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Biomedical subjects

H Drexler

Publications and source records attributed to H Drexler.

At least 163 records · Page 9Linked to original sources
PubMed1993

Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat.

Recent studies in both experimental animals and man have demonstrated the unique efficacy of converting enzyme inhibitors to prevent or attenuate ventricular remodeling after myocardial infarction. Concomitantly, evidence for a trophic role of the renin-angiotensin system (RAS), as well as for the existence of an intracardiac tissue-resident RAS, has been presented, raising the question whether altered regulation of this cardiac RAS may be associated with the process of ventricular remodeling. We conducted the present study to examine whether cardiac angiotensinogen gene expression is altered after myocardial infarction. Experiments were performed in rats 5 and 25 days after ligation of the left coronary artery or sham operation. Coronary artery ligation resulted in relative infarct sizes averaging 29% and 36% of total left ventricular mass at 5 and 25 days and in marked elevations of left ventricular end-diastolic pressure (LVEDP). Angiotensinogen mRNA levels, measured by solution hybridization assay and confirmed in a second, independent experimental group by RNAse protection assay, were significantly elevated in the non-infarcted portion of the left ventricle at 5 days after infarction when compared to the sham group (22.1 + 3.3 vs. 13.4 +/- 2.0 fg/microgram total RNA; ratio of densitometric absorbance for angiotensinogen/beta-actin: 0.356 +/- 0.041 vs. 0.156 +/- 0.02), and showed a significant correlation with infarct size (r = 0.93). At 25 days, angiotensinogen gene expression had returned to control values. Similarly, no significant differences in angiotensinogen mRNA levels between animals with and without infarction were found in other cardiac tissues (atria, right ventricle). Plasma renin activity was significantly increased over baseline in the infarct group at 5, but not at 25 days. Our results demonstrate that acute hemodynamic embarrassment early after LV infarction is associated with augmented angiotensinogen gene expression. The potential significance of this finding is discussed.

Angiotensinogen↗
PubMed1993

Endothelial function in congestive heart failure.

There is evidence that the endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide and, therefore, a defective endothelial function could be involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure. To investigate endothelial function in humans in vivo, agents such as acetylcholine, a short-acting stimulator of the release of endothelium-derived nitric oxide, has been used. Conversely, N-mono-methyl-L-arginine, a specific inhibitor of nitric oxide synthesis from L-arginine, has recently been shown to decrease blood flow during infusion into the brachial artery of healthy volunteers (control subjects) by inhibiting the basal release of nitric oxide. Consistent with experimental studies, the blood flow response to acetylcholine is blunted in patients with chronic heart failure compared with healthy age-matched volunteers. In contrast, the decrease in blood flow induced by N-mono-methyl-L-arginine appears to be exaggerated in congestive heart failure. The blood flow response to nitroglycerin or sodium nitroprusside, endothelium-independent vasodilators, is usually preserved in patients with chronic, nonedematous heart failure, indicating a normal response of the vascular smooth muscle of resistance vessels to exogenous nitric oxide. In contrast, the dilator response of the radial artery diameter to nitroglycerin and flow-dependent dilation is impaired in patients with chronic heart failure, indicating that the abnormal flow-mediated relaxation of large arteries may be caused by both endothelial and structural abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Skin prick tests with solutions of acid anhydrides in acetone.

