Acute heart transplant rejection due to Saint John's wort.
We report here acute rejection in two transplant patients due to a metabolic interaction of St John's wort and cyclosporin.
Azathioprine↗
Biomedical subjects
G Noll
Publications and source records attributed to G Noll.
Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators.
OBJECTIVES: To investigate the hemodynamic effects of the selective endothelin (ET)A receptor antagonist LU135252 in patients with congestive heart failure (CHF). BACKGROUND: Nonselective ET(A/B( receptor antagonists improve hemodynamics in patients with CHF. Since ET(B( receptors mediate the release of nitric oxide and the clearance of ET-1, selective ET(A) antagonists are of special interest. METHODS: The hemodynamic effects of a single oral dose of the selective ET(A) receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II-III) with an ejection fraction < or = 35%. RESULTS: Baseline ET-1 positively correlated with pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (MPAP, r = 0.37-0.50, p < 0.0004) but were inversely related to cardiac index (CI; r = -0.36, p = 0.0004). LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03-0.0002), while heart rate remained constant or decreased slightly. Pulmonary capillary wedge pressure, MPAP, pulmonary vascular resistance and right atrial pressure also decreased significantly (p < 0.035- < 0.0001). Two hours after LU135252, plasma ET-1 did not significantly increase after 1 mg but did so by 23% (p = 0.003), 29% (p = 0.0018), 56% (p < 0.0001) and 101% (p < 0.0001) after 10, 30, 100 and 300 mg, respectively, while plasma catecholamines remained constant. CONCLUSIONS: In patients with CHF, a single oral dose of the selective ET(A) receptor antagonist LU135252 improves hemodynamics in a dose-dependent manner without activation of other neurohumoral systems and is well tolerated over a wide dose range.
Catecholamines↗
Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans.
OBJECTIVES: We sought to investigate baroreceptor regulation of sympathetic nerve activity and hemodynamics after inhibition of nitric oxide (NO) synthesis. BACKGROUND: Both the sympathetic nervous system and endothelium-derived substances play essential roles in cardiovascular homeostasis and diseases. Little is known about their interactions. METHODS: In healthy volunteers, we recorded muscle sympathetic nerve activity (MSA) with microneurography and central hemodynamics measured at different levels of central venous pressure induced by lower body negative pressure. RESULTS: After administration of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 1 mg/kg/min), systolic blood pressure increased by 24 mm Hg (p = 0.01) and diastolic blood pressure by 12 mm Hg (p = 0.009), while stroke volume index (measured by thermodilution) fell from 53 to 38 mL/min/m2 (p < 0.002). Administration of L-NMMA prevented the compensatory increase of heart rate, but not MSA, to orthostatic stress. The altered response of heart rate was not due to higher blood pressure, because heart rate responses were not altered during infusion of the alpha-1-adrenoceptor agonist phenylephrine (titrated to an equal increase of systolic blood pressure). In the presence of equal systolic blood pressure and central venous pressure, we found no difference in MSA during phenylephrine and L-NMMA infusion. CONCLUSIONS: This study demonstrates a highly specific alteration of baroreceptor regulation of heart rate but not muscle sympathetic activity after inhibition of NO synthesis in healthy volunteers. This suggests an important role of NO in reflex-mediated heart rate regulation in humans.
Adrenergic alpha-Agonists↗
Autonomic nervous system-controlled cardiac pacing: a comparison between intracardiac impedance signal and muscle sympathetic nerve activity.
A recently introduced rate responsive cardiac pacing system is based on information derived from the intracardiac impedance signal containing information on the inotropic state of the ventricle. This study compared the inotropic state index (ISI) with muscle sympathetic activity (MSA), both being modulated by the autonomic nervous system. Nine patients (66 +/- 3 years, mean +/- SEM) with Inos2DR pacemakers were included. Each patient was studied at rest and during cold pressor test (CPT). Microneurography of the peroneal nerve was performed to measure MSA continuously, which was digitally stored along with continuous surface ECG and blood pressure. The intracardiac impedance signal was transmitted by the pacemaker and stored simultaneously. Linear correlation between ISI and MSA was calculated for the period of the CPT. During CPT, mean systolic blood pressure increased from 122 +/- 4 to 149 +/- 6 mmHg (P < 0.0001), diastolic blood pressure increased from 74 +/- 8 to 86 +/- 4 mmHg (P = 0.02), and intrinsic heart rate increased from 69 +/- 7 to 75 +/- 7 beats/mill (P = 0.019). ISI increased by 21 +/- 7% (P = 0.018), MSA by 26 +/- 6% (P = 0.004). ISI and MSA were positively correlated during the CPT in eight of nine patients (R2 = 0.86-0.99, P < 0.0001). Negative correlation was found in one patient (R2 = 0.94). This study demonstrates parallel increases of the ISI and MSA during CPT. ISI and MSA showed a close linear relationship during provoked changes of sympathetic activity. These results provide further evidence that the sympathetic nervous system is responsible for the observed ISI changes.
