Jan Svensson

Thromboxane A2: Effects of airway and vascular smooth muscle

Thromboxane A2, an unstable compound derived from prostaglandin G2, was generated by incubation of arachidonic acid with a suspension of human platelets. The activity of thromboxane A2 relative to that of prostaglandin H2 in causing contractions of a number of smooth muscle organs were as follows: rabbit aorta, 7-20; human umbilical artery, 9-60; and guinea pig trachea, 2-12. Intravenous injection of thromboxane A2 into anaesthetized quinea pigs was followed by a pronounced increase in the tracheal insufflation pressure, potency compared to prostaglandin H2, 31-45.

Haemostatic function in myocardial infarction.

Coagulation factor VIII, von Willebrand factor, antithrombin, fibrinogen, plasminogen activator capacity, and inhibitors of fibrinolysis, including a recently discovered fast inhibitor of tissue plasminogen activator, were measured three to six months after myocardial infarction in 116 male and 32 female patients aged less than 45 and in 136 age and sex matched random controls. Plasma concentrations of fibrinogen and the fast inhibitor of tissue plasminogen activator were raised in male patients (with or without correction for orosomucoid levels, blood group distribution, tobacco and alcohol consumption, and weight/height index) and plasminogen activator capacity was reduced. In female patients the concentrations of factor VIII, von Willebrand factor, the fast inhibitor of tissue plasminogen activator, alpha 2-antiplasmin, and C1 inhibitor were significantly increased. The increase in factor VIII concentrations depended strongly on a persisting inflammatory response. Multivariate analysis indicated that a combination of fibrinogen and tissue plasminogen activator inhibitor concentrations gave the best independent discrimination between male patients and controls. For female patients the best combination was von Willebrand factor and tissue plasminogen activator inhibitor. Male patients with multiple vessel atheromatosis at coronary angiography had higher fibrinogen concentrations than those with atheromatosis of a single vessel. Atheromatosis was defined as sharp-edged, plaque-like, or irregular indentations, often multiple, into the vessel lumen without features suggesting fibromuscular hyperplasia.

Prostaglandin endoperoxides IV. Effects on smooth muscle

Abstract The effect on smooth muscle of the endoperoxides PGG2 and PGH2, which are intermediates in prostaglandin biosynthesis, was studied in different systems in vitro and in vivo . On gastrointestinal smooth muscle (gerbil colon, rat stomach) PGG2 and PGH2 produced contractions comparable to those of PGE2 and PGF2a whereas contractions elicited on vascular (rabbit aorta) and airway (guinea-pig trachea) smooth muscle were considerably greater than those of PGE2 and PGF2a respectively. On intravenous injection into guinea-pigs PGG2 and PGH2 caused a triphasic change in blood pressure and were 8–10 times more effective than PGF2a in producing an increase in tracheal insufflation pressure. When given as aerosols the unstable endoperoxides were less effective than PGF2a. It is concluded that the endoperoxides are potent smooth muscle stimulants and that they are more effective than their degradation products (PGD2, PGE2, PGF2a) in some systems.

Prostaglandin d2 as a potential antithrombotic agent.

Prostaglandin D2 was found to be a potent inhibitor of platelet aggregation. Aggregation of human platelets by ADP, collagen and prostaglandin G2 was inhibited more strongly by PGD2 than by PGE1. Although ADP-induced aggregation of rabbit platelets was inhibited more strongly by PGE1 than by PGD2 the latter prostaglandin gave a more long-lasting inhibitory effect on platelet aggregation following intravenous or oral administration. These results coupled with the finding that PGD2 has less hypotensive effects on the cardiovascular system than PGE1 suggest the possible use of PGD2 as an antithrombotic agent.

HYPOSPADIAS IS RELATED TO BIRTH WEIGHT IN DISCORDANT MONOZYGOTIC TWINS

PURPOSE Hypospadias is a common urogenital malformation in boys. The etiology is unknown but genetic and environmental factors are involved. Because monozygotic twins have the same genetic constitution, we studied disease discordant twin pairs to evaluate environmental risk factors while controlling for genetic effects. MATERIALS AND METHODS We used questionnaires to identify 28 male twins discordant for hypospadias at 4 pediatric surgical clinics in Sweden. Using deoxyribonucleic acid fingerprinting, and histopathological examination of the placenta and fetal membranes 18 twin pairs were diagnosed as monozygotic. RESULTS In 16 of the 18 monozygotic pairs discordant for hypospadias the twin with the lowest birth weight has hypospadias. Mean difference in birth weight was 498 gm. (t = 3.8, p <0.01). CONCLUSIONS Environmental factors associated with low birth weight are involved in the etiology of hypospadias.

Thromboxane A2 and prostaglandin H2: Potent stimulators of the swine coronary artery

Thromboxane A2 was generated by incubation of arachidonic acid with a suspension of human platelets. The filtrate contained 266 +/- 46 ng/ml (n=10) of thromboxane A2 and 25 ng/ml or less of prostaglandin endoperoxides (prostaglandins G2+H2). Thromboxane A2 was 2-10 times more potent than prostaglandin H2 and 9-102 times and 26-308 times more potent than prostaglandins E2 and F2alpha, respectively, in causing contractions of the superfused swine coronary artery.

