Amiodarone in pregnancy.
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Abnormalities, Drug-Induced↗
Biomedical subjects
C J Foster
Publications and source records attributed to C J Foster.
Mercaptoacyl amino acid inhibitors of atriopeptidase. 1. Structure-activity relationship studies of methionine and S-alkylcysteine derivatives.
A broad series of N-(3-mercaptoacyl) amino acid derivatives was evaluated for their ability to inhibit atriopeptidase (neutral endopeptidase, EC 3.4.24.11) in vitro and in vivo. Structural parameters studied were (i) the substituent on the 2-position of the 3-mercaptopropionyl moiety, (ii) the amino acid component, (iii) the S-terminal derivative, and (iv) the C-terminal derivative. Optimum activity was observed for derivatives of methionine and S-alkylcysteines. N-[3-Mercapto-2(S)-[(2-methylphenyl)methyl]-1-oxopropyl]-L-methionine was identified as a highly effective inhibitor of atriopeptidase meriting evaluation as a potential cardiovascular therapeutic agent.
Amino Acid Sequence↗
Anaesthesia for the patient with neonatal adrenoleukodystrophy.
The authors present and discuss the care of a nine-month-old with neonatal adrenoleukodystrophy who required general anaesthesia for gastrointestinal endoscopy. Neonatal adrenoleukodystrophy is an inherited disorder of peroxisomal enzymes. Anaesthetic care may be affected by the presence of hypotonia, liver function abnormalities, gastroesophageal reflux, and impaired adrenocortical function. Preoperative sedation is contraindicated because of the risk of precipitating airway obstruction due to pre-existing hypotonia. Anaesthetic induction and tracheal intubation should be performed to minimize the risk for aspiration of gastric contents. The choice of muscle relaxant should take into account the pre-existing hypotonia as well as the possibility of hyperkalaemia in response to succinylcholine. Anaesthetic agents known to decrease the seizure threshold should be avoided in patients with a seizure disorder. In addition, anaesthetic agents that rely on the liver for metabolism should be used with caution in patients with cirrhosis. When time permits, these patients should be screened for adrenocortical insufficiency before surgery, and perioperative steroid coverage is advisable when preoperative testing of adrenocortical function is not feasible. While these patients eventually die after progressive deterioration, full recovery from the effects of anaesthesia and surgery can be achieved with attention to neurological, metabolic, and physical problems.
Adrenoleukodystrophy↗
Modulation of circulating endothelin levels in hypertension and endotoxemia in rats.
We have developed separate radioimmunoassays to measure circulating ET-1 and ET-3 levels in normotensive and different hypertensive rat models so that the role of endothelin in the regulation of vasomotor function can be studied. We also assessed the stimulatory effects of endotoxin on plasma and liver lymph ET-1 and ET-3 levels. The circulating ET-1 levels in normotensive rats, SHRs, and DOCA-salt hypertensive rats were 2.3 +/- 0.5, 2.1 +/- 0.4, and 2.1 +/- 0.9 pg/ml, respectively. Similarly, the plasma ET-3 levels in normotensive and different hypertensive rats were similar, ranging from 19.7 +/- 1.5 to 24.7 +/- 2.2 pg/ml. The data indicate that steady-state circulating levels of endothelins are a poor correlate of the hypertensive state. Endotoxin (30 mg/kg i.v. over 15 min) reduced blood pressure significantly and augmented plasma ET-1 levels by sevenfold (29.1 +/- 3.7 vs. 4.1 +/- 0.6 pg/ml in the vehicle group; p less than 0.05) and ET-3 levels by twofold (47.7 +/- 7.0 vs. 22.7 +/- 4.0 pg/ml in the vehicle group; p less than 0.05). Human TNF-alpha (30 ng/kg/min x 30 min), a putative mediator of endotoxin shock, enhanced plasma ET-1 (18.3 +/- 1.0 vs. 2.7 +/- 0.4 pg/ml in the vehicle group; p less than 0.05) by sevenfold and ET-3 levels by twofold (45.7 +/- 2.0 vs. 27.1 +/- 4.0 pg/ml in the vehicle group; p less than 0.05) without affecting blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Influence of C-ANF receptor and neutral endopeptidase on pharmacokinetics of ANF in rats.