Aged↗
Antihypertensive drugs and the sympathetic nervous system.
The sympathetic nervous system (SNS) plays an important role in the regulation of blood pressure homeostasis and cardiac function. Furthermore, the increased SNS activity is a predictor of mortality in patients with hypertension, coronary artery disease and congestive heart failure. Experimental data and a few clinical trials suggest that there are important interactions between the main pressor systems, i.e. the SNS, the renin-angiotensin system and the vascular endothelium with the strongest vasoconstrictor, endothelin. The main methods for the assessment of SNS activity are described. Cardiovascular drugs of different classes interfere differently with the SNS and the other pressor systems. Pure vasodilators including nitrates, alpha-blockers and dihydropyridine (DHP)-calcium channel blockers increase SNS activity. Finally, central sympatholytics and possibly phenylalkylamine-type calcium channel blockers reduce SNS activity. The effects of angiotensin-II receptor antagonists on SNS activity in humans is not clear; experimental data are discussed in this review. There are important interactions between the pressor systems under experimental conditions. Recent studies in humans suggest that an activation of the SNS with pure vasodilators in parallel increases plasma endothelin. It can be assumed that, in cardiovascular diseases with already enhanced SNS activity, drugs which do not increase SNS activity or even lower it are preferable. Whether this reflects in lower mortality needs to be investigated in intervention trials.
Animals↗
Efficacy and tolerability of fluvastatin and bezafibrate in patients with hyperlipidemia and persistently high triglyceride levels.
Hyperlipidemia is an important cardiovascular risk factor. Lipid-lowering therapy has been shown to decrease morbidity and mortality in these patients. Combination therapy with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and a fibric-acid derivative has been reported to be more efficacious to reduce low-density lipoprotein (LDL) cholesterol and triglycerides but may be associated with an increased risk of myositis. The aim of this study was to investigate the efficacy and tolerability of fluvastatin, an HMG-CoA reductase inhibitor, alone and in combination with bezafibrate, a fibric-acid derivative. In a randomized controlled trial with 454 hypercholesterolemic patients (mean cholesterol, 8.6 +/- 1.6 mM), fluvastatin (20 mg/day) significantly lowered total plasma cholesterol levels (-12.5%; p < 0.0001 vs. placebo), LDL cholesterol (-14%; p < 0.0001), and triglycerides (-4%; p = 0.05). A small increase in high-density lipoprotein (HDL) cholesterol levels (3%, NS) also was observed. Combination therapy with fluvastatin and bezafibrate (400 mg/day) in 71 patients with persistent hypertriglyceridemia during treatment with the statin resulted in a more pronounced reduction in triglyceride (-47%; p < 0.0001) and total cholesterol levels (-15%; p < 0.0001) than did fluvastatin alone. Furthermore, the additional bezafibrate significantly increased HDL cholesterol (+5%; p < 0.001). No significant increases in creatine phosphokinase levels or in frequency of myalgia were observed. In summary, fluvastatin decreases both cholesterol and triglyceride levels. In patients with persistent hypertriglyceridemia, combination therapy with fluvastatin and bezafibrate may be safely used to lower triglyceride and cholesterol levels more efficiently.
Adult↗
Is it all in the genes...? Nitric oxide synthase and coronary vasospasm.
Explore the source record for details and available documents.
Coronary Vasospasm↗
Calcium antagonists. Results of recent studies and their significance for general practice.
Explore the source record for details and available documents.
Calcium Channel Blockers↗
Angiotensin converting enzyme inhibitors and vascular protection in hypertension.