Various low molecular acid anhydrides can act as haptens and induce type I allergies. Immunoglobulin E can be detected by radioallergosorbent test (RAST) with the protein conjugates of the respective anhydrides, which are commercially available for some substances. Being almost nonsoluble in water, these species cannot be applied in a skin prick test as a water solution. We will introduce a practicable skin prick test using acetonic solutions of the haptens. 136 persons were tested with acetone for negative control and histamine for positive control. Tests were carried out with 1 and 5% acetonic solutions of phthalic anhydride (PA). The RASTs with conjugates of the PA were performed with 111 subjects who had been exposed to acid anhydrides and with 5 people who possibly had been exposed. In 14 cases, when immediate-type allergy was suspected clinically, a test was performed in addition to the respective anhydride used at the workplace. In order to avoid unspecific histamine liberation, we tested 20 volunteer control persons who had not been occupationally exposed to acid anhydrides. In the prick test performed with acetonic PA solutions, 10 of the occupationally exposed subjects, who had also had a positive result in the RAST with protein conjugates of the PA, showed positive skin reactions, and in 2 further cases, in which the skin reaction was positive, the results of the RAST were just below the limit of a positive evaluation. The skin reaction was positive in 4 cases, in spite of a negative RAST result, while the prick test was reported to be negative in 3 cases although the RAST results were considered to be positive.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetone↗
PubMed1993

Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension.

The effects of age, atherosclerosis, hypertension, and hypercholesterolemia on vascular function of the coronary circulation were studied by subselective intracoronary infusions of acetylcholine, which releases endothelium-derived relaxing factor, and papaverine, which directly relaxes vascular smooth muscle, in normal patients (n = 18; no risk factors for coronary artery disease), in patients with evidence of early atherosclerosis but normal cholesterol levels and normal blood pressure (n = 12), in patients with hypertension without left ventricular hypertrophy (n = 12), and in patients with hypercholesterolemia (n = 20). Papaverine-induced maximal increases in coronary blood flow were significantly greater in normals, but no differences were noted between the groups of patients with early atherosclerosis, with hypertension, and with hypercholesterolemia. The capacity of the coronary system to increase blood flow in response to acetylcholine was similar in normal and normocholesterolemic patients with epicardial atherosclerosis and/or hypertension but was significantly impaired in patients with hypercholesterolemia, irrespective of evidence of epicardial atherosclerotic lesions. Age (r = -0.62, P < 0.0001) and total serum cholesterol levels (r = -0.70; P < 0.0001) were the only significant independent predictors of a blunted coronary blood flow response to acetylcholine. Thus, hypercholesterolemia and advanced age selectively impair endothelium-mediated relaxation of the coronary microvasculature in response to acetylcholine, whereas endothelial dysfunction is restricted to epicardial arteries in age-matched normocholesterolemic patients with evidence of coronary atherosclerosis and/or hypertension.

Acetylcholine↗
PubMed1993

Are alterations of skeletal muscle ultrastructure in patients with heart failure reversible under treatment with ACE-inhibitors?

In patients with chronic heart failure, exercise capacity and clinical symptoms correlate poorly, if at all with the degree of left ventricular dysfunction. These observations might indicate that peripheral alterations (e.g. reduced perfusion of the exercising muscle) contribute to the functional state and exercise capacity of patients with chronic heart failure. Acute improvements in hemodynamics by means of therapy with vasodilators or positive inotropes, however, could not be translated into an enhanced oxygen consumption. These studies have prompted the hypothesis that in the setting of heart failure, intrinsic abnormalities of the exercising muscle develop that prevent acute improvement in peak VO2. Indeed, ultrastructural analysis of a large cohort of patients with chronic heart failure revealed that volume density of mitochondria and surface density of mitochondrial cristae (both are parameters for the oxidative capacity of skeletal muscle) were reduced by more than 20% as compared to healthy control subjects. In contrast to left ventricular contractility parameters, ultrastructural changes of the skeletal muscle correlated closely with peak oxygen consumption, indicating that abnormalities of the exercising muscle contribute to a decreased exercise capacity in this patient group. Chronic but not acute treatment with angiotensin converting enzyme (ACE) inhibitors increases blood flow to the exercising muscle and improves peak oxygen consumption. These protracted effects of ACE-inhibitors might be due to an inhibitory effect on the vascular renin angiotensin system leading to a beneficial remodelling of the vessel wall. Forearm vessels of patients with heart failure do not respond adequately to acetylcholine and reactive hyperemia, indicating an impaired endothelial function.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Captopril versus digoxin in patients with coronary artery disease and mild heart failure. A prospective, double-blind, placebo-controlled multicenter study. The CADS Study Group.

