Effects of Cytokines, Without and with Helicobacter pylori Components, on Mucus Secretion by Cultured Gastric Epithelial Cells

Cytokines are suspected to play a crucial rolein the pathogenesis of Helicobacter pylori associatedgastric diseases. Hence, considerable attention has beenpaid to the actions of cytokines on gastric cells. We examined the effects of cytokines onmucus secretion by gastric epithelial cells, without orwith H. pylori components. Mucus secretion by culturedgastric epithelial cells was assessed as secretion of [³H]glucosamine-prelabeledhigh-molecularweight glycoproteins. Interleukin(IL)-1 and IL-6 significantly stimulated mucussecretion, but other cytokines such as IL-7, IL-8,IL-10, interferon (IFN)- and tumor necrosis factor (TNF)- had noeffect. H. pylori lysate caused a decrease in both basaland stimulated secretion of mucus. In addition,IFN- significantly potentiated the lysate-induced reduction of basal and stimulated secretion.Cell viability was not affected by any of treatments.These results indicate that IL-1 and IL-6stimulate mucus secretion, while IFN- potentiatesH. pylori-decreased secretion by gastric epithelialcells.     

KT-362 related effects on intracellular calcium release and associated clinical potential: Arrhythmias,myocardial ischemia,and hypertension

Summary The following discourse addresses the pharmacologic profile of KT-362, its clinical potential as an antiarrhythmic agent with associated hypotensive effects, as well as its additional related potential in myocardial ischemia and related sequellae, and the specific cellular actions that may be responsible for these potential therapeutic effects. Although these include specific actions on both sodium and calcium entry, the focus is on the relevance of independent effects on calcium release. KT-362 relaxes arterial smooth muscle, concomitantly reducing the total peripheral resistance and mean arterial blood pressure. Vascular relaxing actions are attributed primarily to inhibitory effects on calcium release and secondarily to inhibitory effects on calcium entry via both potential-gated and receptor-linked channels. The intracellular calcium antagonist properties are correlated with a decrease in the production of the major second messenger, inositol 1,4,5-trisphosphate, which is responsible for calcium release and a concurrent ryanodine-like action that further decreases the amount of calcium released. Ventricular arrhythmias associated with coronary occlusion, cardiac glycosides, catecholamines, and chloroform are prevented by KT-362. General antiarrhythmic properties are associated with a use-dependent block of the fast sodium channel, primarily in the activated state, with ancillary effects on the slow calcium current. More selective effects on arrhythmias specifically associated with delayed afterdepolarizations are attributed to effects on calcium release. In myocardial ischemia, KT-362 primarily reduces myocardial oxygen consumption rather than increases oxygen supply. The former is accomplished by depressing myocardial contractility and reducing afterload, while the latter is associated with a limited effect on coronary collateral blood flow. The negative inotropic effect is fundamentally related to its effects on calcium release, with additional contributions from its effects on calcium entry. Thus, the one intrinsic property of KT-362 that consistently emerges as significant and relevant in cardiovascular disease is the capacity to diminish calcium release.     

Effects of long-term monotherapy with metoprolol CR/XL on the progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure

We examined the effects of long-term monotherapy with the beta-blocker, metoprolol controlled release/extended release (CR/XL), on the progression of LV dysfunction as well as on global and cellular remodeling in dogs with heart failure (HF). Chronic HF was produced by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Dogs were randomized to 3 months oral monotherapy with metoprolol CR/XL (100 mg once daily, n = 7) or no therapy at all (control, n = 7). In control dogs, EF decreased from 38 ± 1% to 31 ± 2% (p = 0.002), and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased (37 ± 2 vs 45 ± 2 ml, p = 0.001; 59 ± 3 vs 65 ± 3 ml, p = 0.001; respectively) during the 3 month follow-up period. In dogs treated with metoprolol CR/XL, EF increased after 3 months from 36 ± 1% to 43 ± 1% (p = 0.001), and ESV decreased (42 ± 2 vs 38 ± 2 ml, p = 0.003), whereas EDV remained unchanged. Compared to controls, treatment with metoprolol CR/XL showed 46% reduction in replacement fibrosis, 54% reduction in interstitial fibrosis and 20% reduction in myocyte cross-sectional area, a measure of myocyte hypertrophy. These findings indicate that metoprolol CR/XL improves LV function and attenuates progressive global and cellular LV remodeling in dogs with HF. The benefits are fully attributable to -blockade alone as no other adjunctive therapy was used.     

