Comparison of the antihypertensive effects of carvedilol and metoprolol on resting and exercise blood pressure

The present study was conducted to assess the efficacy and safety of carvedilol 50 mg as compared to metoprolol 200 mg at rest and during and after a standardized bicycle ergometric exercise test. Carvedilol is a novel non-selective -blocker without intrinsic sympathomimetic activity possessing vasodilatory properties primarily due to an ₁-antagonism in the same dose range. Both drugs were effective in reducing systolic and diastolic blood pressure at rest and during and after exercise. The reduction of diastolic blood pressure was much stronger under carvedilol treatment than under metoprolol treatment at all measurement points. Carvedilol was even effective in the treatment of patients whose blood pressure was unsatisfactorily controlled by metoprolol. This shows the importance of the vasodilation component of carvedilol. No serious adverse events were observed. Carvedilol therefore promises very well as a powerful and safe drug for the treatment of essential arterial hypertension.     

Pharmacological profile of β-adrenoceptor blockers with vasodilating properties, especially carvedilol — rationale for clinical use

The rationale for the combined use of -adrenoceptor antagonists and vasodilators is to improve the efficacy of the antihypertensive therapy and to reduce the incidence of side effects. If suitable coagents are selected and used at appropriate doses, the disadvantages of each separate component (compromised blood flow to individual organs, increase in total peripheral resistance, unfavorable lipid profile for -blockers; stimulation of counter-regulatory mechanisms, retention of water and electrolytes for vasodilators) can be balanced. In addition, the favorable effects of each (reduction in cardiovascular morbidity and mortality for -blockers, and favorable hemodynamic profile for vasodilators) may be used to advantage. Such a treatment rationale can be accomplished by a free combination or by using a dual-acting drug. From the practical point of view, the latter may be preferable. The basic requirement for such a drug is that the two effects are evoked in the same dose range. Carvedilol is a dual-acting drug designed to produce -blockade and vasodilatation in the same dose range. The vasodilatation is mediated predominantly by specific ₁-adrenoceptor blockade; at markedly higher concentrations additional vasodilating actions can be observed. These effects resemble those of Ca²⁺ -antagonistic properties. However, they do not contribute to the acute blood-pressure-lowering activity, but may be responsible for the increased blood flow to some organs. At -blocking doses, carvedilol reduces the total peripheral resistance, and blood flow to the kidneys is preserved. Cardioprotection has been demonstrated in a variety of experimental investigations     

Effect of adrenoreceptor stimulation on spontaneous lymphocyte adhesion in vitro

Laboratory of Clinical Radioimmunology, All-Union Oncologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR N. N. Trapeznikov.) Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 107, No. 1, pp. 54–56, January, 1989.     

Statin treatment and a disease-specific pattern of β-amyloid peptides in Alzheimer’s disease

According to the amyloid cascade hypothesis, sporadic Alzheimers disease (AD) is caused by the production and aggregation of -amyloid (A), and the production of A has recently been linked to the metabolism of cholesterol. We have previously published clinical studies where the effect of statin treatment on A production has been investigated. No effect on A was found, which is in disagreement with cell and animal studies. In the present study we investigated the effect of statin treatment on a disease-specific pattern consisting of a C-terminally-truncated quintet of A peptides. Nineteen patients with AD were treated with simvastatin for 12 months and the quintet of A peptides were analysed in cerebrospinal fluid before and after treatment. Also included was a group of 15 untreated patients with AD. We found that the A peptide pattern at baseline was in agreement with earlier findings; however, we did not find any change in the A peptide pattern after statin treatment. We suggest that clinical studies with extended treatment periods are performed where higher dosages of statins are used. We also believe that the pleiotropic effects of statins should be investigated further in order to elucidate the connection between Alzheimers disease and statin treatment.     

Effect of repeated acupuncture on nociception and on β-endorphin levels in the rat hypothalamus and midbrain

Laboratory of Experimental and Clinical Biochemistry, Central Research Institute of Refler Therapy, Ministry of Health of the USSR, Moscow. (Presented by Academician of the Academy on Medical Sciences of the USSR G. N. Kryzhanovskii.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 107, No. 1, pp. 59–61, January, 1989.     