INR calibration of Owren-type prothrombin time based on the relationship between PT% and INR utilizing normal plasma samples

Prothrombin time (PT) is clinically important and is used to monitor oral anticoagulant therapy. To obtain PT results in international normalized ratio (INR), the current standardization procedure is complex and involves reference reagents. The PT of diluted plasma samples can be determined with a combined thromboplastin (the Owren-type procedure), but not necessarily with a plain thromboplastin (the Quick-type procedure). Owren-type PT procedures can therefore, as an alternative to the INR calibration, be calibrated with diluted normal plasma to give PT results in percent of normal PT activity (PT%). The present study explored if a plasma-based calibration of an Owren-type PT procedure can be used to obtain results in INR. The approach was to establish a relationship between PT% and INR by multi-center analysis of 365 samples from healthy individuals and patients on warfarin treatment. INR values were obtained by manual Quick-type reference procedure and PT% values by various automated Owren-type procedures. A relationship INR = (1/PT% + 0.018)/0.028 was found. A calibration procedure, based on the relationship, was investigated. Calibrators were the median PT of 21 normal plasma at dilutions representing 100%, 50%, 25%, 12.5% and 6.25% of normal PT activity. These were assigned INR values of 1.00, 1.36, 2.07, 3.05 and 6.36. Calibration of various Owren-type assays was repeatedly performed by 5 expert laboratories during 3 consecutive years. The INR values of certain lyophilised or frozen control plasmas were determined. The frozen control plasmas had externally assigned INR values according to WHO guide-lines. Within the laboratory, CV was typically below 3%. No appreciable difference among the results of the different laboratories or the three assay occasions was found. Externally assigned and INR values were essentially identical to those found. These and other results indicated that the calibration procedure was reproducible, precise and accurate. Thus, an Owren-type PT assay can be calibrated with normal plasma samples to give results in INR and the investigated calibration procedure can be proposed for this purpose.

Blood pressure and personality

Abstract Three groups of 18-yr-old male S s were selected from a representative Swedish population according to strict blood-pressure criteria: hypertensives (systotic blood pressure above 146 and diastolic above 90), on two occasions, normotensives (systolic blood pressure between 124 and 131, population mean = 128) and hypotensives (systolic blood pressure between 100 and 106). As a part of a broad multidisciplinary study, personality inventory scales and unpleasantness ratings for various types of situations were administered. The findings for the hypertensives indicated lower assertiveness and higher anxiety-proneness, whereas the hypotensives, compared to normotensives, showed a more impulsive, acting-out personality pattern. The hypertensive group was subdivided according to digital vasoconstriction criteria. The non-vasoconstricted subgroup showed a more impulsive and ‘anger-out’ personality pattern, whereas the pattern obtained in the vasoconstricted subgroup was more similar to the classical hypertensive personality, characterized by anxiety and unexpressed anger.

A global assay of haemostasis which uses recombinant tissue factor and tissue-type plasminogen activator to measure the rate of fibrin formation and fibrin degradation in plasma

The global assay of Overall Haemostasis Potential we previously described has been refined. The coagulation cascade in platelet-poor plasma is triggered by adding a minimal dose of recombinant tissue factor together with purified phospholipids and calcium; fibrinolysis is initiated by adding recombinant tissue type-plasminogen activator in a concentration similar to what can be obtained during thrombolysis. Numerical differentials of optical densities reflecting rates of fibrin formation and degradation are calculated by a new software, and the Coagulation Profile (Cp) and the Fibrinolysis Profile (Fp) are determined. The combined effect of these counteractive systems is expressed as a ratio of Cp to Fp, called the Overall Haemostasis Index. Commercially available coagulant-deficient patient plasma samples and plasma with various amounts of added PAI-1 are examined; changes of fibrin turbidity demonstrate that this assay can determine Cp and Fp in a physiologically relevant way. Increased Cp and decreased Fp in prothrombotic patients, as well as expected effects of heparin or a thrombin inhibitor on Cp and Fp, suggest that our method can detect hypercoagulability and assist in monitoring antithrombotic treatment. Ongoing studies will show whether this simple assay can be of value in clinical routine.

Pyridine nucleotides in glucose metabolism and diabetes: a review.

Nicotinamide adenine dinucleotide (NAD) and its derivatives NADH, NADP and NADPH have regulatory functions in the generation of triose phosphates and pyruvate from glucose. In many studies of the influence of the diabetic state on relationships between pyridine nucleotide and glucose metabolism, the focus has been on the sorbitol pathway. Less attention has been paid to other aspects of the role of pyridine nucleotides in pyruvate formation from glucose, in particular the effects of the NAD precursors nicotinamide and nicotinic acid on glucose metabolism. This paper reviews current knowledge of the involvement of pyridine nucleotides and their precursors in glucose catabolism in the normal and diabetic state.