Calcium channel antagonists part II: Use and comparative properties of the three prototypical calcium antagonists in ischemic heart disease,including recommendations based on an analysis of 41 trials

Summary An analysis of 41 trials of angina of all varieties confirms that calcium antagonists are an important advance and are now established therapy for these syndromes. In effort angina, verapamil in a dose of 360–480 mg daily is better than propranolol in standard doses. Although nifedipine is highly effective against vasospastic angina, its use in threatened myocardial infarction or severe unstable angina is not supported by recent studies, unless combined with a betablocker. Diltiazem has recently been tested with apparent benefit in non-Q-wave myocardial infarction. Otherwise, these calcium antagonist agents all seem to have approximate equipotency in clinical ischemic syndromes including effort and vasospastic angina. Subjective side effects seem most troublesome in the case of nifedipine. All three calcium antagonists, especially nifedipine, have been successfully combined with beta-blocker therapy, yet occasional additive negative inotropic or chronotropic or dromotropic interactions may occur when verapamil or diltiazem is added to beta-blockade, and occasionally the direct negative inotropic potential of nifedipine may become evident. The choice between the calcium antagonists is determined not only by the clinical picture but also by the anticipated side effects in a given patient and by the overall cardiovascular status. In patients with supraventricular tachycardias or sinus tachycardia, verapamil or diltiazem is preferred, whereas in patients with a resting bradycardia or borderline heart failure nifedipine is likely to be chosen.This report was refereed by four external reviewers whose opinions were transmitted to the San Francisco office of this journal for editorial decision.     

Increased glomerular permeability to albumin induced by exercise in diabetic subjects

Summary The urinary excretion of albumin was measured in insulin-dependent diabetics under ordinary conditions of life and in response to exercise. Possible mechanisms of exercise induced albuminuria in diabetics were also investigated. Under ordinary conditions of life the insulin-treated diabetics, as a group, had a higher mean urinary albumin excretion than normal controls; however, half of the diabetics had albumin excretion rates within the control range. A given exercise load (600 kpm/min for 20 min) produced an exaggerated albumin excretion in diabetics, particularly evident in the post-exercise period. The elevated urinary albumin excretion was due to an increased transglomerular passage of albumin, not to reduced tubular reabsorption. The increase was not associated with differences in blood pressure or urine flow between controls and diabetics. This exercise test has proved to be a suitable provocation test to unmask abnormalities in the glomerular handling of albumin that might not be recognisable at rest.Presented in part at the 12th Annual Meeting of the European Association for the Study of Diabetes, Helsinki, 1976     

Effects of the calcium antagonist gallopamil on the increase of myocardial extracellular potassium activity during LAD occlusion in dogs

Summary It has been implied that the increase of myocardial extracellular potassium activity ([K⁺]_c) in the early stage of acute myocardial ischemia is a major cause of the increased likelihood of arrhythmia after acute coronary artery occlusion. There is also experimental evidence that some calcium antagonists reduce the occurrence of ischemia-induced early ventricular arrhythmias. In order to clarify the antiarrhythmic effect of gallopamil during the early phase of acute LAD occlusion, the influence of this calcium antagonist on the time course of [K⁺]_c during acute ischemia was measured in open-chest anesthetized dogs using a K⁺-selective surface multielectrode. The regional myocardial blood flow was determined with 9 m radioactive tracer microspheres.After application of gallopamil (bolus, 25 g/kg and infusion 2.5 g/kg·min for 30 min) the maximal and mean rate of rise of [K⁺]_c as well as the plateau of [K⁺]_c reached during ischemia were significantly diminished compared with the control occlusions. 90 min after gallopamil, the rate of rise of [K⁺]_c as well as the plateau of [K⁺]_c reached were still significantly reduced, but 180 min after the gallopamil application, no significant differences between the time course of [K⁺]_c and that of the two control occlusions could be found. Gallopamil significantly elevated, myocardial blood flow in the non-ischemic area, but did not influence blood flow in the ischemic region.While collateral perfusion remains unchanged, the slowed and reduced increase of myocardial [K⁺]_c during acute coronary artery occlusion may be an important component of the antiarrhythmic effect of gallopamil during early ischemia.Preliminary results were presented at the International Symposium on Calcium entry blockers and tissue protection, Rome, 1984, at the 59th Meeting of the Deutsche Physiologische Gesellschaft, Dortmund, 1984, at the 50th meeting of the Deutsche Gesellschaft für Herz- und Kreislaufforschung, Mannheim, 1984, and at the IXth European Congress of Cardiology, Düsseldorf, 1984.     