Synoviocytes in chronic synovitis in situ and cytokine stimulated synovial cells in vitro neo-express α1, α3 and α5 chains of β1 integrins

The expression of the 1 integrins was examined immunohistochemically in synoviocytes from normal synovial membrane and from chronic synovitis of different aetiology and intensity. Normal synoviocytes were 61-positive but lacked 1 through 5. In mild inflammation type A synoviocytes neo-expressed 1, 3, and 5 chains. In severe inflammation both type A and B synoviocytes expressed 3, 4, 5, and 6 chains. The effects of inflammatory cytokines, as single agents or in combination, on the 1 integrin expression in cultured normal synoviocytes was determined by immunocytochemistry and flow cytometry. The 1 chain, while absent in unstimulated synoviocytes, was induced by interleukin-1 (IL-1), tumour necrosis factor- (TNF-), and interferon- (INF-). This effect was enhanced by combining IL-1 and TNF-. Expression of the 3 chain was up-regulated by IL-1 and, more intensely, by IFN-. Transforming growth factor (TGF-) inhibited the up-regulating effect of IL-1 and antagonized the effect of IFN- on 3 chain expression. Expression of the 5 chain was up-regulated significantly by co-stimulation through IL-1 together with TGF- or TNF-. Thus, the 1 integrin profile of cytokine activated synoviocytes in vitro resembled that of synoviocytes in synovitis in situ. These data suggest that IL-1, TNF-, IFN-, and TGF- are likely to be among the effectors regulating 1 integrin expression in synoviocytes in vivo.     

Glucocorticoids modulate TGF-beta production

TGF- is thought to play a central role in pulmonary fibrosis inducing fibroblast differentiation and extracellular matrix synthesis. In human lung fibroblasts, it is still unclear how various TGB- isoforms affect TGF- production and whether glucocorticoids, commonly used agents to treat fibrotic lung disease, modulate these processes. To this end, human fetal lung fibroblasts (HFL-1) were cultured with various concentrations of glucocorticoids (budesonide, dexamethasone or hydrocortisone) with and without TFG-1, -2, and -3. TGF- mRNA was assessed by real time RT-PCR. Smad 2, 3, and 4 and AP-1 complex (c-fos and c-Jun) cellular localization were evaluated by immunostaining. TGF-2 and -3 stimulated TGF-1 production significantly (p < 0.01 relative to control). TGF-1 stimulated TGF-2 production (p < 0.01 relative to control). TGF-3 was undetectable. Glucocorticoids significantly inhibited TGF-1 and -2 production and reduced expression of the upregulated TGF-1 and -2 mRNA induced by exogenous TGF-1, -2 or -3 (p < 0.01 for each) but had no effect on Smads. Although c-jun-related nuclear staining was not intensified in TGF--stimulated cells, it was reduced by glucocorticoids. Thus, TGF- isoforms may stimulate production of various TGF- isoforms in the lung. Glucocorticoids then may block TGF- production by modulating mRNA levels and c-Jun.     

Exercise induces pentane production and neutrophil activation in humans. Effect of propranolol

Summary The effect of -adrenergic receptor blockade on exercise-induced lipid peroxidation in man has been examined by measuring the production of pentane in expired air. For this purpose, five healthy male subjects were subjected to dynamic exercise of graded intensity on a cycle ergometer (10 min at 45%, 5 min at 60% and 75% maximal oxygen uptake 1 h after ingestion of either a placebo or 40-mg propranolol. At rest, mean pentane concentration ([pent]) with placebo was 4.13 pmol · l^–1, SD 2.14. After exercise, this value significantly increased by 310% (17.1 pmol · l^–1, SD 7.73, P < 0.01). Oral administration of 40-mg propranolol significantly lowered the mean resting [pent] to 1.75 pmol · l^–1, SD 0.77, P < 0.05. After exercise, the increase of [pent] was much smaller (240%) and was less significant (P < 0.2) than with the placebo. The mechanism of this inhibitory effect of propranolol remains to be elucidated. However, as indicated by the measurement of plasma myeloperoxidase concentration, it can be concluded that the antioxidant property of propranolol cannot be attributed to the inhibition of neutrophil activation, a possible source of free radicals during exercise.     

Acid carboxypeptidase deficiency in galactosialidosis

Carboxypeptidase activity with an optimal pH at 5.7 was found to be deficient in cultured lymphoblastoid cells and skin fibroblasts from 16 galactosialidosis patients of Japanese origin. The amounts of residual enzyme activities did not correlate with clinical phenotypes (early infantile and juvenile/adult). Four parents of the patients from different families showed enzyme activities at an intermediate level between the patients and normal controls. It was concluded that this enzyme deficiency is closely connected to the genetic defect of protective protein. Further characterization with various protease inhibitors indicated that the enzyme deficient in galactosialidosis cells is a serine carboxypeptidase with histidine and cysteine residues at or near the active site.     