Strategically located between the circulating blood and the vascular smooth muscle, endothelial cells release numerous vasoactive substances regulating the function of vascular smooth muscle and circulating blood cells. Endothelium-derived vasodilators include prostacyclin, nitric oxide and endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin, nitric oxide exerts potent antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by vasoconstrictors, such as angiotensin II and endothelin (ET)-1, both of which exert prothrombotic and growth-promoting properties. In hypertension, elevated blood pressure causes vascular disease by inducing endothelial dysfunction. Hence, modern therapeutic strategies in human hypertension focus on preserving or restoring endothelial integrity. Beyond inhibiting the renin-angiotensin system, angiotensin-converting enzyme (ACE) inhibitors diminish the inactivation of bradykinin, thus leading to an augmentation of nitric oxide release. In addition, the compounds stabilize the B2-receptor, and reduce oxidative stress and tissue ET-1 levels. In patients with coronary artery disease, chronic ACE inhibition improves endothelial function. Further clinical studies are already under way which will prove whether these beneficial vascular effects of ACE inhibitors on endothelial dysfunction result in a clinical benefit for patients with hypertension.
Angiotensin-Converting Enzyme Inhibitors↗
Rejected asylum seekers: the problem of return.
Explore the source record for details and available documents.
Demography↗
Endothelial dysfunction in acute renal failure: role of circulating and tissue endothelin-1.
The kidney is an important target and source of the potent vasoconstrictor and mitogen endothelin-1 (ET-1). However, its exact role in acute renal failure (ARF) remains to be determined. ARF was induced in male Wistar-Kyoto rats (n = 7) in a 2-kidney, 2-clip model of 30-min clamping. Twenty-four hours after clamp release, contractions to angiotensin I (Angl) and II, ET-1, and big ET-1 were studied in isolated aortic and renal artery rings. Endothelium-dependent and -independent relaxations were assessed by acetylcholine and sodium nitroprusside. ET-1 clearance, tissue uptake, plasma levels, and vascular and kidney content were investigated. In addition, ET(A) and Et(B) receptor mRNA expression was determined. Sham-operated animals served as controls (n = 7). In ARF, ET-1 plasma levels and tissue content of the renal artery, the aorta, and the kidney markedly increased (P<0.01). Plasma half-life of radiolabeled 125I-ET-1 was markedly prolonged, whereas 125I-ET-1 tissue uptake decreased in the kidney in ARF. Contractions to AngI and AngII were blunted (P<0.05) and those to KCl were unchanged, whereas vascular responses to big ET-1 and ET-1 were enhanced in the renal artery and also in the aorta in ARF (P<0.05 to 0.001). Correspondingly, ET(A) and Et(B) receptor mRNA expression significantly increased in both vascular beds. In addition, endothelium-dependent relaxation to acetylcholine was diminished and inversely correlated with vascular ET-1 protein levels in the renal artery (r = -0.827, P<0.001) and the aorta (r = -0.812, P<0.001). In conclusion, the present study demonstrates that increase of circulating and tissue ET-1 protein levels and ET(A) and Et(B) receptor gene expression occurs, which induces endothelial dysfunction and enhanced vasoconstriction in different vascular beds in ARF.
Acute Kidney Injury↗
Endothelial dysfunction in the aorta of transgenic rats harboring the mouse Ren-2 gene.
The renin-angiotensin system plays an important role in the pathophysiology of hypertension. We studied vascular function in the aorta of mouse Ren-2 transgenic rats (TGR(mRen2)27). Changes in isometric tension of isolated aorta of TGR(mRen2)27 and Sprague-Dawley rats (SD) were recorded in organ chambers. Contractions to angiotensin II (AII), big-endothelin and endothelin-1 (ET-1), but not KCl were decreased in TGR. Blockade of nitric oxide (NO)-synthase by L-NAME or removal of the endothelium did not alter these decreased contractions to ET-1 and AII in TGR, suggesting that receptors or signaling pathways of these two agonists are downregulated during hypertension. Contractions to norepinephrine (NE) were also lower in TGR, however blockade of NO-synthase by L-NAME or removal of the endothelium evoked similar contractions to NE in both strains, suggesting that basal release of NO reduces contractions to NE to a greater extent in transgenic than control rats. In the presence of L-NAME, acetylcholine evoked endothelium-dependent contractions (EDCF) in TGR, which were blocked by the thromboxane/prostaglandin H2 receptor antagonists SQ 30741, and partially by the thromboxane synthase inhibitor CGS 13080, suggesting that prostaglandin H2 is the mediator. Endothelium-dependent relaxation to acetylcholine was decreased in TGR, while endothelium-independent relaxations to sodium nitroprusside were similar in both strains. SQ 30741 did not improve relaxations to acetylcholine in TGR indicating that impaired relaxations to acetylcholine are due to a decreased acetylcholine-receptor mediated release of NO rather than increased release of EDCF. Thus, Ren-2 hypertension leads to marked alterations of vascular functions in the aorta. These changes could contribute to hypertension and its vascular complications in TGR(mRen2)27 rats.
