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Biomedical subjects

H Drexler

Publications and source records attributed to H Drexler.

At least 109 records · Page 6Linked to original sources
PubMed1997

Myocardial contractile effects of L-arginine in the human allograft.

OBJECTIVES: In the present study, we investigated, in transplant recipients, whether L-arginine (L-arg) potentiates the myocardial contractile effects of receptor-mediated coronary endothelial stimulation. Moreover, because inducible nitric oxide synthase (iNOS) is frequently expressed in transplanted myocardium, we also performed intracoronary infusion of L-arg in the absence of receptor-mediated coronary endothelial stimulation to investigate whether similar left ventricular (LV) contractile effects could be induced by providing more substrate for iNOS. BACKGROUND: Nitric oxide (NO), released from coronary endothelium after receptor-mediated stimulation by substance P (SP), affects vascular smooth muscle tone and modulates LV contractile performance. L-arg augments receptor-mediated endothelium-dependent coronary vasodilation in transplant recipients by increasing substrate availability for endothelial NO production. METHODS: Sixteen transplant recipients were studied at the time of annual coronary angiography. In eight transplant recipients, microtip LV pressures were recorded before and during intracoronary (IC) SP (20 pmol/min) and after the addition of IC L-arg (160 mumol/min) to IC SP. In eight transplant recipients, microtip LV pressures were recorded before and during IC L-arg (160 mumol/min) alone, and in six of these patients, endomyocardial biopsy samples were obtained to detect the expression of iNOS gene by reverse transcription-polymerase chain reaction. RESULTS: Addition of IC L-arg to IC SP induced a fall (mean +/- SEM) in LV peak systolic pressure (-16 +/- 4 mm Hg), which was larger (p < 0.01) than that observed during IC SP (-7 +/- 2 mm Hg). During IC L-arg alone, there was no change in LV peak systolic pressure despite the presence of iNOS mRNA in five of the six biopsy samples. CONCLUSIONS: In transplant recipients, L-arg potentiates the paracrine myocardial contractile effects of receptor-mediated coronary endothelial stimulation, probably by providing more substrate for endothelial NO production. Despite the myocardial expression of iNOS gene, L-arg alone fails to elicit similar contractile effects.

Arginine↗
PubMed1997

Differential CD95 expression and function in T and B lineage acute lymphoblastic leukemia cells.

CD95 (Fas/APO-1) is a cell surface receptor able to trigger apoptosis in a variety of cell types. The expression and function of the CD95 antigen on leukemic blasts from 42 patients with B lineage and 53 patients with T lineage acute lymphoblastic leukemia (ALL) were investigated using immunofluorescence staining and apoptosis assays. The CD95 surface antigen was expressed in most ALL cases, with the T lineage ALL usually showing a higher intensity of surface CD95 expression as compared with the B lineage ALL cells (relative fluorescence intensity, RFI: 4.8 +/- 0.47 vs 2.2 +/- 0.23, respectively, P < 0.01). Functional studies disclosed that upon oligomerization by anti-CD95 monoclonal antibodies the CD95 protein was either not able to initiate apoptosis of leukemic cells (75% of cases) or induced low rates of apoptosis (20% of cases). Only in 5% of cases did the apoptosis rate exceed the 20% level of the CD95-specific apoptosis. Most of the CD95-sensitive cases were found among T lineage ALLs (38% of T lineage vs 10% of B lineage ALLs). Overall, the extent of CD95-induced apoptosis did not correlate with the expression level of CD95. Similarly, no significant correlation between expression level and functionality of CD95 in human leukemia cell lines of B and T cell origin could be observed. Bcl-2 protein has been associated with prolonged cell survival and has been shown to block partially CD95-mediated apoptosis, but for ALL cells no correlation between bcl-2 expression and spontaneous or CD95-mediated apoptosis could be found. The results obtained in this study indicate that, despite constitutive expression of CD95, the ALL cells are mainly resistant to CD95-triggering. More detailed investigations of the molecular mechanisms involved in the intracellular apoptotic signal transduction, such as interactions of the bcl-2 and the other members of the bcl-2 family, and functionality of the interleukin-1beta converting enzyme (ICE) like-proteases, may give new insights into key events responsible for the resistance or sensitivity to the induction of apoptosis in acute leukemia.