The role of C-atrial natriuretic factor (ANF) receptors and neutral endopeptidase (NEP) in the pharmacokinetics and hydrolysis of 125I-labeled ANF was evaluated in rats by using C-ANF and SCH 39370 to block the nonenzymatic and enzymatic pathways, respectively. After a bolus injection of 125I-ANF, the resulting area under the plasma concentration curve (AUC) with C-ANF treatment was seven times the control value with regard to trichloroacetic acid-precipitable (TCA-ppt) radioactivity (intact ANF). SCH 39370 tended to increase AUC, but the changes were not significant. Nevertheless, SCH 39370 suppressed the appearance of TCA-soluble radioactivity (hydrolytic products), indicating that in vivo inhibition of ANF degradation had occurred. SCH 39370 plus C-ANF produced a 15-fold increase in AUC for TCA-ppt radioactivity and a reduction in plasma TCA-soluble radioactivity. High-performance liquid chromatography (HPLC) analysis confirmed that combination treatment increased intact ANF and reduced hydrolytic products in the plasma. SCH 39370 reduced clearance (C) without altering volume of distribution in steady state (Vss) and half-life (t1/2). C-ANF decreased both C and Vss leading to a fourfold increase in t1/2, which was further prolonged by SCH 39370 (7.5 times control). Bilateral nephrectomy caused a proportionally similar decrease in Vss and C without changing t1/2, suggesting significant extrarenal metabolism of ANF. SCH 39370 systemically inhibits ANF hydrolysis; the resulting increase in ANF, however, is masked by the great capacity of ANF clearance receptors but can be revealed with excess C-ANF, suggesting that the plasma ANF concentrations are determined by the interplay of the C-ANF receptor and NEP systems.
Animals↗
Potent peptide inhibitors of smooth muscle myosin light chain kinase: mapping of the pseudosubstrate and calmodulin binding domains.
Smooth muscle myosin light chain kinase (MLCK) is activated by calcium-calmodulin and, in turn, phosphorylates and activates the smooth muscle actomyosin ATPase, resulting in muscle contraction. The amino acid sequence of the regulatory domain of MLCK is known, and it contains a region that binds calmodulin and also bears a strong homology to the phosphorylation site in the substrate. Thus, it has been called the "pseudosubstrate". It has been proposed that calmodulin activates MLCK by binding to and reversing the autoinhibitory function of the pseudosubstrate. Synthetic peptides based on this sequence inhibit MLCK both by binding to calmodulin and by competing with the substrate at the active site. In the work reported here, we have synthesized a large number of peptides from the regulatory region of MLCK (MLCK 480-516). The region was systematically analyzed by dividing it into fragments of two to six amino acids, each containing one or more basic residues, in order to map in detail the calmodulin binding site and the autoinhibitory region. It was observed that both calmodulin binding and autoinhibition are mediated by several different fragments of the regulatory sequence. Two nonoverlapping peptides, MLCK 480-493 and MLCK 494-504, are similar in potency in inhibiting the enzyme (IC50's of 2 and 6 microM, respectively). Larger fragments, combining multiple inhibitory regions, are more potent inhibitors. For example, MLCK 480-504 is extremely potent, with an IC50 of 13 nM. The calmodulin binding site and active site directed inhibitory regions overlap, but are not identical. Residues 505-512 are important only for calmodulin binding.
Amino Acid Sequence↗
Rapid receptor-mediated catabolism of 125I-atrial natriuretic factor by vascular endothelial cells.