Acetylcholine↗
A rationale for treatment of endothelial dysfunction in hypertension.
Strategically located between the circulating blood and the vascular smooth muscle, endothelial cells release numerous vasoactive substances that regulate the function of vascular smooth muscle and circulating blood cells. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide (NO) and, independent of the former, endothelium-derived hyperpolarizing factor. In particular, NO inhibits cellular growth and migration. In concert with prostacyclin, NO exerts potent antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by vasoconstrictors, angiotensin II and endothelin-1, both of which exert prothrombotic and growth-promoting properties. In hypertension, elevated blood pressure transmits into cardiovascular disease by causing endothelial dysfunction. Hence, modern therapeutic strategies in human hypertension focus on preserving or restoring endothelial integrity. Calcium antagonists counteract angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing the inflow of Ca2+ and facilitating the vasodilator effects of NO. Besides inhibiting the renin-angiotensin system, angiotensin-converting enzyme inhibitors diminish the inactivation of bradykinin, leading to an augmented release of NO. Newly developed vasopeptidase inhibitors induce potent antihypertensive effects in low-, normal-, and high-renin models of hypertension, not only because of the decreased breakdown of natriuretic peptides, but also because of the inhibition of endothelin-1 generation. Furthermore, experimental studies suggest that endothelin antagonists effectively lower blood pressure and prevent target-organ damage in salt-sensitive forms of hypertension. Further clinical studies are already underway to examine whether restoring endothelial dysfunction results in a clinical benefit in hypertension.
Angiotensin-Converting Enzyme Inhibitors↗
Corrected formula for the calculation of the electrical heart axis.
The calculation of the heart axis in the frontal plane can be performed with the combination of any two leads. The use of combination of bipolar (I, II, III) and unipolar leads (aVR, aVL and aVF) can produce wrong results. Calculation of the electrical axis from leads I and aVF without correction (sometimes used in ECG recorders): EA= Arctan (aVF/I) results in lower values (in our study: 34 4 , n = 48) as compared to the values obtained with formula that uses leads I and II: EA= Arctan ((2*II-I)/(Sqr(3)*I)) (axis = 33+/-7 degrees, n=48; p<0.005, paired t-test with Bonferroni correction) or with corrected formula which uses leads I and aVF: EA=+/-Arctan ((2*aVF)/(Sqr(3)*I)) (axis = 374 degrees, n=48; p<0.005, paired t-test with Bonferroni correction). The correction factor 2/Sqr(3) is required because the unipolar and bipolar leads have different strengths. Although the difference rarely reach clinical significance, our results suggests that the ECG recorders should be proofed on formulas used for the calculation of the electrical axis.
Electrocardiography↗
Hemodynamic and coronary effects of the endothelin antagonist bosentan in patients with coronary artery disease.
BACKGROUND: Endothelin is a potent endothelium-derived vasoconstrictor peptide with proliferative properties. Elevated levels of the peptide occur in coronary artery disease; however, its pathophysiological role as a regulator of coronary tone and structure is uncertain. Endothelin-receptor antagonists are specific tools to clarify this issue and might be useful in the treatment of coronary artery disease. METHODS AND RESULTS: In a double-blind, placebo-controlled randomized study, we investigated the effects of the ETA/ETB endothelin-receptor antagonist bosentan or placebo on systemic and coronary hemodynamics in 28 patients with angiographically documented stable coronary artery disease by quantitative coronary angiography and an intracoronary Doppler guidewire. Bosentan 200 mg IV decreased systolic blood pressure (P<0. 05), whereas heart rate increased slightly (P<0.05). Coronary diameter increased, particularly in vessels with no or mild angiographic changes (P<0.01). Glycerol trinitrate did not further dilate these segments, whereas coronary diameter increased significantly after nitrate in the placebo group. The increase in coronary diameter after bosentan correlated inversely with plasma LDL-cholesterol levels (P<0.01) in both stenotic and angiographically normal coronary segments. Coronary flow velocity did not change. Bosentan was well tolerated. CONCLUSIONS: Endogenous endothelin exerts a vasoconstrictor tone in epicardial coronary arteries of patients with coronary artery disease, as evidenced by the vasodilation exerted by the combined ETA/ETB endothelin-receptor antagonist bosentan under acute conditions. Bosentan can safely be given to these patients. Hence, further long-term studies are necessary to determine the therapeutic potential of endothelin-receptor antagonists in patients with coronary artery disease.