We conducted a prospective, double-blind, placebo-controlled multicenter trial in order to evaluate the long-term effects of captopril (50 mg/day), digoxin (0.25 mg/day) and placebo on quality of life, cardiovascular events, clinical symptoms and exercise tolerance in patients with documented myocardial infarction, resulting in regional wall motion abnormalities, and with mild heart failure (NYHA class II to III without treatment) and exercise not limited by angina. 222 patients were studied, 63 were randomized to captopril, 66 to digoxin, 67 to placebo. Follow-up was conducted for two years. Base line characteristics in the three treatment groups were similar. After one year of therapy, digoxin had significantly improved general well-being (p < 0.01 vs captopril), symptom score (p < 0.05 vs captopril and placebo), and vitality (p < 0.05 vs captopril). Digoxin improved NYHA class in 45% as compared to placebo (28%, p < 0.05). Worsening of angina was more frequent with captopril as compared to digoxin (p < 0.05). However, cardiovascular events during follow-up were lower in the captopril group as compared to placebo and digoxin (p < 0.01 captopril vs placebo). No differences between groups were observed in baseline and follow-up exercise tolerance between the three groups. Dizziness during upright tilt and cough were more frequent with captopril as compared to digoxin or placebo. After two years of follow-up (captopril n = 32, digoxin n = 29, placebo n = 27) general well-being was improved with both digoxin and captopril (p < 0.004 and p < 0.03 vs placebo).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Effect of angiotensin-converting enzyme inhibitors on the peripheral circulation in heart failure.

In patients with chronic heart failure, the increase in blood flow to working muscle is attenuated and oxygen consumption is lower for any given workload of exercise, compared with normal subjects. This impaired metabolic vasodilation during exercise cannot be restored with short-term administration of angiotensin-converting enzyme (ACE) inhibitors. However, long-term ACE inhibition increases blood flow to skeletal muscle, and this increase is closely correlated with improvement in systemic oxygen consumption. The delayed effect of ACE inhibitors may be related to an interference with the vascular tissue renin-angiotensin system and remodeling of the vascular wall. In addition, endothelial-dependent dilation in response to acetylcholine is blunted in the forearm of patients with chronic heart failure, indicating an impaired endothelial function in this setting. There is experimental evidence that long-term ACE inhibition improves endothelial dysfunction; thus, one might speculate that the beneficial long-term effect of ACE inhibitors on peripheral flow may be, in part, related to its ability to restore normal endothelial function. Vasodilators such as hydralazine that improve blood flow to working muscle after acute administration do not increase skeletal muscle oxygen consumption, indicating that oxygen utilization is not improved. Ultrastructural analysis of skeletal muscle revealed that intrinsic alterations of skeletal muscle exist in patients with chronic heart failure; that is, the oxidative capacity of skeletal muscle is impaired in severe heart failure and contributes to the reduced exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Endothelial function in chronic congestive heart failure.

There is evidence that the endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide. The hypothesis that an impairment of this mechanism is involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure (CHF) was tested. Acetylcholine and N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthesis from L-arginine, were infused in the brachial artery of healthy volunteer subjects (controls) and patients with severe CHF. The radial artery diameter was determined by a high-precision A-mode ultrasound device, using a 10 MHz probe. Forearm blood flow was calculated from vessel diameter and blood flow velocity measured simultaneously by Doppler. The blood flow response to acetylcholine was blunted in patients with CHF compared with that in control subjects. In contrast, the decrease in blood flow induced by L-NMMA was exaggerated in CHF, and the blood flow response to nitroglycerin was preserved. The changes in radial artery diameter induced by acetylcholine and L-NMMA were not significant in control subjects and CHF patients, but dilation of the radial artery by nitroglycerin was significantly reduced in CHF. The results demonstrate an impaired endothelium-dependent dilation of forearm resistance vessels in CHF, suggesting a reduced release of nitric oxide on stimulation. In contrast, the basal release of nitric oxide from endothelium of forearm resistance vessels is preserved or may even be enhanced, and may play an important compensatory role in chronic CHF by antagonizing neurohumoral vasoconstrictor forces in CHF.