The binding, internalization and degradation of 200 pM monoiodinated human atrial natriuretic factor-(99-126) (125I-hANF) by cultured bovine aortic endothelial cells (BAECs) were studied at 37 degrees C. 125I-hANF was rapidly cleared from the extracellular medium (t1/2 approximately 10 min), whereas preincubation of the cells in the presence of 20 mM-NH4Cl or 0.2 mM-chloroquine resulted in a significant inhibition of this process. The BAECs rapidly produce three major degradation products of 125I-hANF, namely [125I]iodotyrosine 126 (125I-Y), Arg125-[125I]iodotyrosine126 (125I-RY) and Phe124-Arg125-[125I]iodotyrosine126(125I-FRY), which were detected in the extracellular medium. NH4Cl and chloroquine acted to inhibit the generation of 125I-Y and 125I-RY, but not that of 125I-FRY. Furthermore, excess unlabelled hANF (300 nM) completely blocked the rapid production of 125I-Y and 125I-RY in the first 5 min, but only partially (49%) inhibited the generation of 125I-FRY. Thus, in contrast with our previous findings with cultured smooth-muscle cells [Johnson, Arik & Foster (1989) J. Biol. Chem. 264, 11637-11642], BAECs bind, internalize and rapidly degrade 125I-hANF, resulting in the release of 125I-Y and 125I-RY into the extracellular medium. Similarly to smooth-muscle cells, the BAECs generate 125I-FRY from 125I-hANF via an extracellular proteolytic event. The rapidity of the receptor-mediated process and its sensitivity to NH4Cl and chloroquine suggest that the 125I-hANF is proteolytically processed in the endosomes of BAECs and that its receptors cycle between the cell surface and intracellular stores.
Ammonium Chloride↗
Partial characterization of a metalloendopeptidase activity produced by cultured endothelial cells that removes the COOH-terminal tripeptide from 125I-atrial natriuretic factor.
The presence of the COOH-terminal region of human atrial natriuretic factor-(99-126) (hANF) is necessary for the full expression of its biological activity. Here, we report on the partial characterization of a proteolytic activity in the conditioned medium from cultured bovine aortic endothelial cells that cleaves the Ser123-Phe124 bond of 125I-hANF generating the COOH-terminal tripeptide. The concentrated conditioned medium was fractionated by gel filtration high performance liquid chromatography and fractions were assayed for the ability to generate the COOH-terminal tripeptide from 125I-hANF. This analysis indicated that the protein responsible for this activity had an approximate molecular weight of 200,000 daltons. Of 16 protease inhibitors tested, only 1,10 phenanthroline, EDTA, EGTA and N-ethylmaleimide significantly inhibited the endopeptidase activity. Thus, we conclude that cultured bovine aortic endothelial cells produce a potentially novel phosphoramidon-insensitive metalloendopeptidase that removes the COOH-terminal tripeptide from 125I-hANF.
Animals↗
Metabolism of 125I-atrial natriuretic factor by vascular smooth muscle cells. Evidence for a peptidase that specifically removes the COOH-terminal tripeptide.
The addition of 200 pM monoiodinated human atrial natriuretic factor-(99-126) (125I-hANF) to cultured bovine aortic smooth muscle cells at 37 degrees C resulted in a rapid clearance from the medium (t1/2 approximately 7.5 min). Within 5 min, [125I]iodotyrosine126 (125I-Y), Arg125-[125I]iodotyrosine126 (125I-RY) and Phe124-Arg-[125]iodotyrosine126 (125I-FRY) appeared in the medium. The identities of these degradation products were confirmed by 1) retention time on high performance liquid chromatography (HPLC) relative to standards, 2) products generated by digestion with aminopeptidase M, and 3) the absence of the Met110. Preincubation of the cells with ammonium chloride or chloroquine resulted in a significant increase in the intracellular accumulation of radiolabel, indicative of endocytosis and rapid delivery of 125I-hANF to an acidic intracellular compartment (endosome and/or lysosome). Neither ammonium chloride, chloroquine, nor excess unlabeled hANF blocked the rapid appearance in the medium of 125I-RY or 125I-FRY. Bestatin inhibited the generation of 125I-RY, with a concomitant increase in 125I-FRY, suggesting that the 125I-RY is produced by aminopeptidase action on 125I-FRY. The endopeptidase 24.11 (enkephalinase) inhibitor, SCH 39370, did not inhibit the formation of 125I-FRY. These results provide evidence of a peptidase capable of specifically removing the COOH-terminal tripeptide from 125I-hANF. The COOH-terminal tripeptide, Phe124-Arg-Tyr126, was also isolated from cell digests of hANF by HPLC and its identity confirmed by amino acid analysis. Since it is generally believed that the COOH-terminal tripeptide is critical to many of atrial natriuretic factor-(99-126)'s bioactivities, this enzyme may be involved in the inactivation of atrial natriuretic factor-(99-126) in target tissues.