Antigens, Neoplasm↗
PubMed1997

G protein-coupled receptors control vascular smooth muscle cell proliferation via pp60c-src and p21ras.

The binding of vasoactive peptides to their respective G protein-coupled receptors has been implicated in the pathogenesis of vascular smooth muscle cell proliferation, leading to the development of hypertension, arteriosclerosis, and restenosis after vascular injury. We previously showed that the cytosolic tyrosine kinase pp60c-src is crucial for angiotensin II (ANG II)-induced activation of the protooncogene p21ras. Therefore, we investigated the role of pp60c-src and p21ras in rat aortic smooth muscle cell proliferation induced by several G protein-coupled receptors. ANG II, endothelin-1, or thrombin increased cell proliferation and DNA synthesis. Electroporation of anti-pp60c-src antibodies into cells abolished proliferation in response to these G protein-coupled receptor ligands but not in response to platelet-derived growth factor-BB (PDGF-BB). In contrast, electroporation of anti-p21ras antibody completely blocked DNA synthesis and cell proliferation in response to ANG II, endothelin-1, thrombin, and PDGF-BB. Our data indicate that the pp60c-src tyrosine kinase is necessary and specific for vascular smooth muscle cell proliferation and DNA synthesis in response to G protein-coupled receptors but not classic growth factor receptors.

Angiotensin II↗
PubMed1997

Endothelial function and bradykinin in humans.

The endothelium controls vascular smooth muscle tone by secreting relaxing and contracting factors. There is a constant release of endothelium-derived relaxing factors (EDRFs) under basal conditions. In addition, the endothelium can increase the release of EDRFs in response to humoral stimulation by vasoactive substances such as acetylcholine or bradykinin. Under physiological conditions, the most important stimulus to the release of EDRFs is an increase in blood flow leading to increased shear stress on endothelial cells. Recent experimental studies raised the possibility that bradykinin plays an important role in the regulation of vascular tone at rest and during flow-stimulated conditions. Bradykinin is a very potent vasodilator that exerts its vasodilatory actions by causing endothelial release of nitric oxide, prostacyclin and/or a hyperpolarising factor [endothelium-derived hyperpolarising factor (EDHF)]. This concept is also supported by recent studies in humans demonstrating that bradykinin contributes to the regulation of coronary vascular tone under resting and flow-stimulated conditions. This mechanism has now been shown to be important in both human peripheral and coronary arteries. Angiotensin converting enzyme (ACE) inhibitors not only reduce angiotensin II, but also increase bradykinin levels, since the angiotensin converting enzyme is identical to kininase II, an enzyme that degrades bradykinin. This raises the possibility that beneficial vascular effects of ACE inhibitors may be related to increased availability of bradykinin. Indeed, we have recently shown that ACE inhibition improves flow-dependent, endothelium-mediated vasodilation and that this beneficial effect of ACE inhibition is bradykinin dependent. These findings raise the possibility that the beneficial effects of ACE inhibition in heart failure and coronary artery disease might be partly due to improved endothelial function.

Angiotensin II↗
PubMed1996

Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL.