The action of β-adrenergic blocking and stimulating agents on insulin secretion. Characterization of the type of β receptor

Summary As a result of our experiments designed to studyin vivo in the anaesthetized dog, the role of the beta-adrenergic receptors involved in insulin secretion, we have found: 1. that isoprenaline (global stimulator of the beta-adrenergic receptors) provoked a considerable increase in the secretion of insulin. — 2. that propranolol (blocking agent of the beta-adrenergic receptors) partially and temporarily inhibited the secretion of insulin. — 3. that isoprenaline, after blockage of the beta-adrenergic receptors by propranolol, provoked a strong, long-lasting inhibition of insulin secretion. — 4. that practolol (selectively ₁ blocking agent) did not counteract the stimulating effects of isoprenaline ( ₁ and ₂ stimulating agent). This suggests that the beta-adrenergic receptor involved in insulin secretion is of the type ₂. — 5. that salbutamol (selective ₂ stimulating agent) provoked an abundant secretion of insulin, an effect which was found to be blocked by propranolol. This last fact confirms that the beta-adrenergic receptor involved in the insulin secretion provoked by isoprenaline is of type ₂. — All these findings underline the importance of the ₂ adrenergic receptors of the beta cell of the islets of Langerhans, in the process of insulin secretion.

---

Die Wirkung von blockierenden und stimulierenden, -adrenergischen Substanzen auf die Insulinsekretion. Charakterisierung des -Rezeptortyps

Zusammenfassung Wir fanden in unseren Experimenten, die dazu angelegt waren, am anästhesierten Hundin vivo die Rolle der-adrenergischen Rezeptoren für die Insulinsekretion zu erforschen: 1. daß Isoprenaline (welches die-adrenergischen Rezeptoren stimuliert), eine starke Erhöhung der Insulinsekretion hervorruft. — 2. daß Propranolol (ein Blocker der-adrenergischen Rezeptoren) die Insulinsekretion hemmt. — 3. daß Isoprenaline nach der Blockierung der-adrenergischen Rezeptoren durch Propranolol die Insulinsekretion stark, und dauerhaft hemmt. — 4. daß Practolol (welches mehr die Rezeptoren ₁ hemmt) nicht die Stimulation des Isoprenaline aufhebt, welches sowohl auf die ₁ und ₂ Rezeptoren wirkt. Dieses deutet darauf hin, daß die-adrenergischen Rezeptoren, die bei der Insulinsekretion mitwirken, dem Typ ₂ angehören. — 5. daß Salbutamol (welches mehr die ₂-Rezeptoren anregt) eine übermäßige Insulinsekretion bewirkt, die wiederum durch Propranolol zu hemmen ist. Diese Tatsache bestätigt, daß die-adrenerischen Rezeptoren, welche an der durch Isoprenaline hervorgerufenen Insulinsekretion beteiligt sind, dem Typ ₂ angehören. — Alle diese Tatsachen unterstreichen die Bedeutung der ₂ adrenergischen Rezeptoren der-Zelle der Langerhansschen Inseln für den Prozess der Insulinsekretion.