Antihypertensive Agents↗
Adoptive immunotherapy of feline leukemia virus infection using autologous lymph node lymphocytes.
Adoptive immunotherapy using autologous cells expanded ex vivo from lymph nodes was examined in cats infected with the retrovirus feline leukemia virus (FeLV). Cells were obtained from popliteal lymph nodes from 18 FeLV-antigen-positive cats without complications; a mean of 6.2 x 10(7) cells were obtained. Lymph node cells were cultured with 600 IU/ml interleukin-2 (IL-2) for 7 days. Cells expanded 0.8- to 11-fold (mean, 2.7; median, 2.4); were 80% +/- 8.0% CD3+, 29% +/- 8.1% CD4+, and 41% +/- 7.0% CD8+, and exhibited cytolytic activity against FeLV-transformed FL74 cells. Sixteen cats received a single intravenous infusion of 0.13 to 3.9 x 10(8) cells. Cell infusion was well tolerated; fever developed approximately 1 hour postinfusion. Clinical activity, antiviral activity, or both was observed in 10 cats. Nine cats had clinical responses with improvement in weight, activity, appearance, or a combination of these that began 2 to 4 weeks after cell infusion and that lasted for up to 13 or more months. FeLV antigen became undetectable in 4 cats. These results indicate that adoptive immunotherapy using autologous lymph node cells, activated and expanded ex vivo in short-term cultures with low concentrations of IL-2, can modulate the course of a retroviral infection.
Animals↗
[Is arteriosclerosis an infectious disease?].
There are three findings suggesting the inflammatory and immunogenic nature of the atherosclerosis: Firstly the colocalisation of macrophages/monocytes and T-lymphocytes in all phases of the atherosclerosis, starting with intimal damages and developing into the end stage of atheromatous plaques, secondly the production of cytokines and thirdly the expression of MHC II antigens. The persisting chlamydia pneumoniae bacteria infection, which has been repeatedly detected in the intima, sustains this inflammatory process. Endothelial dysfunction and an expression of adhesion molecules, which might have been triggered by the chlamydial infection, could lead to atherosclerotic lesions according to the "response to injury" theory. The chlamydiae specific findings can well be integrated into this concept: Two of three classical Koch postulates are nearly fulfilled. There is additional direct and indirect evidence--particularly the first positive results of oral antibiotic therapy after acute myocardial infarction--suggesting a causative role. The unfavourable changes in the lipid profile, which might be brought about by the infection, may also contribute. Repeated chlamydial reinfections trigger the immune system through the cellular memory of T-lymphocytes sustaining the intramural inflammatory process. This leads to an activation of metalloproteinases with a fissuring on the plaques and finally to thrombosis. If this suggested link is confirmed, the latent chlamydia infections could be another treatable risk factor apart from the classical cardiovascular risk factors.
Acute-Phase Reaction↗
Pathogenesis of atherosclerosis: a possible relation to infection.
Atherosclerosis is the main underlying cause of coronary heart disease, which in turn is the most common cause of death in the industrialized world. An acute event in coronary heart disease is typically precipitated by thrombosis occurring at the site of atherosclerotic plaque disruption. Atherosclerotic plaques consist of a fibrous cap overlying a lipid-rich core. Many cell types are involved in their formation, including platelets, endothelial cells, activated monocytes, macrophages derived from monocytes and smooth muscle cells. The currently accepted hypothesis is that atherosclerosis develops as a response to injury and that it is primarily a chronic inflammatory condition. The endothelium plays an important role in regulating vascular blood flow and it is now apparent that endothelial dysfunction is an important contributor to the pathogenesis of atherosclerosis. There is growing evidence that infection may be a risk factor for atherosclerosis and myocardial infarction. Numerous studies have reported associations between human coronary heart disease (CHD) and bacterial and viral infections. At present, interest is focused on the potential aetiological role of C. pneumoniae which has been repeatedly identified, using various diagnostic techniques, in atherosclerotic lesions. There is also increasing seroepidemiological evidence of the association between C. pneumoniae and CHD. The role of this organism in atherosclerosis may be analogous to that of chronic C. trachomatis infection in trachoma.
Animals↗