Amino Acids↗
Evaluation of myocardial thallium tomography in patients with chest pain.
Thirty-seven patients with chest pain have been studied by exercise thallium tomography and coronary arteriography to assess the accuracy of thallium tomography in the identification of patients with coronary artery disease and to evaluate whether knowledge of clinical data improves this accuracy. Thallium tomography was also used to identify which coronary arteries were stenosed. Thallium tomography when compared with coronary arteriography has a sensitivity of 97%, a specificity of 75%, and an overall accuracy of 92% for the detection of coronary artery disease. When clinical information was made available, these results improved to a sensitivity of 100%, a specificity of 75%, and an overall accuracy of 95%. In the identification of which coronary arteries were stenosed, thallium tomography had a sensitivity of 85%, a specificity of 89%, and an overall accuracy of 86%. These results show that exercise thallium tomography can be an accurate non-invasive screening test in patients with chest pain thought to be angina.
Angina Pectoris↗
Multidisciplinary assessment of applicants for sheltered housing.
Three hundred applicants for sheltered housing underwent multidisciplinary geriatric assessment for suitability as a part of a joint assessment scheme with Local Authority Housing and Social Services Departments. Ninety-four applicants sought a move for health reasons while 206 applicants quoted housing and social reasons and denied medical problems. The assessment showed no significant disability necessitating sheltered housing facilities for 41 (44%) of the 94 people applying on health grounds. Severe disability made sheltered housing placement inappropriate for ten (10%) of the applicants with health problems. In the 206 applicants denying medical problems, the assessment revealed significant unreported physical illness in 46 (22%) and undiagnosed dementia in a further 26 (13%). Allocation of sheltered housing was affected in 99 (33%) of the 300 applicants. Eighty-two applicants were considered unsuitable, whereas 17 applicants originally thought to be unsuitable were recommended for sheltered housing. Multidisciplinary geriatric assessment is of considerable benefit in determining suitability of applicants for sheltered housing and will help in achieving better placement by avoiding inappropriate moves.
Aged↗
SCH 39370, a neutral metalloendopeptidase inhibitor, potentiates biological responses to atrial natriuretic factor and lowers blood pressure in desoxycorticosterone acetate-sodium hypertensive rats.
SCH 39370 (N-[N-[1-(S)-carboxyl-3-phenylpropyl]-(S)-phenyl-alanyl]-(S)-isoserin e) is a potent and specific inhibitor of neutral metalloendopeptidase (NEP) from rabbit kidney (IC50 = 11.2 +/- 1.9 nM) and is devoid of angiotensin-converting enzyme inhibitory activity at 1 microM. We evaluated the effect of NEP inhibition with SCH 39370 on the inactivation of atrial natriuretic factor (ANF) and on cardiovascular function in rats. SCH 39370 effectively prevented in vitro degradation of ANF (99-126) by a purified rabbit kidney NEP. SCH 39370 (30 mg/kg s.c) significantly delayed the disappearance of immunoreactive (ir) ANF from plasma in rats after an i.v. infusion of ANF (1 microgram/kg/min for 30 min): the plasma ir ANF level at 15 min postinfusion was 1.5 +/- 0.3 ng/ml vs. 0.3 +/- 0.04 ng/ml in the control. SCH 39370 also delayed the disappearance of ir ANF after infusion of the peptide (0.1 microgram/kg/min for 30 min) which increased plasma levels to those observed during volume expansion. This effect was accentuated markedly in rats with bilateral nephrectomy. The hypotensive response to injection of ANF (30 micrograms/kg i.v.) in spontaneously hypertensive rats (-38 +/- 6 mm Hg vs. -13 +/- 2 mm Hg in the control) and the diuretic and natriuretic responses to ANF in normal rats were potentiated by SCH 39370 (30 mg/kg s.c.), respectively. The results suggest that NEP can play a role in ANF disposition in vivo and that potentiation of the biological activities of high doses of ANF by SCH 39370 may be consequent to its inhibitory effect on ANF degradation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cross-sectional echocardiographic demonstration of biventricular thrombus.