---

Action sur l'insulino-sécrétion des substances bloquant et stimulant les récepteurs adrénergiques. Caractérisation du type de récepteur

Résumé Il résulte de nos expériences destinées à étudierin vivo, chez le chien anesthésié, le rôle des récepteurs-adrénergiques impliqués dans l'insulino-sécrétion: 1. que l'isoprénaline (stimulant des récepteurs bêta-adrénergiques) provoque une augmentation importante de la sécrétion d'insuline. — 2. que le propranolol (bloquant des récepteurs bêta-adrénergiques) freine temporairement la sécrétion d'insuline. — 3. quel'isoprénaline, après blocage des récepteurs bêta-adrénergiques par le propranolol, inhibe l'insulino-sécrétion d'une manière puissante et durable. — 4. que le practolol (bloquant plus sélectif des récepteurs ₁) ne s'oppose pas aux effets stimulants de l'isoprénaline qui agit sur les récepteurs ₁ et ₂, ce qui suggère que le récepteur bêta-adrénergique impliqué dans l'insulinosécrétion est de type ₂. — 5. que le salbutamol (stimulant plus sélectif des récepteurs ₂) provoque une abondante sécrétion d'insuline, effet qui se trouve bloqué par le propranolol. Ce fait confirme que le récepteur adrénergique impliqué dans l'insulino-sécrétion provoquée par l'isoprénaline est de type ₂. -Tous ces faits soulignent l'importance des récepteurs adrénergiques ₂ de la cellule bêta des îlots de Langerhans dans le processus d'insulinosécrétion.

     

Comparative studies on hepatic DNA alkylation in rats by N-nitrosomethylethylamine and N-nitrosodimethylamine plus N-nitrosodiethylamine

Summary The purpose of this study was to determine whether quantitative differences in hepatic DNA methylation or ethylation are sufficient to explain differences in the carcinogenicity of N-nitrosomethylethylamine (NMEA), N-nitrosodimethylamine (NDMA), and N-nitrosodiethylamine (NDEA). Methylation and ethylation of hepatic DNA were determined in male Fischer 344 rats following a single IP dose of NMEA, NDMA, NDEA or an equimolar mixture of NDMA plus NDEA. The total nitrosamine dose ranged from 0.05 to 0.25 mmol/kg. After 5 h survival, hepatic DNA was extracted by adsorption onto hydroxyapatite. Acid hydrolysates were analyzed by cation exchange HPLC with fluorescence detection. DNA methylation by NMEA (170 mol O⁶-methylguanine/mol guanine at 0.1 mmol/kg) was comparable to that observed in animals given an equimolar mixture of NDMA plus NDEA, indicating that NMEA is one-half as effective a methylating agent as NDMA. In contrast, the amount of ethylation by NMEA (5.9 mol O⁶-methylguanine/mol guanine at 0.1 mmol/kg) was approximately 4 times less than that observed in animals treated with an equimolar mixture of NDMA and NDEA. The presence of NDEA had little effect on DNA methylation by NDMA, suggesting that neither synergism nor competition occurs in the simultaneous activation of these two nitrosamines. The role of -hydroxylation of NMEA as a metabolic pathway that reduces the extent of DNA ethylation is discussed.Presented at the SEK workshop DNA Adducts and Chemical Carcinogenesis, Tübingen, February 28–March 1, 1986     

Changes in the hydroxyproline,hexosamine and sialic acid of the diabetic human and β, β′-iminodipropionitrile-treated rat retinal vascular systems

Summary The retinal vasculature has been isolated from nondiabetic and diabetic post mortem human eyes by controlled trypsin digestion. Chemical analysis demonstrated increases in the hydroxyproline and hexosamine contents in diabetes. There was no general increase in the sialic acid content. These results have been related to histological preparations of sectors of the same retinas. Administration of, -iminodipropionitrile to rats caused a retinopathy characterised by endothelial cell proliferation, increased PAS-positivity and microaneurysms. Chemical analysis of retinal vascular systems from, -iminodipropionitrile-treated rats revealed increases in hydroxyproline, hexosamine and sialic acid contents.

