Biomedical subjects
Publications and source records attributed to G Baumann.
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Elevated pulmonary vascular resistances occur to a variable degree in patients with chronic congestive heart failure (CHF). These might be caused by increased levels of endogenous vasoconstrictors, defective endothelial vasodilatory mechanisms or structural vascular abnormalities. To determine the contribution of defective endothelial mediated vasodilation, we tested 10 patients with CHF due to coronary artery disease (n = 4) or dilated cardiomyopathy (n = 5), and congenital corrected transposition of the great arteries (n = 1) (median pulmonary artery pressure 36 mmHg, range of pulmonary vascular resistance 0.94-10.7 WE). Patients were in median functional class NYHA III, median left ventricular ejection fraction was 21%, median oxygen uptake at the anaerobic threshhold was 8.25 ml/kg/min. Flow was measured by a flow wire (0.018 inch) positioned in a pulmonary artery branch with a diameter of 3-8 mm determined by intravascular ultrasound before. Acetylcholine infusion was adjusted to 10(-6), 10(-5) and 10(-4) molar concentrations in the pulmonary artery branch. A dose dependent increase in flow between 64 to 140% was seen in 8 out of 10 patients. We conclude: Acetylcholine mediated vasodilation is found in patients with CHF and elevated pulmonary vascular resistances.
Histamine is known to act as a direct stimulator. In the heart, two types of histamine receptors are present: H1- and H2-receptors. H2-receptors cause an increase in heart rate and contractility as well as coronary vasodilatation, whereas H1-receptors mediate chronotropic effects and coronary vasoconstriction. During anaphylactic states, histamine is released from cardiac tissue where it is stored in large amounts. The present study was designed to ascertain the role of cardiac histamine release during cardiac anaphylaxis. In guinea pigs, sensitization was produced by intraperitoneal administration of ovalbumin (O). 14 days after sensitization, the effects of an intracoronary infusion of O (1.1 x 10(-8) moles/min) were tested in the isolated perfused heart preparation. The response of the sensitized hearts to O was characterized by a rapid increase in contractile force (dp/dtmax 120% above baseline after 30 s), followed by a decrease reaching a minimum of 30% below baseline after 10 min. Over the same time range, the heart rate first increased (+24%), then decreased, concurrent with the appearance of arrhythmias, before reaching baseline level. Coronary flow decreased (-40% after 1 min) and finally stabilized at a new steady state (-20% below baseline). It is concluded that histamine might be an important mediator of these effects, since in the presence of H2-receptor blockade with cimetidine (6.2 x 10(-7) moles/min), the positive inotropic and chronotropic effects were completely antagonized. Furthermore, a decrease in heart rate and contractility occurred (-25% and -50% after 2 min, respectively). Finally, coronary constriction was intensified and resulted in coronary spasm with flow rates approaching zero after 1 min.(ABSTRACT TRUNCATED AT 250 WORDS)
The platelet activating factor (PAF), a low molecular phospholipid, plays an important role in inflammation, anaphylaxis, and shock state development. In the isolated perfused guinea pig heart, PAF induces a decrease in coronary flow and cardiac contractility and atrioventricular conduction disturbances. Furthermore, PAF mediates a powerful bronchoconstrictory action causing a severe impairment in respiratory function. In the present study an attempt was made to separate cardiac from respiratory events during PAF-induced shock in vivo. PAF was injected intravenously (0.1-10 micrograms/kg) into anesthetized guinea pigs ventilated with room air or 100% oxygen. Administration of 10 micrograms/kg PAF was uniformly lethal: already within 2 min, cardiac output decreased by 60% and end-diastolic left ventricular pressure increased markedly indicating cardiac failure. ECG recordings showed signs of acute myocardial ischemia. Arrhythmias occurred in terms of atrioventricular conduction delay. Blood pressure initially increased, then declined continuously to below baseline within 10 min. All animals died within 25 min. Ventilation with room air was paralleled by development of severe hypoxia. However, under ventilation with 100% oxygen a dissociation between PAF-mediated cardiac and respiratory effects occurred. It is concluded that the PAF-induced shock is primarily based on direct cardiac damage. Furthermore, the ECG signs of ischemia are most likely due to coronary spasms.