BACKGROUND: Risk factors for atherosclerosis such as hypercholesterolemia and hypertension are associated with endothelial dysfunction of conduit and resistance vessels; however, the interaction of these risk factors and underlying mechanisms affecting endothelial function remain to be determined. The present study investigated the role of long-term smoking and hypercholesterolemia and their impact on endothelial function of peripheral resistance vessels in relation to plasma levels of autoantibodies against oxidized LDL, which has been implicated in the development of endothelial dysfunction and atherosclerosis. METHODS AND RESULTS: The vascular responses to the endothelium-dependent agent acetylcholine (7.5, 15, 30, and 60 micrograms/min) and the endothelium-independent agent sodium nitroprusside (1,3, and 10 micrograms/min) were studied in normal control subjects (n = 10), patients with hypercholesterolemia (n = 15), long-term smokers (n = 15), and hypercholesterolemic patients who smoked (n = 15). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by venous occlusion plethysmography. The FBF responses to acetylcholine were significantly blunted in all three patient groups compared with normal control subjects (P < .05). The acetylcholine-induced increase in FBF was significantly attenuated in patients with hypercholesterolemia who smoked compared with hypercholesterolemic nonsmokers and normocholesterolemic smokers (P < .05 for both). The response to sodium nitroprusside was not statistically different in all four groups. Plasma levels of autoantibody titer against oxidized LDL were inversely related to acetylcholine-induced changes in FBF (r = -.53, P < .002) and were substantially increased in the group with both risk factors. CONCLUSIONS: These results demonstrate that cigarette smoking and hypercholesterolemia synergistically impair endothelial function and that their combined presence is associated with increased plasma levels of autoantibodies against oxidized LDL. These observations raise the possibility that long-term smoking potentiates endothelial dysfunction in hypercholesterolemic patients by enhancing the oxidation of LDL.

Acetylcholine↗
PubMed1996

Physical training improves endothelial function in patients with chronic heart failure.

BACKGROUND: Chronic heart failure is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). Since endothelial function is thought to play an important role in coordinating tissue perfusion and modulating arterial compliance, interventions to improve endothelial dysfunction are imperative. METHODS AND RESULTS: To assess the potential of physical training to restore FDD, 12 patients with chronic heart failure were studied and compared with FDD of 7 age-matched normal subjects. With a recently developed high-resolution ultrasound system, diameters of radial artery were measured at rest, during reactive hyperemia (with increased flow causing endothelium-mediated dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Determination of FDD was repeated after intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA, 7 mumol/min) to inhibit endothelial synthesis and release of nitric oxide. The protocol was performed at baseline, after 4 weeks of daily handgrip training, and 6 weeks after cessation of the training program. FDD was impaired in heart failure patients compared with normal subjects. L-NMMA attenuated FDD, indicating that the endothelial release of nitric oxide is involved in FDD. Physical training restored FDD in patients with heart failure. In particular, the portion of FDD inhibited by L-NMMA (representing FDD mediated by nitric oxide) was significantly higher after physical training (8-minute occlusion: 8.0 +/- 1% versus 5.4 +/- 0.9%; P < .05; normal subjects: 9.2 +/- 1%). CONCLUSIONS: These results indicate that physical training restores FDD in patients with chronic heart failure, possibly by enhanced endothelial release of nitric oxide.

Adult↗
PubMed1996

Pullback atherectomy (PAC) for the treatment of complex bifurcation coronary artery disease.

We report initial successful results using a novel retrograde cutting (pullback) atherectomy catheter (PAC) to treat complex bifurcation coronary artery disease, in 2 patients. In one case a bifurcation lesion involving the left anterior descending and a large diagonal branch was treated without the need for two-wire or kissing-balloon technique. In the second case a high-grade eccentric lesion of the right coronary artery at the site of a right ventricular marginal branch was treated successfully. This report describes the first clinical application of pullback atherectomy in human coronary circulation, and suggests that this device may play a useful role in the treatment of complex bifurcation coronary artery disease.

Angioplasty, Balloon, Coronary↗
PubMed1996

Calcium cycling proteins and force-frequency relationship in heart failure.