---

Änderungen des Gehaltes an Hydroxyprolin, Hexosamin und N- azetyl- Neuraminsäure in den Netzhautgefäen von menschlichen Diabetikern und mit , Iminodiproprionitril behandelten Ratten

Zusammenfassung Die Netzhautgefäße wurden post-mortal aus diabetischen und nichtdiabetischen Augen mit Hilfe einer kontrollierten Trypsin-Behandlung gewonnen. Bei der chemischen Analyse fand sich ein Anstieg des Hydroxyprolin- und Hexosamingehaltes in den diabetischen Augen. Der N-azetyl-Neuraminsäuregehalt war im allgemeinen nicht erhöht. Diese Resultate wurden in Beziehung gebracht zu den histologischen Befunden, die an den einzelnen Sektoren der gleichen Retina erhoben wurden. Verabreichung von, -Iminodiproprionitril an Ratten bewirkte eine Retinopathie unter den Zeichen einer Wucherung der Endothelzellen, verstärkter PAS-Anfärbbarkeit und Mikroaneurysmen. Die chemische Analyse der Netzhautgefäße von mit, -Iminodiproprionitril behandelten Ratten zeigte einen erhöhten Gehalt an Hydroxyprolin, Hexosamin und N-azetyl-Neuraminsäure.

---

Variations de l'hydroxyproline, de l'hexosamine et de l'acide sialique dans les systèmes vasculaires rétiniens de l'homme diabétique et du rat traité par le , -iminodipropionitrile

Résumé Le système vasculaire rétinien a été isolé, par digestion trypsique contrôlée, après la mort, à partir d'yeux humains de non-diabétiques et de diabétiques. L'analyse chimique a révélé l'augmentation du contenu en hydroxyproline et en hexosamine, dans le diabète. Il n'y avait pas d'augmentation générale du contenu en acide sialique. Ces résultats ont été rapprochés des préparations histologiques de portions des mêmes rétines. L'administration de, -iminodipropionitrile à des rats provoquait une rétinopathie caractérisée par une prolifération des cellules endothéliales, une PAS-positivité augmentée et des microanévrismes. L'analyse chimique des systèmes vasculaires rétiniens des rats traités par le,-iminodipropionitrile, a révélé l'augmentation du contenu en hydroxyproline, en hexosamine et en acide sialique.

     

Intracellular sodium activity and Bretschneider's cardioplegia: Continuous measurement by ionselective microelectrodes at initial equilibration

Summary Intracellular sodium activity (a_Na ⁱ), intracellular pH (pH_i) and membrane potential were directly and continuously measured in sheep cardiac Purkinje fibers using neutral carrier liquid membrane ionselective microelectrodes. Changing the superfusing medium from normal Tyrode's solution to the cardioplegic solution HTK according to Bretschneider (6) a depolarization from –73.7±7.2 mV to –55.0±9.5 mV (n=25), a decrease of a_Na ⁱ from 9.1±1.9 mM to 4.0±1.4 mM (n=25) and an intracellular acidification from pH_i 7.18±0.06 to pH_i 7.01±0.06 (n=11, x±S.D.) occurred at 35°C. The decrease of intracellular sodium activity was not effected by replacement of K, Mg, or histidine by mannitol in the cardioplegic solution. Addition of 4 mM Ca somewhat enhanced a_Na ⁱ decline. Inhibition of the sodium pump with the cardiac steroid dihydroouabain (10^–4 M) lowered the effect of HTK on intracellular sodium by approximately 35% (n=5). Sodium decline was also sensitive to equilibration temperature, giving a Q₁₀ of 1.54 for the initial decrease velocity (temperature range 20 to 35°C), which is less than that found by other investigators for pure sodium pump activity. It is suggested that although the electrochemical sodium gradient remains inward throughout, sodium may leave myocardial cells on induction of Bretschneider's cardioplegia because of a reduction of inward fluxes by simultaneously increasing sodium pump activity, thus increasing Na efflux. Na/Ca exchange is assumed to be of minor importance and the Na/H exchange may be involved. With respect to the clinical application of the low Na and nominally Ca-free cardioplegic solution HTK lowering of intracellular sodium activity is interpreted as a factor minimizing the risk of a calcium paradox on reperfusion with Ca at serum levels, as well as a possible mechanism preventing early development of cellular edema.Supported by the DFG, SFB 330 Organprotektion.Part of this work has already been published in abstract form (Pflüg. Arch. 1987: 408, R11) and comprises unpublished results of E. Krohn's thesis.The technical assistance of Mrs. U. Markmann and Mrs. E. Neumeyer is gratefully acknowledged.     