Nine months following extensive myocardial infarction, a 60-year-old man presented with intermittent right heart failure. Cross-sectional echocardiography demonstrated biventricular thrombi, the right ventricular thrombus being very close to the tricuspid valve and possibly interfering with its function. Post-mortem examination confirmed the echocardiographic findings.
Echocardiography↗
Percutaneous removal of ventricular pacemaker electrodes using a Dormier basket.
Four permanent ventricular endocardial pacemaker electrodes which could not be removed via their insertion site have been retrieved via the femoral vein using a Dormier basket. Apart from short-lived ventricular arrhythmias no complications occurred in any case. Where removal of an otherwise unaccessible ventricular pacemaker electrode is considered essential the use of a Dormier basket percutaneously appears to be effective and more acceptable than surgical removal.
Adult↗
Amiodarone in pregnancy. Case report and review of the literature.
A case of the use of amiodarone in pregnancy is reported and the literature on this subject reviewed. The data available to date show: there is no risk of teratogenic effects, the QT interval is prolonged during infancy (no associated arrhythmias noted), infant bradycardia occurs and should be monitored and thyroid function can be affected and should be monitored at birth. If fetal electrocardiographic monitoring is performed before and during labour and after birth, and thyroid function is assessed, then, to date, there does not appear to be any significant contraindication to the use of amiodarone during pregnancy. In view of the potential side effects, however, the use of amiodarone should be restricted to arrhythmias which are life-threatening or not controlled by conventional therapy.
Adult↗
Detection of coronary artery bypass graft patency as assessed by magnetic resonance imaging.
In a study of 22 patients with 60 coronary artery bypass grafts, magnetic resonance imaging (MRI) correctly assessed graft patency or occlusion in 90% of cases when compared with selective coronary graft angiography and computed tomography. It is concluded that MRI can detect a normally functioning coronary artery bypass graft and could be used as a non-invasive technique to assess graft patency in patients presenting with post-operative angina.
Adult↗
Digital subtraction angiography of the left ventricle.
Twenty-eight patients have been studied by left ventricular angiography and digital subtraction angiography, using either a peripheral venous injection (16) or a central venous injection (12) of contrast medium. Digital subtraction angiography compared favourably to angiography in the qualitative assessment of left ventricular size and function. Measurement of ejection fraction demonstrated a good correlation (r = 0.83) between digital subtraction angiography and left ventricular angiography. In the assessment of left ventricular segmental wall motion the use of a central venous injection, particularly in those patients with severely impaired ventricular function, proved superior to the use of a peripheral injection.
Coronary Disease↗
A comparison of the incidence of cardiac arrhythmias produced by two intravenous contrast media in coronary artery disease.
The incidence of cardiac arrhythmias in patients with coronary artery disease receiving intravenous contrast medium has been studied and comparison made between a conventional ionic medium (meglumine iothalamate) and a low osmolar medium (sodium meglumine ioxaglate). Occasional ventricular and atrial ectopics were frequently observed both before and during administration of the contrast medium and were regarded as insignificant. Significant arrhythmias occurred in five cases. Three of these however, were in the presence of acute myocardial ischaemia or recent infarction. There was no significant difference in the incidence of arrhythmias between the two contrast media. These results show that, in the absence of acute myocardial ischaemia, the incidence of life threatening arrhythmias in patients with proven coronary artery disease receiving intravenous contrast media is much lower than previously suspected.
Arrhythmias, Cardiac↗