Acetylcholine↗
PubMed1992

Modulation of myocardial sarcoplasmic reticulum Ca(++)-ATPase in cardiac hypertrophy by angiotensin converting enzyme?

Myocardial hypertrophy in response to hemodynamic overload is an established risk factor for cardiovascular morbidity and mortality. Partially, this may be due to alterations in cardiac gene expression, resulting in a more fetal-like myocyte phenotype with a fragile Ca(++)-homeostasis. Depressed expression of the sarcoplasmic reticulum Ca(++)-ATPase is the hallmark of this overload phenotype, contributing to prolonged cytosolic Ca(++)-transients, disturbed diastolic relaxation, altered force-frequency relation, and probably, electrophysiologic instability with susceptibility to malignant arrhythmias. Since angiotensin II is a growth-promoting factor in several cellular systems, the local formation of angiotensin II within the myocardium might contribute to the trophic response and the phenotype shift of overloaded myocardium. Several observations are consistent with this hypothesis: the cardiac expression of ACE and angiotensinogen is enhanced in experimental myocardial overload and in human endstage congestive heart failure; prolonged observations of experimental cardiac overload with hypertrophy-induced putative normalisation of myocardial systolic wall stress demonstrated a renormalization of ventricular tissue ACE activity and of ventricular sarcoplasmic Ca(++)-ATPase expression and activity; normalizing ventricular tissue ACE activity in experimental cardiac overload by chronic nonhypotensive ACE inhibitor therapy caused a parallel partial normalization of hypertrophy and underexpression of sarcoplasmic CA(++)-ATPase. This partial normalization of myocyte Ca(++)-homeostasis in overload hypertrophy by non-hypotensive chronic ACE-inhibition is attenuated by concomitant chronic application of bradykinin-2 receptor blockade, indicating an involvement of altered bradykinin metabolism in the phenotype modulation due to chronic ACE inhibition. While these observations are consistent with a direct influence of local ACE activity on the sarcoplasmic reticulum, the cell type contributing to the enhanced ACE expression in overload and the specific mechanism of this influence are unknown.

Animals↗
PubMed1992

Endothelial dysfunction of hindquarter resistance vessels in experimental heart failure.

Local vascular alterations may contribute to increased peripheral vasoconstriction in chronic heart failure. To test whether endothelial dysfunction might be involved, the effect of acetylcholine, nitroglycerin, and NG-monomethyl-L-arginine (L-NMMA) was investigated in a constant-flow perfused hindquarter of rats with and without chronic heart failure (CHF) due to myocardial infarction. Changes in perfusion pressure were measured as an index of changes in hindlimb vascular resistance. The endothelium-dependent vasodilator effect of acetylcholine was significantly reduced in rats with large infarcts (greater than 40% of the left ventricle). However, the endothelium-independent vasodilator effect of nitroglycerin and the vasoconstrictor effect of L-NMMA were similar for infarct and normal animals. The vasodilator response to acetylcholine was partially inhibited by pretreatment with L-NMMA. Thus the basal release of nitric oxide from hindquarter resistance vessels is preserved in CHF. However, the endothelium-mediated dilation in response to acetylcholine is attenuated, in part, due to a depressed stimulated release of nitric oxide. The latter mechanism might be involved in the impaired vasodilatory capacity in the peripheral circulation in CHF, e.g., during exercise.

Acetylcholine↗
PubMed1992

Alterations of skeletal muscle in chronic heart failure.