Heart Function Challenged with β-Receptor Agonism or Antagonism in a Heart Failure Model

We have shown that chronic treatment with carteolol, a non-selective -adrenergic receptor antagonist, improved left ventricular (LV) function and survival in an avian model of dilated cardiomyopathy (DCM). The aim of the present study was to compare ex vivo heart function with and without -agonist and antagonist challenge. We investigated whether intracoronary infusion of a -blocker, carteolol or -agonist, isoproterenol decreased contractility. In the DCM group, isoproterenol resulted in a significantly greater increase in heart rate (71% vs. 28% compared to control hearts). To investigate the mechanism for the increase in heart rate, we exposed spontaneously beating neonatal cardiomyocytes to serum immunoglobulin (IgG) isolated from DCM animals. Serum IgG resulted in a significant increase in spontaneous beating rate in neonatal rat cardiomyocytes that was blocked by pre-treatment with a -blocker. Carteolol challenge did not significantly change heart rate but did significantly increase LV peak pressure in DCM hearts (62%) while coronary artery flow remained unchanged (2.7 ± 0.1 vs 2.7 ± 0.5 ml/min/g). These results show that 1) -receptor stimulation results in a greater tachycardic response in DCM animals, and 2) carteolo challenge improves myocardial contractility in hearts from DCM animals independent of heart rate or changes in coronary artery flow.     

Overproduction of inhibitory hematopoietic cytokines by lipopolysaccharide-activated peripheral blood mononuclear cells in patients with aplastic anemia

The aim of this study was to measure the level of cytokines produced by peripheral blood mononuclear cells (PBMNC) in patients with aplastic anemia (AA) and to determine their effect on the clonal growth of normal bone marrow (BM) cells. Twenty-one patients with AA and 11 normal controls were enrolled in this study. Medium conditioned by PBMNC of AA patients in the presence of lipopolysaccharide (LPS) was found to be suppressive to the colony growth of normal BM cells. Thus, we further determined the presence in the PBMNC-conditioned medium (CM) of both inhibitory cytokines: macrophage inflammatory protein-1 (MIP-1), tumor necrosis factor- (TNF-), transforming growth factor-2 (TGF-2), and interferon- (IFN-), and stimulatory cytokines: interleukin-3 (IL-3) and stem cell factor (SCF). Spontaneous production of MlP-1 was higher in the AA patients than the normal controls (1887±174 pg/ml vs 1643±93 pg/ml), but the difference was not significant. After LPS stimulation, the production of MIP-1 was markedly increased in the AA patients, and its level was significantly higher than that of the normal controls (2360±149 pg/ml vs 1517±92 pg/ml, p=0.0022). The level of TNF was also higher in the AA patients. However, IFN-, TGF-2, SCF, and IL-3 were not detectable in the PBMNC-CM of either AA patients or normals. The myelopoietic suppressing effect of AA-PBMNC-CM from each AA patient was significantly blocked by pretreatment with anti-TNF-, resulting in a colony-forming enhancement of 174%±12%. A similar effect was noted in six of 11 AA patients by pretreatment with anti-MIP-1. We conclude that TNF and MIP-1 can be overproduced by the PBMNC of some AA patients, which may play a role in the progression of AA.     

TCR1+ large granular lymphocyte proliferation in rheumatoid arthritis

The T-lymphoproliferative syndrome is characterized by a proliferation of large granular lymphocytes (LGL). It is often associated with neutropenia, and in 30% of cases with rheumatoid arthritis (RA). Phenotypic analysis has demonstrated that in most cases of RA with T-proliferative disease, the LGL represent T cells with a clonal rearrangement of the / T cell receptor (TCR2). Here, three patients with / TCR1⁺ LGL proliferation suffering from long-standing arthritis and neutropenia are described. The first patient with RA showed an expansion of a heterogeneous CD2⁺ CD16⁺ CD56^- LGL population, of which 30% coexpressed TCR1 with V1 rearrangement. The second patient with ankylosing spondylitis and RA was suffering from proliferation of TCR1⁺ (V9^-, V1^-), CD2⁺ CD16^- CD56^- LGL with low coexpression of CD8. The third patient with RA was suffering from a proliferation of TCR1⁺ (V1⁺, V9^-) CD4^- CE8^- CD16^- CD56^- lymphocytes. On the basis of these unusual findings, the pathogenetic role of TCR1⁺ T cells in RA is discussed.     

