Felodipine-induced dilatation of epicardial coronary arteries. A randomized, double-blind study

Dilatation of large coronary arteries is of potential value in the treatment of angina pectoris. In this double-blind study, the acute effect of felodipine or placebo on coronary artery dilatation was studied in patients with severe angina pectoris with the aid of coronary arteriography. There were two parallel groups, one with 9 patients who received felodipine, the other with 12 patients who received placebo. Measurements of vessel diameters were performed at a proximal position of the affected artery, at the site of the stenosis, and distal to the lesion. The mean plasma felodipine concentration was 17+/-6 nmol/l. The systolic blood pressure was reduced from 156+/-15 to 145+/-13 mm Hg after felodipine (p less than 0.05), but was unaffected by placebo. The heart rate and arterial catecholamine levels were basically unchanged in both groups of patients. The proximal arterial segment was dilated 7% after felodipine (p = 0.05), the stenosis area 9% (N.S.) and the distal part of the vessel 7% (p less than 0.05). There were no changes in coronary diameters in the placebo group. In conclusion, felodipine dilates large coronary arteries, and this mode of action may be valuable in the treatment of patients with coronary artery disease, especially in cases where coronary spasm is a prominent feature.     

In Vitro Work Load and Rat Heart Metabolism

The isolated working rat heart preparation was used to study the effects of well defined work loads on heart protein synthesis. The rate of protein synthesis was evaluated by measuring the incorporation rate of phenylalanine-³H into whole heart protein. Increased pressure load (afterload) accelerated the protein synthesis. A stimulatory effect was demonstrated with glucose or palmitate as substrate and with 1 or 5 times the normal rat plasma levels of all amino acids in the perfusion medium. The protein synthesis of both control and overloaded hearts was significantly accelerated with palmitate as substrate or with high levels of all amino acids. The work load effect could, thus, be obtained under conditions optimal for heart protein synthesis in vitro. In contrast to the stimulatory effect of in-creased afterload the rate of protein synthesis was not changed when the left atrial filling pressure (preload) was increased, although the external heart work was raised several times. End systolic volume was markedly increased in pressure overloaded hearts compared to hearts perfused under control conditions or with increased preload. It is concluded that an increase in contractile tension during systole and/or an increase in the end systolic volume was a necessary requirement for the acceleration of protein synthesis.     

In Vitro Work Load and Rat Heart Metabolism: II. Effect on amino acid transport

In vitro pressure overload was found to accelerate protein synthesis in the isolated working rat heart (Hjalmarson and Isaksson 1972 a). Since membrane transport of amino acids is considered to be one rate-limiting step in protein synthesis, the amino acid transport in the isolated rat heart was investigated using the non-utilizable amino acids α-aminoisobutyric acid (AIB) and 1-aminocyclopentane carboxylic acid (cycloleucine). Increased pressure load (afterload) accelerated amino acid uptake after a perfusion period of 15 ruin, and a 50—100% increase in the intracellular to extracellular distribution ratio of the amino acids was seen after 60 min of perfusion. This accelerated uptake was not inhibited by cycloheximide, suggesting that the work load effect was not dependent upon a continuous synthesis of proteins. The accumulation rate continued to be stimulated for some time after normalization of the work load and coronary flow, indicating that the work load effect was not directly linked to coronary flow. Increased preload did not stimulate amino acid uptake. Hearts from hypophysectomized rats showed a decreased concentrative uptake but the amino acid uptake was still accelerated by pressure overload. It is suggested that an increased uptake of amino acids could be of physiological significance in relation to the increased protein synthesis under these conditions.     

Characterization of anti-peptide antibodies directed against an extracellular immunogenic epitope on the human alpha 1-adrenergic receptor.

Lesions of the common inflammatory skin disease psoriasis are characterized by epidermal hyperproliferation, leucocyte adhesion molecule expression and leucocyte infiltration. The local release of proinflammatory cytokines, such as TNF-alpha, may play an important role in the induction of these events. We have, therefore, analysed aqueous extracts of lesional and uninvolved (clinically normal) stratum corneum for the presence of TNF-alpha immunoreactivity and biological activity. TNF-alpha immunoreactivity and bioactivity were consistently higher in lesional compared with uninvolved samples. By using an anti-TNF-alpha neutralizing antibody it was demonstrated that the biological activity measured was due to the presence of TNF-alpha alone. Concentrations of soluble TNF receptors (p55 and p75) were also higher in lesional stratum corneum extracts, with the p55 form predominating. The plasma of psoriatic patients was also found to contain elevated concentrations of soluble p55 compared with normal controls. These results confirm the presence of immunoreactive TNF-alpha and, for the first time, conclusively demonstrate TNF-alpha biological activity and quantifiable concentrations of soluble TNF receptors (p55 and p75) in lesional psoriatic samples. TNF-alpha recovery from stratum corneum probably reflects synthesis in deeper, viable layers, where it is likely to exert its biological effects. Local and systemic release of soluble TNF receptors, in particular p55, may serve to regulate the effects of TNF-alpha in psoriasis.     

Antigenic analysis of the second extra-cellular loop of the human beta-adrenergic receptors.