BACKGROUND: The present study was designed to define the prevalence and characteristics of skeletal muscle alterations in patients with chronic heart failure (CHF) and their relation to exercise capacity. METHODS AND RESULTS: The ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry in 57 patients with CHF and 18 healthy controls. The volume density of mitochondria (Vvm) and the surface density (Svmc) of mitochondrial cristae were evaluated as a structural correlate of oxidative capacity of skeletal muscle. Vvm and Svmc were reduced by approximately 20% in patients with severe CHF irrespective of age and etiology. The cytochrome oxidase activity in mitochondria as determined by cytochemistry and subsequent morphometry in a subset of patients (n = 10) was significantly decreased in heart failure (p less than 0.01). The capillary length density of skeletal muscle was reduced in CHF (n = 12, p less than 0.05), and the fiber type distribution was shifted to type II fibers (n = 15, p less than 0.05). Vvm and Svmc were significantly related to peak exercise VO2 (r = 0.56, p less than 0.001, n = 60) and to VO2 at anaerobic threshold (r = 0.535, p less than 0.0001, n = 60). In 16 patients with severe heart failure, Vvm was inversely related to the duration of heart failure (r = 0.545, p less than 0.03). In 11 patients who underwent repeat biopsies after 4 months, a correlation was observed between the change in Vvm and the change in peak exercise VO2 (r = 0.89, p less than 0.001). CONCLUSIONS: These findings indicate that patients with CHF develop significant ultrastructural abnormalities of skeletal muscle reflecting a depressed oxidative capacity of working muscle. It appears that these alterations of skeletal muscle contribute to the decreased exercise capacity of these patients but are, in principle, reversible by an effective treatment regimen.

Aging↗
PubMed1992

Effects of inhibition of nitric oxide formation on regional blood flow in experimental myocardial infarction.

BACKGROUND: Large myocardial infarction is associated with reactive hypertrophy and dilation of the left ventricle, depressed coronary flow reserve, and the development of heart failure including systemic vasoconstriction. We hypothetized that changes in endothelial function, e.g., in the synthesis or action of nitric oxide in the coronary and peripheral vasculatures, might be involved in the depressed coronary flow reserve and increased systemic vascular resistance observed in postinfarction myocardial hypertrophy and failure. METHODS AND RESULTS: The regional blood flow changes that occur as a result of inhibiting the basal release of nitric oxide with NG-monomethyl-L-arginine (L-NMMA) and how this regional pattern may be altered in large MI (infarct size, 30-51% of left ventricle) were examined. Measurements were made 24 hours and 8 weeks after myocardial infarction or sham operation in conscious rats. The left ventricular end-diastolic pressure and effects of L-NMMA on left ventricular end-diastolic pressure was similar 24 hours and 8 weeks after myocardial infarction. The effects of L-NMMA (30 mg/kg i.v.) on heart rate and blood pressure were similar in infarcted and sham animals. L-NMMA exerted a marked vasoconstriction in the renal, splanchnic, cutaneous, and cerebral circulations of similar magnitude in sham-operated rats and animals with myocardial infarction. The coronary vasoconstrictor effect of L-NMMA was attenuated significantly in the hypertrophied right and noninfarcted left ventricle of 8-week-old infarcted rats (p less than 0.01 versus sham-operated animals) but not 24 hours after induction of myocardial infarction when cardiac hypertrophy has not yet developed. The increase in left ventricular coronary resistance in 8-week-old infarcted animals was inversely related to infarct size (r = -0.787, p = 0.012, n = 9). Nitroglycerin exerted similar increases in coronary blood flow in rats with chronic myocardial infarction and sham-operated animals, arguing against a reduced vascular responsiveness to nitric oxide. Transmission electron microscopy of coronary resistance vessels in 8-week-old infarcted animals did not reveal endothelial abnormalities. CONCLUSIONS: These data suggest that the basal release of nitric oxide in the renal, intestinal, and cutaneous circulations is not affected adversely in this model of myocardial infarction and failure. However, the blunted coronary vasoconstrictor effect of L-NMMA late after large myocardial infarction supports the view that the basal release of nitric oxide is impaired in postinfarction reactive cardiac hypertrophy.