Calcium channel antagonists part II: Use and comparative properties of the three prototypical calcium antagonists in ischemic heart disease,including recommendations based on an analysis of 41 trials

Summary An analysis of 41 trials of angina of all varieties confirms that calcium antagonists are an important advance and are now established therapy for these syndromes. In effort angina, verapamil in a dose of 360–480 mg daily is better than propranolol in standard doses. Although nifedipine is highly effective against vasospastic angina, its use in threatened myocardial infarction is not supported by recent studies, unless combined with a beta-blocker. Diltiazem has recently been tested with apparent benefit in non-Q-wave myocardial infarction. Otherwise, these calcium antagonist agents will all seem to have approximate equipotency in clinical ischemic syndromes including effort and vasospastic angina. Subjective side effects seem most troublesome in the case of nifedipine. All three calcium antagonists, especially nifedipine, have been successfully combined with beta-blocker therapy, yet occasional additive negative inotropic or chronotropic or dromotropic interactions may occur when verapamil or diltiazem is added to beta-blockade, and occasionally the direct negative inotropic potential of nifedipine may may become evident. The choice between the calcium antagonists is determined not only by the clinical picture but also by the anticipated side effects in a given patient and by the overall cardiovascular status. In patients with supraventricular tachycardias or sinus tachycardia, verapamil or diltiazem is preferred, whereas in patients with a resting bradycardia or borderline heart failure nifedipine is likely to be chosen.[This article appeared in Cardiovascular Drugs & Therapy, 1: 461–491, 1988]     

Characteristics of lysosomal phosphomannosyl-enzyme receptors in the rat heart

Summary The receptor system recognizing mannose 6-phosphate groups of lysosomal enzymes has been characterized, e. g. in fibroblasts and liver cells. The purpose of this study was to demonstrate the presence of a phosphomannosyl receptor system in rat heart muscle. The characterization of receptors was accomplished with -N-acetylglucosaminidase (-GA) secreted by rat embryo fibroblasts after ammonium chloride stimulation. The receptor binding of ligand enzymes was saturated by adding increasing concentrations of -GA and the binding increased linearly when the content of membrane protein was increased. The binding of -GA was inhibited by mannose and glucose phosphates, especially mannose 6-phosphate. Mannose itself did not inhibit binding of the enzyme, showing that the binding was not mediated by mannose receptors. Alkaline phosphatase treatment of -GA decreased the binding of ligand enzymes to receptors. Alkaline conditions increased the dissociation of receptorligand complexes, whereas the dissociation was minimal between pH 5.5 and 6.5. The proportion of endogenous -GA activity in membranes probably representing receptor-bound location, varied between 40 and 55% of the total activity in various parts of rat cardiac muscle. The differences in the content of phosphomannosyl receptors, however, were insignificant between various cardiac muscle samples. At the organelle level the highest specific binding capacity, as well as the highest endogenous ß-GA activity, was in the sarcolemmal fraction. These results suggest that phosphomannosyl receptors also function in the endocytosis and transport of lysosomal enzymes in cardiomyocytes, as well as in several other cell types studied.     

Normothermic ischemic cardiac arrest in the isolated working rabbit heart: Effects of dl-nebivolol and atenolol

Summary The effect of pretreatment with selective ₁-adrenoceptor blockers (dl-nebivolol or atenolol) on myocardial mechanical activity, mitochondrial function, morphology, and calcium cytochemistry was studied during normothermic ischemic arrest and reperfusion of isolated working rabbit hearts. The hearts subjected to 25 min of ischemia followed by 30 min of post-ischemic reperfusion showed typical signs of severe myocardial ischemic damage. The ultrastructural changes showed a good relation with the changes in mechanical activity and mitochondrial function. To determine whether these changes could be prevented or reduced by ₁-adrenoceptor blockade, dl-nebivolol or atenolol (0.62 mg/liter) was added to the perfusate 30 min before the induction of ischemia. The results showed that dl-nebivolol exerted a protective effect on recovery of mechanical activity, on mitochondrial function during reperfusion as well as on the ultrastructure as examined at the end of the reperfusion period. On the other hand, atenolol failed to protect the myocardium against ischemia-reperfusion damage in the isolated working rabbit heart.     