Myocardial function, intracellular calcium and levels of calcium cycling proteins were analyzed in failing and nonfailing human myocardium. Myocardial function was evaluated by the isometric force-frequency relation, and intracellular calcium was studied by aequorin light emission. When stimulation frequency was increased above 30 min-1, there was a continuous increase in isometric tension development in the nonfailing myocardium. In contrast, in failing myocardium, frequency potentiation of contractile force was blunted or inverse. As a consequence, at higher rates of stimulation, twitch tension was reduced significantly in failing compared to nonfailing human myocardium. Aequorin measurements indicated that the contractile deficit in the failing myocardium at higher rates of stimulation is associated with decreased free intracellular calcium concentration. Western blot analysis indicated that in the failing myocardium protein levels of SR-Ca(2+)- ATPase are significantly reduced and protein levels of Na(+)-Ca(2+)- exchanger are significantly increased. Levels of phospholamban are slightly reduced in the failing myocardium, and ryanodine receptor and calsequestrin protein levels are unchanged. There was a close positive correlation between the protein levels of SR-Ca(2+)-ATPase and frequency potentiation of contractile force. From these data, we conclude that in failing compared to nonfailing human myocardium 1) force-frequency relation is blunted or inverse. 2) Frequency-dependence of contractile force is closely correlated with frequency-dependence of intracellular calcium cycling. 3) Protein levels of SR-Ca(2+)-ATPase may determine frequency-dependence of sarcoplasmic reticulum calcium release. 4) Calcium elimination by an increased number of Na(+)-Ca2-exchanger molecules may be a compensatory mechanism to prevent diastolic calcium accumulation in failing myocardium with a reduced number of SR calcium pumps.

Calcium↗
PubMed1996

Left ventricular wall stress and sarcoplasmic reticulum Ca(2+)-ATPase gene expression in renal hypertensive rats: dose-dependent effects of ACE inhibition and AT1-receptor blockade.

BACKGROUND: Cardiac hypertrophy is associated with altered Ca2+ handling and may predispose to the development of LV dysfunction and cardiac failure. At the cellular level, the re-expression of ANF represents a well-established marker of myocyte hypertrophy while the decreased expression of the sarcoplasmatic reticulum (SR) Ca(2+)-ATPase is thought o play a crucial role in the alterations of Ca2+ handling and LV function. We assessed the dose-dependent effect of chronic ACE inhibition or AT1 receptor blockade on cardiac function in relation to the cardiac expression of the SR Ca(2+)-ATPase and ANF. METHODS AND RESULTS: Renal hypertensive rats (2K-1C) were treated for 12 weeks with three different doses of the ACE inhibitor benazepril, the AT1-receptor antagonist valsartan (each drug 0.3, 3, and 10 mg/kg per day i.p.) or placebo. LV dimensions, hypertrophy and wall stress were determined in vivo by magnetic resonance imaging and the gene expressions of ANF and SR Ca(2+)-ATPase were quantified by Northern blot. Low doses of both drugs did not affect blood pressure, hypertrophy, systolic wall stress and the ANF and SR Ca(2+)-ATPase gene expression. High doses of each drug reduced systolic blood pressure, wall stress, and LV hypertrophy to a similar extent and to values comparable to normotensive, age-matched rats. In addition, high dose treatment reduced LV end-systolic and end-diastolic volume as compared to untreated 2K-1C animals and normalized the mRNA levels of both ANF and SR Ca(2+)-ATPase (as compared to normotensive animals). CONCLUSIONS: We conclude that in this model, high doses of ACE inhibition and AT1-receptor blockade are necessary to normalize systolic blood pressure, LV hypertrophy and systolic LV wall stress which, in turn, is associated with restoration of a normal cardiac phenotype with respect to SR Ca(2+)-ATPase and ANF and normalization of cardiac function.

Angiotensin II↗
PubMed1996

Importance of endothelial function in chronic heart failure.