The assessment of growth hormone (GH) secretory status is often difficult because of the intermittent nature of GH release and resulting wide swings in plasma GH levels. Urinary GH excretion holds promise as an index of integrated plasma GH free of this limitation, but technical problems have prevented its use until recently. We adapted a recently developed method for accurately measuring GH and its various molecular forms in urine to the determination of GH excretion rates. The method involves diafiltration and immunoextraction of GH from urine, with monitoring of recovery and final quantification by radioimmunoassay. Twenty-four h GH excretion rates were determined in 30 normal adults (15 men and 15 women) and 4 acromegalic patients. They ranged from 1 to 81 ng/24 h in men, from 1 to 70 ng/24 h in women and from 87 to 1660 ng/24 h in acromegaly (medians = 8.7, 18.0 and 267 ng/24 h, respectively). Excretion rates varied widely, not only between subjects, but also within the same subject on different days. Women and younger subjects tended to excrete more GH than men and older subjects, although these trends were not statistically significant. Acromegalics excreted significantly more GH than normals (p less than 0.001). Twelve normal subjects underwent simultaneous assessment of 24 h integrated plasma GH (sampling every 20 min) and urine GH excretion. Urine GH correlated weakly (r = 0.45) with integrated plasma GH.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Since hyperhomocysteinaemia is an independent risk factor for development of atherosclerosis as well as for arterial and venous thrombosis we investigated whether elevated homocysteine levels are associated with procedural excess risk which complicates coronary interventions including coronary angioplasty (PTCA), stenting, or directional coronary atherectomy (DCA). DESIGN: Consecutive cases receiving coronary catheter interventions. SETTING: Tertiary referral centre in Germany. METHODS: Fasting total plasma homocysteine levels (tHcy) were determined in 648 consecutive coronary artery disease patients who underwent catheter interventions (272 PTCA, 102 DCA, and 274 stenting). Hyperhomocysteinaemia was defined as tHcy >/=15 micromol/l. The patients were investigated for a 30-day composite endpoint, including need for target-vessel revascularization, myocardial infarction, and death. RESULTS: Among the 648 patients, 78 (12%) demonstrated elevated tHcy levels. The composite endpoint occurred in 41 patients (6.3%). For the entire intervention group there was no evidence that hyperhomocysteinaemia was associated with excess procedural risk (odds ratio [OR]: 1.27; 95% confidence interval [CI]=0.52 to -3.13; P=0.62). In further analyses according to device, hyperhomocysteinaemia also failed to predict complications in the device related subgroups. CONCLUSION: The results indicate that hyperhomocysteinaemia is not a major risk factor for 30-day adverse events complicating PTCA, DCA, or stenting.
The contractile cycle of the cardiac myocyte is essentially controlled by the concentration of intracellular calcium ([Ca2+]i). Measurement of [Ca2+]i using Ca2+-dependent fluorescence and simultaneous monitoring of cell dynamics enable characterization of a variety of substances interacting with ion channels and contractile proteins. In this report we describe a novel method featuring up to 480 frames/s for monitoring rapid changes in cellular calcium and cell length, in which every individual cycle allows effective evaluation of major cell parameters. Computers aid in determination of time to peak (in ms), time to 50% decrease (ms), diastolic Ca2+ (relative fluorescence units, rfu), systolic Ca2+ (rfu), Ca2+ transients (rfu), DeltaCa2+/Delta(t) rise (rfu/s), and DeltaCa2+/Delta(t) fall (rfu/s). Contractile parameters are as follows: maximum cell length (microm), minimum cell length (microm), absolute cell shortening (microm), peak DeltaL/Delta(t) shortening (microm/s), and peak DeltaL/Delta(t) relaxation (microm/s). In summary, we succeeded in demonstrating that this system is a unique and valuable tool that allows simultaneous and accurate assessment of contractile parameters and of calcium movements of isolated adult cardiac myocytes.
Left ventricular infarctions were produced in guinea pigs, and the contractile response to beta-adrenergic and H2-histaminergic stimulation was tested in isolated perfused heart preparations. Adenylate cyclase activity and binding characteristics of sarcolemmal beta 1-, H2-, and muscarinic cholinergic receptors were determined in sarcolemmal membrane preparations of the uninvolved right ventricle of the same hearts. Three days after infarction, the positive inotropic effects of isoproterenol (2.8 X 10(-9) mol/L) and tyramine (5.5 X 10(-5) mol/L) were nearly abolished, while the inotropic effects of impromidine (4.6 X 10(-7) mol/L) and dimaprit (8.5 X 10(-6) mol/L) were not impaired. Stimulation rates of cardiac adenylate cyclase activity by isoproterenol were markedly reduced (-90%) whereas impromidine, dimaprit, and NaF revealed stimulation rates equivalent to the sham-operated control group. beta-Receptor binding studies with [3H]dihydroalprenol revealed 90% loss and nearly 10 times lowered affinity (KD) of the remaining receptors, while specific binding of [3H]tiotidine and [3H]quinuclidinyl-benzylate was unchanged in the same preparations. All of the above alterations could be prevented to a similar extent by treatment with different beta-blocking agents, but differences between the drugs were seen with respect to survival rates and reduction of infarct size. In agreement with previous findings, we conclude that the observed alterations in the nonischemic surviving myocardium are the result of specific damage of sarcolemmal beta-receptors due to excessive exposure to increased catecholamines after infarction. The stimulation of the uninvolved H2-receptors may be of therapeutic value.