β-Adrenoceptor and adenylate cyclase regulation in cardiac myocyte growth

Summary We studied the effect of growth on -adrenergic receptor properties of neonatal rat heart myocytes cultured in serum-free medium with transferrin and insulin. Growth was induced by addition of 1 M (–)-norepinephrine for two days, 200 nM of the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) for two days, or 30 nM T₃ for six days. The K_d values for -receptor binding (¹²⁵I-ICYP) were unaffected by growth. The maximum number of -receptor binding sites calculated as sites/cell was increased 1.47-fold by T₃ (p<.005), but was decreased to 54% of control values by (–)-norepinephrine (p<.005); TPA had no effect on either Kd or B_max values. (–)-Isoproterenol-stimulated adenylate cyclase activity was augmented only in membranes from T₃-treated cells and was reduced by 69% in membranes from (–)-norepinephrine treated cells. TPA had no effect on(–)-isoproterenol-stimulated adenylate cyclase activity. We conclude that the mechanisms controlling -adrenergic receptor number may be distinct from those controlling growth, since receptor number does not correlate with cell enlargement. Furthermore, in (–)-norepinephrine-stimulated growth, which we have shown previously is an ₁-adrenoceptor mediated response, -adrenergic signal transduction is modulated in a directionally opposite fashion.Supported by grants from the Veterans Administration Research Service, American Heart Association California Affiliate, and National Heart, Lung, and Blood Institute Grant HL31113. Dr. Simpson is a Clinical Investigator of the Veterans Administration Research Service.     

Effects of celiprolol vs. nifedipine on serum lipoproteins in patients with mild to moderate hypertension

Summary During a double-blind, randomized study in hypertensive patients, changes in plasma lipid and lipoprotein levels during treatment with celiprolol were compared with those occurring during nifedipine treatment. Fifty-three patients (28 men and 25 women) with mild-to-moderate hypertension, aged 20–64 years, were studied. After a 1-month placebo run-in period, patients were randomly assigned to receive either nifedipine (40 mg daily) or celiprolol (200 mg daily), each time using a double-dummy technique. After 6 weeks, dosages of each drug could be doubled. After 6 weeks, there were no differences in plasma lipids between the two treatment groups. However, the changes after 12 weeks of treatment were different (p<0.05) between the groups, leading to lower levels of plasma esterified cholesterol, low-density lipoprotein (LDL) cholesterol, and apoprotein AI, AII, and B in the celiprolol group. Plasma lecithin cholesterol acyltransferase activity (LCAT) was not modified. The present study showed that celiprolol was at least equivalent to nifedipine in terms of secondary effects on plasma lipids and lipoprotein.     

The inability of isoproterenol or propranolol to alter the lateral dimensions of experimentally induced myocardial infarcts

Summary The relationship between the blood flow pattern immediately following coronary artery occlusion and the resulting infarct 24 hours later was studied in dogs treated with isoproterenol (0.5 g/kg/min for 2 hours) or with propranolol (2mg/kg every 6 hours). The coronary artery of a closed chest dog was perfused via a special cannula with arterial blood. A 2-mm diameter plastic bead was introduced into the perfusate to embolize a coronary branch. One minute after occlusion, radiolabelled microspheres were injected into the perfusate. The dogs were then allowed to recover. 24 hours later the dogs were reanesthetized and their hearts removed. The hearts were sliced into 4 mm thick sections and the microsphere distribution was visualized by autoradiography of the tissue. Superimposition of developed autoradiographs and tracings of the infarct pattern of stained sections allowed direct comparison of the blood flow pattern immediately after occlusion to the eventual pattern of infarction. In all 8 control dogs, all 6 isoproterenol dogs and all 12 propranolol dogs the lateral borders of blood flow and infarction were superimposable indicating no lateral change in infarct size resulting from treatment. In the control group there was a subepicardial region of the ischemic zone which did not infarct (15.2±2.3% of the ischemic zone). Though isoproterenol did not significantly change the size of this zone, propranolol increased it to 35.9±6,5% (p<0.005) indicating vertical but not lateral salvage.Supported by Grant HL-20648 from NIH: HLBI and a Grant-in-aid from the American Heart Association and with funds contributed in part by the Northwest Ohio Chapter, Inc.