Polyclonal antibodies were raised in rabbits by immunization with free peptides corresponding to positions 197-222 of the human beta 1-adrenergic receptor (beta 1 peptide) and the corresponding sequence (172-197) of the human beta 2-adrenergic receptor (beta 2 peptide). While the beta 2 peptide yielded antibodies that cross-reacted with the beta 1 peptide, the antibodies against the beta 1 peptide did not cross-react with the beta 2 sequence. Cross-reactivity of the anti-beta 2 peptide antibodies and the selectivity of the anti-beta 1 peptide antibodies were also revealed in the recognition by immunoblots of the beta 1- and beta 2-adrenergic receptors of different species or of the receptor gene products expressed in a bacterial vector. These antibodies could be used immunohistochemically to visualize the beta-adrenergic receptors on rabbit heart. The anti-beta 2 peptide antibodies did not show any functional effect on the beta-adrenergic receptors; the anti-beta 1 peptide antibodies were able to displace agonist affinity to higher values. Recognition of truncated peptides by the anti-beta 1 and anti-beta 2 peptide antibodies suggested that the cross-reaction of the anti-beta 2 peptide antibodies was due to the recognition of a common epitope on the C-terminal part of the peptides. The anti-beta 1 peptide antibodies recognized the N-terminal part of the peptide better than the C-terminal part. These results suggest that the second extracellular loop postulated in the structure of the human beta-adrenergic receptor contains the T and B cell epitopes necessary for induction of an immune response. The selectivity and the functional properties of the antibodies raised against that loop in the beta 1 adrenergic receptor could have relevance in induction of auto antibodies in certain cardiomyopathic conditions.     

In Vitro Work Load and Rat Heart Metabolism: III. Effect on ribosomal aggregation

In two preceding papers increased pressure load (afterload) was found to accelerate whole heart protein synthesis and amino acid transport in the perfused working rat heart (Hjalmarson and Isaksson 1972, Ahren et at. 1972). To further analyse this effect, sucrose gradient analysis of the postmitochondrial supernatant was performed to evaluate reactions involved in the ribosome cycle. When hearts were perfused in vitro under control conditions with buffer containing normal plasma levels of amino acids and with glucose as substrate, levels of polysomes decreased and levels of ribosomal subunits increased. These findings together with a decreased rate of protein synthesis indicated that a block in initiation of peptide chains had developed during perfusion. Perfusion of hearts with increased afterload increased the levels of polysomes and decreased the levels of ribosomal subunits and accelerated protein synthesis. The effects were obtained both when glucose and palmitate were used as substrate. Insulin further increased the levels of polysomes in pressure overloaded hearts and the ribosome profiles attained by overload in presence of insulin were identical to those obtained from unperfused hearts. Increased levels of polysomes and decreased levels of ribosomal subunits together with an increase in protein synthesis suggested that pressure overload stimulated reactions involved in the initiation of polypeptide chains. It is concluded that increased pressure load increases levels of initiation factors or changes the activity of enzymes regulating initiation processes in the ribosome cycle.     

Ten year mortality in relation to original size of myocardial infarct: results from the Gothenburg metoprolol study.

OBJECTIVE--To describe the relation between the extent of a myocardial infarct, measured according to maximum serum enzyme activity of lactate dehydrogenase, and mortality at 10 years. PATIENTS--In 759 patients with acute myocardial infarction in whom serum activity of heat stable lactate dehydrogenase had been determined every 12 hours for 108 hours after randomisation in an early intervention trial with metoprolol. MAIN OUTCOME MEASURE--Mortality at 10 years in relation to quartile of maximum serum lactate dehydrogenase activity and history of cardiovascular disease. RESULTS--Among all patients mortality at 10 years was 39% in the lowest quartile, 51% in the second quartile, 50% in the third, and 59% in the fourth (p < 0.001 for relation between infarct size and 10 year mortality). Among patients without a history of myocardial infarction, angina pectoris, diabetes mellitus, or hypertension the mortality in each quartile was 29%, 32%, 41%, and 56%, respectively (p < 0.001 for relation between infarct size and 10 year mortality). Among patients with any of these risk indicators the association between the estimated infarct size and mortality at 10 years was weak (p < 0.05). CONCLUSION--Estimated size of a myocardial infarct and mortality over 10 years seem to be related but mainly in patients without a history of cardiovascular disease.     

Spectrum of chronic lung disease in a population of newborns with extremely low gestational age

Aims: To determine how the ability to oxygenate the blood develops after birth in infants of extremely low gestational age (ELGANs) and to find risk factors for chronic lung disease. Method: A prospective, population‐based, cohort study was undertaken in one tertiary‐care centre. The alveolar–arterial oxygen pressure difference (AaDO₂) was monitored. Results: Of 41 survivors, 21 had a period of normal lung function in the first week of life, after which oxygenation deteriorated. Low gestational age and low Apgar score at 5 min were found to be strong and independent predictors of AaDO₂ in the first month of life. Mechanical ventilation did not appear as a risk factor. Lung function at 36 weeks of gestation and duration of oxygen treatment could be better predicted by the severity of lung disease in the first month than by gestational age at birth. Conclusions: Difficulty in oxygenation was a general observation in ELGANs and not only a particular subset. Gestational age and Apgar score were independent predictors of the degree of difficulty over the first month of life. As oxygenation failure often developed after a few days, the process may be possible to treat or prevent once the pathogenesis is known.     

Long-term follow-up of health-related quality of life in patients with suspected acute myocardial infarction when the diagnosis was not confirmed

This study describes the outcome in terms of health-related quality of life (QL) five years after onset of symptoms in 397 patients with an initial suspicion of acute myocardial infarction (MI) but in whom the diagnosis was not confirmed. The patients were approached by means of a postal inquiry that comprised two questionnaires. The most pronounced impairment in health-related QL was expressed as decreased energy, whereas social life was the least affected area. The overall QL was very similar to that in patients who had a confirmed MI. Subsets of patients with impaired QL were those given the diagnosis of angina pectoris or possible infarction.