Chronic heart failure (CHF) is associated with neurohumoral activation and alterations of the peripheral circulation. Several mechanisms are involved in the impaired peripheral perfusion, including increased sympathetic tone. Recent data suggest an important role of the endothelium for peripheral perfusion in CHF. Endothelium-dependent dilation of resistance vessels is blunted in patients with severe CHF and may be involved in the impaired reactive hyperemia in these patients. In conductance vessels, flow-dependent dilation is reduced in CHF, reflecting endothelial dysfunction of large conduit vessels. To investigate endothelial function in humans in vivo, agents such as acetylcholine are used to stimulate the release of endothelium-derived nitric oxide (NO). Conversely, N-mono-methyl-L-arginine (L-NMMA), a specific inhibitor of NO synthesis from L-arginine, decreases forearm blood flow by inhibiting the basal release of NO. Conversely to the impaired stimulated release of NO by acetylcholine, the decrease in blood flow induced by L-NMMA appears to be exaggerated in CHF. The blood flow response to nitroglycerin or sodium nitroprusside, both endothelium-independent vasodilators, is usually preserved in patients with nonedematous CHF, indicating a normal response of the vascular smooth muscle of resistance vessels to exogenous NO. Therefore, impaired endothelium-dependent dilation of peripheral resistance vessels emerges in CHF, suggesting a reduced release of NO on stimulation. Endothelial dysfunction may therefore be involved in the impaired vasodilator capacity in the peripheral circulation, e.g., during exercise. In contrast, the basal release of NO from endothelium of resistance vessels appears to be enhanced and may play an important compensatory role in CHF.

Animals↗
PubMed1996

Explaining fatigue in congestive heart failure.

Fatigue is a prominent symptom in patients with chronic heart failure, limiting physical activity and impairing quality of life. Although the underlying mechanisms are not clearly identified, alterations associated with peripheral adaptation in heart failure appear to play an important role, including a variably impaired peripheral perfusion during exercise, reduced oxidative capacity of skeletal muscle, impaired muscle strength, and possibly reflex mechanisms associated with alterations in the metabolism of skeletal muscle. Exercise training can, in part, reverse these peripheral alterations, improve exercise capacity, and alleviate fatigue.

Activities of Daily Living↗
PubMed1996

Cardiac Na+/Ca2+ exchange activity in patients with end-stage heart failure.

OBJECTIVE: The aim of the present study was to investigate the functional activity and expression of the sarcolemmal Na+/Ca2+-exchanger in the failing human heart. METHODS: Left ventricular samples were taken from eleven patients with end-stage heart failure and six organ donors (normal controls). The Na+/Ca2+-exchanger activity was assessed by measuring Na+ gradient-induced 45Ca2+ transport into sarcolemmal vesicles of quantitatively collected crude membrane preparations. The abundance of the Na+/Ca2+-exchanger protein was determined by Western blot analysis using a specific antiserum and the results were normalized to myocyte specific beta-myosin heavy chain protein content. RESULTS: In membrane preparations of failing human hearts, both the Na+ gradient-induced 45Ca2+ transport activity and the level of immunoreactive Na+/Ca2+-exchanger protein were increased (P < 0.01) by 87% and 160% compared to controls, respectively. CONCLUSIONS: In human end-stage heart failure the increased sarcolemmal Na+/Ca2+-exchanger activity appears to be due to an elevated expression of this protein. An increase in the expression and activity of the Na+/Ca2+-exchanger in the failing human heart may be of important functional significance: while a resulting increase in Ca2+ extrusion across the sarcolemma may limit diastolic Ca2+ overload, a corresponding influx of Na+ may be associated with membrane depolarization and enhanced arrhythmogenesis if the Na+/Ca2+-exchanger operates primarily in the forward mode.

Adult↗
PubMed1996

Carbon disulphide. IV. Cardiovascular function in workers in the viscose industry.

