. RESULTS: The drug combination dose-dependently decreased systolic blood pressure and its hypotensive effect was more marked than those induced by each treatment administered alone (untreated 208 +/- 5 mmHg, indapamide 185 +/- 5 mmHg, perindopril 150 +/- 3 and the combination 123 +/- 7 mmHg). A 12-week treatment with the drug combination (1 mg/kg per day) was not accompanied by any change in diuresis or urinary excretion of Na or K. The same treatment decreased cardiac hypertrophy and collagen. At the vascular level, the drug combination decreased aortic, carotid and femoral media cross-sectional areas, as well as aortic and carotid collagen density. This latter effect was accompanied by a significant increase in carotid artery compliance assessed in vivo at constant pressure. Finally, in isolated aortae, chronic combined drug treatment was associated with an increased basal release of nitric oxide and a decrease in the hypertension-induced endothelium-dependent contractions in response to acetylcholine. CONCLUSION: These experiments suggest that chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor and a diuretic such as indapamide may be of value in the treatment of hypertension.

Acetylcholine↗

PubMed1996

Peripheral artery structure and endothelial function in heart failure: effect of ACE inhibition.

Chronic heart failure (CHF) induces peripheral vasoconstriction and impairs endothelium-dependent relaxation of large arteries. We investigated in a rat model of CHF (coronary artery ligation) 1) whether endothelial dysfunction also exists in resistance arteries, 2) whether this is associated with vascular morphological changes, and 3) the effect of angiotensin-converting enzyme (ACE) inhibition on these parameters. After 1 mo or 1 yr, CHF reduced the vasodilatory response to acetylcholine of isolated, perfused femoral and mesenteric artery segments. This impairment was more marked in femoral than in mesenteric arteries. However, CHF did not induce any arterial remodeling. Chronic treatment with the ACE inhibitor perindopril improved the response to acetylcholine and reduced media cross-sectional area and collagen density. Thus at the level of small peripheral arteries, CHF induces an endothelial dysfunction but does not affect vascular structure. ACE inhibition prevents the CHF-induced endothelial dysfunction and induces vascular remodeling. These changes could contribute to the observed beneficial effects of ACE inhibitors on hemodynamics and survival in CHF.

Acetylcholine↗

PubMed1996

Improvement of tidal breathing pattern analysis in children with asthma by on-line automatic data processing.

The time taken to achieve peak tidal expiratory flow as a proportion of total expiratory time (t PTEF/t E) during tidal breathing (TB) is used as a parameter of airway obstruction in children with asthma. Curve selection bias is one of the most important limitations to the method. This study evaluates three curve selection methods, including a computer program, which on-line selects and analyses TB curves (Masterscreen Paediatric; Jaeger, Germany). TB analysis was performed in 26 children (aged 4-7 yrs) with asthma, before and after methacholine provocation and after subsequent bronchodilatation. Levels and stability of TB parameters derived from computer-selected, unselected and unbiased eye-selected curves were compared. t PTEF/t E ratios of the computer-selected curves agreed well with the unbiased eye-selected curves (limits of agreement -4.8 and +5.8%), but were significantly different from the ratios of unselected curves. Computer-derived t PTEF/t E ratios had the highest level of stability: the reliability coefficient of baseline measurements was 0.96 for computer selection, 0.84 for eye selection and 0.87 for no selection (reliability index = 1 at maximal stability). Tidal volume, respiratory rate, inspiratory and expiratory time were also assessed accurately by the computer program. The mean t PTEF/t E ratio (computer selection) dropped after methacholine provocation (from 30 +/- 9 to 22 +/- 9% at provocative dose at which forced expiratory volume in one second had dropped > or = 20% from baseline (FEV1-PD20 level), p < 0.001) and was restored after bronchodilation (30 +/- 6%; p < 0.001). We conclude that on-line computer analysis is preferable to no selection and to by-eye selection. The use of the program avoids curve selection bias and enhances the applicability of tidal breathing analysis as a measure of airflow obstruction in young children.

Asthma↗

PubMed1996

Computer-aided skeletal age scores in healthy children, girls with Turner syndrome, and in children with constitutionally tall stature.