We determined stimulation rates of cardiac adenylate cyclase activity by isoproterenol and impromidine in particulate sarcolemmal membrane preparations from human papillary muscles resected during open heart replacement of mitral and aortic valves. In addition, specific receptor binding studies with [3H]dihydroalprenolol [( 3H]DHA) to cardiac beta-receptors and [3H]tiotidine [( 3H]TIOT) to cardiac H2-receptors were carried out in the same preparations. Compared with the response in patients with pure mitral valve stenosis, the response of cardiac adenylate cyclase activity to isoproterenol showed a marked decrease (-90%) in patients with combined mitral and aortic valve disease, corresponding to the severity of degree of insufficiency at both valves. Similar changes were observed in receptor binding studies with [3H]DHA, in which the reduction of beta-receptor density was of the same order of magnitude. In contrast, stimulation of the enzyme by impromidine and binding capacity of [3H]TIOT to cardiac H2-receptors were found to be unaltered in the same membrane preparations of all 16 patients. We conclude that treatment with H2-agonists may be a new therapeutic approach to congestive heart failure, especially in patients not responding to beta-adrenoceptor stimulation with beta-sympathomimetic drugs.
BACKGROUND: Forty-nine consecutive patients undergoing partial left ventriculectomy (Batista) surgery between January 1995 and June 1998 were studied. METHODS: Patient ages ranged from 12 to 85 years, and all patients were in New York Heart Association functional Class III or IV. Thirty-three patients had ischemic cardiomyopathy, and 16 had idiopathic myopathy. Inclusion criteria were left ventricular end diastolic volume index of > 150 mL/m2, left ventricular ejection fraction of < 20%, or left ventricular end-diastolic diameter of > 70 mm. Sixteen patients were transplant candidates. Partial left ventriculectomy and mitral valve repair by means of a Cosgrove annuloplasty ring plus the Alfieri repair constituted only part of the complex cardiac reconstruction in 38 patients. RESULTS: Five patients died early and five patients died late between 3 and 30 months postoperatively. The actuarial 1-year survival rate was 81%. Twenty-seven patients with coronary artery disease underwent one to five bypass grafts when appropriate. In addition, three patients received aortic valve replacement, four received tricuspid valve repair, two received mitral valve replacement, and two underwent dynamic cardiomyoplasty. Left ventricular (LV) diameter could be reduced from a preoperative mean of 71 to 56 mm postoperatively. LV ejection fraction increased to 36% postoperatively. Ninety percent of patients are in New York Heart Association functional Class I or II. CONCLUSIONS: Patients with end-stage idiopathic or ischemic cardiomyopathies can be improved considerably with partial left ventriculectomy. Any cardiac comorbidity should be repaired simultaneously.
Pituitary adenylate-cyclase-activating peptides (PACAPs) are potent dilators of arteries, including human coronary arteries. We tested the importance of specific K+ channel regulatory mechanisms in human arterial smooth muscle relaxation induced by PACAPs, using contraction and patch clamp measurements on human coronary artery vascular smooth muscle cells. PACAP27 and PACAP38 produced dose-dependent relaxations of 5 microM PGF2alpha-preconstricted rings, with half-maximal relaxations at 1.0 nM and 2.0 nM, respectively. Both peptides induced complete relaxation at 100 nM. Pretreatment of the vessels with the ATP-dependent K+ (K(ATP)) channel blocker glibenclamide (1 microM) or with the Ca2+-activated K+ (K(Ca)) channel blocker iberiotoxin (100 nM) inhibited PACAP27-induced relaxation in an additive manner. Moreover, in the patch clamp experiments on freshly isolated cells from human coronary arteries, PACAP27 (100 nM) induced a large, nonrectifying, outward (I(K)(ATP)) K+ current in a proportion of cells and a voltage-dependent outward (I(K)(Ca)) K+ current in other cells. The PACAP27-induced I(K)(ATP) was blocked by glibenclamide (3 microM), while the PACAP27-stimulated I(K)(Ca) was blocked by iberiotoxin (100 nM). These findings provide the first evidence that relaxation of arterial smooth muscle cells by PACAPs is mediated by opening of K(ATP) and K(Ca) channels. The data indicate that both K(ATP) and K(Ca) channels in vascular smooth muscle cells may serve as final common pathway to induce vasorelaxation by endogenous vasoactive signals in man.
In 12 patients with coronary heart disease, the end-systolic and end-diastolic left-ventricular volumes were measured employing three-dimensional echocardiography. Cardiac output (COe) and stroke volume (SVe) were calculated and correlation with simultaneous thermal dilution measurements (COth, SVth) was performed. In 9 subjects the variability between the mean heart rate and the heart rate at any given time was found to be < 10% (observer 1:SVe vs. SVth r = 0.78, p < 0.01, COe vs. COth r = 0.86, p < 0.01 and in 9 cases with steady heart rate SVe vs. SVth r = 0.95, p < 0.01; observer 2:SVe vs. SVth r = 0.78, p < 0.01, COe vs. COth r = 0.77, p < 0.01 and in 9 cases with steady heart rate SVe vs. SVth r = 0.93, p < 0.01). Using the new bedside approach three-dimensional imaging and volumetry becomes possible by means of one examination.