Animals↗
PubMed1992

Neurohormonal inhibition and hemodynamic unloading during prolonged inhibition of ANF degradation in patients with severe chronic heart failure.

BACKGROUND: The purpose of this study was to investigate the therapeutic potential of prolonged inhibition of atrial natriuretic factor (ANF) degradation in patients with severe chronic heart failure. METHODS AND RESULTS: The effects of repeated doses of the endopeptidase inhibitor candoxatrilat (150 mg i.v.) were examined over a 24-hour period in patients with severe chronic heart failure (New York Heart Association class III-IV). Plasma alpha-hANF(99-126) was elevated at baseline (235 +/- 59 pg/ml), increased 2.5-fold at 2 hours after the first dose, and remained significantly elevated throughout the 24-hour protocol. In contrast, pro-hANF(31-67) decreased from 3,151 +/- 616 to 2,072 +/- 362 pg/ml (p less than 0.05). Cardiac index (CI) increased only transiently after the first dose of candoxatrilat (CI, 2.11 +/- 0.2 to 2.67 +/- 0.28 l/min/m2, p less than 0.05). Sodium excretion increased sixfold (p less than 0.05) 2 hours after the first dose of candoxatrilat and remained significantly elevated throughout the protocol. Degree of natriuresis and diuresis in response to candoxatrilat was closely related to baseline cardiac output. Glomerular filtration rate and volume excretion did not change significantly. Pulmonary capillary wedge pressure fell from 23 +/- 3 to 18 +/- 3 mm Hg (p less than 0.05) and remained below baseline throughout the 24 hours. Arterial pressure, heart rate, and total peripheral resistance did not change significantly during the 24-hour period. Urinary cGMP excretion increased fivefold (p less than 0.05), whereas urinary ANF immunoreactivity and plasma cGMP levels remained unchanged. Excretion of prostacyclin metabolite 6-keto-PGF-1 alpha increased 3.3-fold (p less than 0.05). Plasma norepinephrine and epinephrine levels decreased significantly after candoxatrilat and remained suppressed over the 24-hour period. There was also a transient reduction in plasma vasopressin, aldosterone levels, and plasma renin activity. Hematocrit, total protein content, and plasma albumin concentrations did not change, indicating that no fluid shift into the extravascular space had occurred. CONCLUSIONS: 1) The inhibition of ANF degradation causes sustained drop in left and right atrial pressures that appears to be mediated by an inhibition of neurohumoral activity; 2) concomitant inhibition of bradykinin breakdown (which in turn stimulates renal prostacyclin synthesis) contributes to natriuresis; 3) the close correlation between renal response and baseline cardiac index indicates that an inadequate renal perfusion secondary to low cardiac output diminishes the efficacy of this treatment modality. This spectrum of action would be advantageous for a first-line diuretic agent early in the course of disease rather than in patients with advanced chronic heart failure.

Aged↗
PubMed1992

Platelet-derived growth factor is angiogenic in vivo.

PDGF receptors have recently been found to be expressed in microvascular endothelium in vivo under circumstances of endothelial cell activation and angiogenesis suggesting that PDGF may have a direct effect on endothelial cells. We have tested the angiogenic activity of PDGF-AA and -BB homodimers in the chick chorioallantoic membrane in vivo. PDGF-BB was found to consistently induce an angiogenic response whereas PDGF-AA was less active. Morphological analyses revealed that there was little inflammation associated with this response but an increase in vessel density suggested a direct effect of PDGF on embryonic chorioallantoic endothelial cells. In vitro, PDGF-BB was found to be more potent than PDGF-AA in stimulating the chemotaxis of rat brain capillary endothelial cells. This is consistent with a direct effect of PDGF on endothelial cells. Thus, this novel angiogenic activity of PDGF has implications for several developmental and pathological events in which PDGF, particularly the B-chain, is expressed.

Allantois↗