Naloxone in treatment of circulatory shock resistant to conventional therapy

Summary The effect of naloxone (4.4–5.9 mg i.v.) was evaluated in 10 patients with circulatory shock (sepsis,n=7; intoxication,n=1; cardiogenic shock,n=2) not responding to full conventional therapy. In addition, we measured plasma ACTH and immunoreactive -endorphin before and 60 min after administration of naloxone and compared the results with hormone concentrations in 10 intensive care patients without shock. Only in two patient with septic shock a transient increase (duration 15 min and 60 min, respectively) of systolic blood pressure was observed, while naloxone was ineffective in the remaining eight patients. No adverse effects of naloxone were found. Plasma ACTH and immunoreactive -endorphin concentrations in patients with shock were not different from those in controls (ACTH, 79±28 vs 120±60 pg/ml; immunoreactive -endorphin, 952±262 vs 1,070±378 pg/ml).Our findings suggest that naloxone in a single dose of 4.4–5.9 mg i.v. does not improve the management of circulatory shock unresponsive to conventional treatment. -endorphin seems to play no major role in the hypotension of shock.Abbreviations ACTH Adrenocorticotrophic hormone - HD intermittent hemodialysis - HF heart rate - ir immunoreactive - RR_syst systolic blood pressure Supported by Landesamt für Forschung, NRW     

The effect of beta-adrenergic blockade on leg blood flow with repeated maximal contractions of the triceps surae muscle group in man

Summary The effect of -adrenergic blockade on torque output and leg blood flow was examined in seven healthy young men during repeated maximal isometric voluntary contractions of the triceps surae muscle group. Exercise was performed in either a bent- or straight-leg position during each of four drug treatments: placebo, propranolol, metoprolol, oxprenolol. Contractions were sustained for 5 s with 5 s relaxation for a total of 10 min followed by a 10-min recovery. Leg blood flow was measured during the 5 s relaxation separating contractions using strain gauge plethysmography. Torque output decreased during the 10-min contractions with no differences between the four drug treatments. Leg blood flow was lower with -blockade during the initial stages of exercise and recovery in the bent-leg position but no differences were observed after 3 min exercise or recovery. Leg blood flow in the straight-leg position was not different between any of the four drug treatments, but it was significantly less than in bent-leg exercise. The lower blood flows during the initial stages of exercise in the -blocked conditions probably reflect a slowing of the central cardiovascular response because of ₁-receptor blockade of the heart rather than on the ₂-receptors effects on peripheral vacular resistance. It is concluded that local vasodilator substances released from the working muscle may play a more important role than ₂-receptor stimulation of smooth muscle in skeletal muscle resistance vessels in regulating local muscle blood flow during maximal exercise of the triceps surae muscle group.     

Free radical lipid peroxidation inhibits enzymatic conversion of beta-carotene into vitamin A

Free radical oxidation of arachidonic acid with soybean lipoxygenase was accompanied by inhibition of retinal synthesis from -carotene catalyzed by enzyme preparation from rabbit intestinal mucosa. Lipoxygenase inhibitor salicylhydroxamic acid and antioxidants suppressing free radical reactions (ethyl gallate, -tocopherol, astaxanthine, and quercetin) promoted conversion of -carotene into retinal catalyzed by -carotene-15,15'-dioxygenase. These results indicate that lipoperoxides and/or products of their homolysis attenuate enzymatic conversion of -carotene and confirm the important role of natural antioxidants in the maintenance of stable vitamin A content in mammals.     

Parallel minisequencing followed by multiplex matrix-assisted laser desorption/ionization mass spectrometry assay for β-thalassemia mutations

-thalassemia is a common monogenic disease caused by mutations in the human -globin gene (HBB), many of which are differentially represented in human subpopulations stratified by ethnicity. This study describes an efficient and highly accurate method to screen for the eight most-common disease-causing mutations, covering more than 98% of HBB alleles in the Taiwanese population, using parallel minisequencing and multiplex assay by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The MALDI-TOF MS was optimized for sensitivity and resolution by mass tuning the PinPoint assay for eight HBB SNPs. Because of the close proximity and clustering of mutations in HBB, primer extension reactions were conducted in parallel. Efficient sequential desalting using POROS and cationic exchange chromatography allowed for an unambiguous multiplex genotyping by MALDI-TOF MS. The embellishing SNP assay allowed for highly accurate identification of the eight most-common -thalassemia mutations in homozygous normal control, carrier, and eight heterozygous carrier mixtures, as well as the diagnosis of a high-risk family. The results demonstrated a flexible strategy for rapid identification of clustering SNPs in HBB with a high degree of accuracy and specificity. It can be adapted easily for high-throughput diagnosis of various hereditary diseases or to establish family heritage databases for clinical applications.     

Role of adrenergic structures in functional control over the cerebral circulation

An investigation of the cerebral circulation by the thermoelectric method showed that stimulation of the cervical sympathetic nerve leads to considerable changes in the blood supply to the brain. The changes in blood flow are biphasic in character: An initial small increase is followed by a decrease below the original level. Pharmacological analysis with and adrenoblockers showed that the constrictor response of the cerebral vessels is due to excitation of -adrenergic structures and the dilator response to excitation of -adrenergic structures. A possible mechanism of these changes is postulated.Laboratory of Pathophysiology of Respiration, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. M. Chernukh). Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 1, pp. 9–12, January, 1976.