The manual Tanner-Whitehouse 2 method has recently been transformed into a computer-aided skeletal age scoring system (CASAS), which rates either the complete TW-RUS score (13b model) or a subset consisting of radius, ulna, and the four bones of the third finger (6b model). In this study the reliability of CASAS was evaluated in healthy children, and the 13b model was compared with the manual ratings and with the 6b model in (subgroups of) 151 healthy children, 87 girls with Turner syndrome, and 362 children with constitutionally tall stature. In addition, reference curves for bone maturation in Turner syndrome and constitutionally tall stature are presented. Some of mean differences in methods were statistically significant; however, because these mean differences were less than 0.4 bone age "year," they are clinically not significant. In all comparisons the range of the difference between the methods (either with the 6b or the 13b model) was considerable, but the combined within- and between-components of variance (0.7%) were in the same order of magnitude as reported for the manual readings. In general, the percentage of equal stage ratings on duplicate assessments was high (+/- 90%). Our data indicate that this computerized method is applicable in these groups of children. The use of the 6b model seems preferable because it is less time-consuming than the rating of 13 bones. In view of the percentages of manual insertions of a stage (up to 8% in all groups) the clinical use of this CASAS version (3.5) seems to be more efficient, particularly with longitudinal studies. Manual substitution of a stage should be avoided, and when performed its percentage and the limits for the acceptance of disagreement should be reported.

Adolescent↗

PubMed1995

Vascular and myocardial protective effects of converting enzyme inhibition in experimental heart failure.

Systemic vasoconstriction due to stimulation of the sympathetic and renin-angiotensin-aldosterone systems is a hallmark of heart failure and this is accompanied by impaired endothelium-dependent relaxations at the level of large arteries. This study investigated, in a rat model of heart failure, whether such an endothelial dysfunction also exists at the level of the resistance artery, and whether this is associated with morphologic changes, as well as the effects of chronic treatment with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg/day). After 12 months, arterial pressure, left ventricular (LV) end diastolic pressure (LVEDP), and LV dP/dt were measured in anesthetized rats. Responses to acetylcholine and nitroprusside were determined in isolated and perfused mesenteric artery segments (diameter: 280 +/- 15 microns). After fixation, vessel diameter, media cross-sectional area, and media collagen and elastin densities were measured by image analysis. After 12 months, untreated rats showed signs of heart failure, i.e., reduced LV dP/dt, and increased LVEDP, heart weight/body weight, LV cavity circumference, and myocardial collagen density. In mesenteric vessels the endothelium-dependent vasodilator response to acetylcholine was impaired, whereas the response to the nitric oxide donor nitroprusside was unaffected. Heart failure did not affect vascular morphological parameters. Perindopril decreased blood pressure and LVEDP without any modification of LV dP/dt, and prevented cardiac remodeling. At the vascular level, perindopril improved the response to acetylcholine and reduced media cross-sectional area and collagen density without affecting internal vessel diameter or elastin density. Thus, heart failure decreases endothelium-dependent vasodilator response to acetylcholine without modification of vessel structure.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1995

Prevention of endothelial dysfunction in small and large arteries in a model of chronic heart failure. Effect of angiotensin converting enzyme inhibition.

Chronic heart failure (CHF) impairs endothelium-dependent vasodilatation of large conductance arteries. We investigated whether a similar reduction also occurs in small arteries, and whether such a reduction can be prevented by the angiotensin converting enzyme inhibitor perindopril (P) in a rat model of CHF (left coronary artery ligation). After 1 month treatment with placebo or P (2 mg/kg/day), rats were anesthetized and arterial pressure, left ventricular end-diastolic pressure, and central venous pressure were measured with a micromanometer. Segments of aorta and mesenteric artery (mean diameter, 281 +/- 8 microns) were then isolated, cannulated, and perfused at constant pressure using an arteriograph. Responses to increasing concentrations of acetylcholine (Ach), nitroprusside, and to 10(-4) mol/L NG-nitro-L-arginine methyl ester (L-NAME) were studied after preconstriction by phenylephrine. Heart failure resulted in a decrease in systolic and diastolic pressures, an increase in left ventricular end-diastolic and central venous pressures, and a significant depression of Ach-induced dilatation of the mesenteric artery (maximal dilatation, from 90 +/- 4% to 63 +/- 4%, P < .05) but not of the aorta (from 56 +/- 8% to 45 +/- 5%, NS) without any modification in the endothelium-independent vasodilatation induced by nitroprusside. In the group treated by the angiotensin converting enzyme (ACE) inhibitor perindopril, systolic and diastolic pressures were slightly decreased, whereas left ventricular end diastolic, central venous pressures, and the endothelium-dependent vasodilating response to Ach were normalized. Responses to L-NAME were not affected by CHF or perindopril. Perindopril also decreased hypertrophy, as evidenced by a significantly lower heart weight in treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