The biochemical mediators responsible for variations in stature among normal subjects are largely unknown. To obtain some initial information about potential endocrine factors, we measured the serum concentrations of GH, IGF-1, IGFBP-3 and GHBP in healthy young men shorter than 159 cm and taller than 187 cm. We studied 14 volleyball and basketball players (tall group), and 14 jockey students from a horse racetrack (short group). A careful medical history was taken, including dietary intake, and physical examination with special attention to the possible presence of genetic stigmata was performed. Serum prealbumin was determined as an index of nutritional status. A buccal smear was performed to exclude Klinefelter's syndrome. The BMI and serum prealbumin levels were comparable in both groups of individuals. The nutritional survey, however, revealed that the tall subjects had a higher intake of calories (42.2+/-11.2 vs. 30.1+/-15.15 kcal/kg, p<0.05), and protein (1.5+/-0.6 vs. 0.8+/-0.4 mg/kg, p<0.01). Serum concentrations of GHBP did not differ in the two groups (0.95+/-0.37 nmol/l in the tall, and 0.95+/-0.53 nmol/l in the short group), and did not correlate with height, serum IGF-I levels, or BMI. We observed a significant difference in the serum concentrations of IGF-I in the two groups of individuals (42.02+/-9.37 nmol/l in the tall and 31.79+/-3.18 nmol/l in the short group, p<0.05), and this growth factor showed a positive correlation with height (r = 0.5, p<0.01). These preliminary findings suggest that final height differences in young men do not appear to be mediated by variations in GHBP concentrations.
Platelet-activating factor (PAF) has been called an important mediator of cardiovascular shock due to immunological reactions including anaphylaxis and endotoxic reactions. According to previous reports, PAF dose-dependently decreases ventricular contractility and coronary flow rates. Diverse mechanisms of the PAF-induced cardiodepressive effects have been postulated. Besides direct receptor stimulation, the release of other vasoactive mediators such as the eicosanoids has been reported. In this study, an attempt was made to characterize the direct PAF effects on the coronary circulation of the isolated constant pressure perfused guinea pig heart. A further objective was to evaluate whether PAF releases the potent vasoconstrictor thromboxane A2 in biologically relevant amounts. A continuous intracoronary infusion of the selective PAF antagonist WEB 2086 (3.7 x 10(-9) mol/min and 1.1 x 10(-7) mol/min, related to coronary flow rates of 1 ml/min) induced a dose-dependent vasodilation resulting in final perfusate concentrations of 2.5 x 10(-6) mol/l and 5.5 x 10(-5) mol/l, respectively. An intracoronary bolus injection of PAF in a submaximal dose (2.3 x 10(-10) mol, related to coronary flow rates of 1 ml/min) markedly decreased coronary flow rates and produced a significant increase in immunoreactive thromboxane B2 levels in the coronary effluent. WEB 2086 antagonized the PAF-induced coronary constriction in a dose-dependent manner. In addition, thromboxane release ceased entirely. In contrast, the selective thromboxane A2 receptor antagonist BM 13505 (0.9 x 10(-4) mol/1) attenuated the initial phase of coronary constriction only moderately. It is therefore concluded that the detected thromboxane release plays a subordinate role in the PAF-mediated coronary effects.
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Two growth hormone-binding proteins (GHBPs), one with high and the other with low affinity, have recently been described in the blood of humans and several other species. The high-affinity GHBP represents a circulating fragment of the GH receptor, encompassing its extracellular domain. The molecular nature of the low-affinity GHBP is not known in detail. GHBPs form complexes with circulating GH, prolong its biological half-life, restrict its distribution in the body, and modulate the binding of GH to receptors in tissues. Their net effect in vivo is to enhance GH action. The level of high-affinity GHBP in plasma probably reflects receptor concentrations in tissues. The level/activity of GHBP is linked to GH action, and several congenital or acquired conditions with altered GHBP levels are characterized by parallel changes in GH action (Laron-type dwarfism, pygmy dwarfism, malnutrition, obesity, insulin-dependent diabetes mellitus, liver cirrhosis, renal insufficiency). The GHBP/receptor level is nutritionally regulated, with levels low in undernutrition and high in overnutrition. Regulation of lean body mass anabolism/catabolism at the level of the GHBP/receptor provides a rational explanation for the derangements in the GH axis and their biological consequences (retarded or accelerated somatic growth) observed in nutrition disorders.