OBJECTIVE: The aim of the study was to examine whether an increase can be detected in the prevalence of coronary heart disease or a higher prevalence of unusual cardiological findings in workers with occupational exposure to carbon disulphide (CS2) at the level of the threshold limit value of 10 ppm currently valid in occupational medicine. METHODS: In a cross-sectional study we investigated 247 men occupationally exposed to CS2 and a comparable control group (n = 222). The current exposure to CS2 was measured using personal air monitoring and biological monitoring of all test persons. A cumulative exposure index (median of CS2 exposure in the past multiplied by the duration of employment) was calculated. In addition to collecting comprehensive anamnestic data on all persons, we carried out a physical examination, an ultrasound examination of the large arteries, a resting and exercise ECG and an echocardiographic examination. RESULTS: No increase could be found in the prevalence of coronary heart disease or of arteriosclerotic findings in the exposed subjects. There was no difference in the distribution of the performance of the two groups in the ergometric tests. The echocardiogram showed a median increase in the diameter of the left atrium and left ventricle of 1-2 mm in the exposed subjects. These differences could also be confirmed statistically after multiple linear regression analysis. The left ventricular, telesystolic diameter was positively associated (P < 0.05) with internal exposure (CS2 metabolite in urine), and fractional shortening revealed a plausible negative trend (P = 0.0755). Current external exposure (CS2 in air) and cumulative exposure did not influence any of the parameters investigated. CONCLUSION: The findings may indicate a negatively inotropic effect of CS2 so far unknown in man. However, no clinical relevance for this effect was apparent.

Carbon Disulfide↗
PubMed1996

[Sympathetic nervous system in heart failure: effect of catecholamines and nitric oxide].

Norepinephrine and epinephrine stimulate alpha- and beta-adrenergic receptors which, in turn, modulate force of contraction in heart muscle cells. However, chronic stimulation may be associated with growth-promoting effects and modulation of the cardiac phenotype. Sympathetic tone is chronically enhanced in chronic heart failure and results in a selective down regulation of beta 1 adrenergic receptors, most likely due to local mechanisms. Beyond reduced beta 1 receptor density and increased levels of inhibitory Gi proteins, there is now evidence that NO can modulate the beta-adrenergic stimulation in the human myocardium. Increased NO activity generated by an inducible NO synthase is associated with a reduced positive inotropic response to beta-agonists, a mechanism which may play an important role in inflammatory states such as myocarditis or sepsis. Experimental data suggests that stimulation of alpha-adrenergic receptors of cardiomyocytes results in cardiac growth and changes in phenotype which, in turn, may affect the functional properties of the myocardium. For example, phenylephrine can upregulate the expression of the sodium/calcium exchanger, while the expression SR Ca2+ ATPase may be reduced. The latter is also affected by angiotensin II. Similar changes in the expression of these crucial proteins for the cardiac calcium homeostasis have been reported in the failing human heart, raising the possibility that the increased sympathetic tone and the activated renin-angiotensin system may be involved in these changes.

Animals↗
PubMed1995

Role of endogenous bradykinin in human coronary vasomotor control.

BACKGROUND: Bradykinin is a potent vasodilator that acts through B2 kinin receptors to stimulate the release of endothelium-derived nitric oxide, prostacyclin, and hyperpolarizing factor. In this study, we investigated the contribution of endogenous bradykinin to vasomotor control in the human coronary circulation. METHODS AND RESULTS: The selective bradykinin B2 receptor antagonist HOE 140 was infused into the left main coronary artery (200 micrograms/min for 15 minutes) in 15 patients without significant coronary stenoses. Epicardial responses were evaluated by quantitative coronary blood flow with a Doppler flow-velocity wire. Flow-dependent dilation (n = 10; intracoronary papaverine) and acetylcholine responses (n = 5) were assessed before and after HOE 140. After HOE 140, there was a reduction in luminal area in the proximal (P < .001), mid (P < .001), and distal (P < .05) coronary arteries. HOE 140 led to an increase in coronary vascular resistance (P < .001) and a decrease in coronary blood flow (P < .001). After bradykinin B2 receptor blockade, there was a reduction in flow-dependent dilation (23.4 +/- 6.9% to 3.9 +/- 6.0%, P < .001), the extent of which correlated with the degree of basal vasoconstriction after HOE 140 in the same vessel segment (P < .05). Acetylcholine responses were unchanged after HOE 140. CONCLUSIONS: The results of this study demonstrate for the first time a role for endogenous bradykinin in mediating normal vasomotor responses in resistance and epicardial coronary vessels under basal and flow-stimulated conditions in the human coronary circulation.

Animals↗