Biomedical subjects

D Gustafsson

Publications and source records attributed to D Gustafsson.

At least 37 records · Page 2Linked to original sources

PubMed1997

The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis.

The relation between the antithrombotic effect in vivo, and the inhibition constant (Ki) and the association rate constant (k(on)) in vitro was investigated for eight different thrombin inhibitors. The carotid arteries of anaesthetized rats were exposed to FeCl3 for 1 h, and the thrombus size was determined from the amount of incorporated 125I-fibrinogen. The thrombin inhibitors were given intravenously, and complete concentration- and/or dose-response curves were constructed. Despite a 50,000-fold difference between the Ki-values comparable plasma concentrations of hirudin and melagatran were needed (0.14 and 0.12 micromol l(-1), respectively) to obtain a 50% antithrombotic effect (IC50) in vivo. In contrast, there was a comparable in vitro (Ki-value) and in vivo (IC50) potency ratio for melagatran and inogatran, respectively. These results can be explained by the concentration of thrombin in the thrombus and improved inhibition by the low-molecular-weight compounds. For all eight thrombin inhibitors tested, there was an inverse relationship between k(on)-values in vitro and the slope of the dose response curves in vivo. Inhibitors with k(on)-values of < 1 x 10(7) M(-1) s(-1) gave steep dose response curves with a Hill coefficient > 1. The association time for inhibition of thrombin for slow-binding inhibitors will be too long to give effective antithrombotic effects at low plasma concentrations, but at increasing concentrations the association time will decrease, resulting in a steeper dose-response curve and thereby a more narrow therapeutic interval.

Amino Acid Chloromethyl Ketones↗

PubMed1996

New model for in vivo studies of pharmacological interventions with endogenous fibrinolysis: effects of thrombin inhibitors.

A new rat model for investigation of the interactions of thrombin inhibitors with endogenous fibrinolysis in vivo is described. The method utilizes the thrombin-like snake enzyme batroxobin, which mainly cleaves the fibrinopeptide A from fibrinogen and activates factor XIII only to a slight degree. Compared to thrombin-formed fibrin, batroxobin-formed fibrin is more readily lysed by plasmin, since it only cross-links fibrin to a minor extent. Radiolabeled fibrinogen (125I) was given intravenously to monitor the effects of batroxobin on fibrinogen and the effects of plasmin on the fibrin formed. Batroxobin was given intravenously in a dose that converted most fibrinogen to fibrin. Five to 10 minutes after batroxobin administration, 125I-activity in the blood decreased, indicating the disappearance of fibrinogen from the circulating blood. At the same time, the 125I activity as measured with a gamma counter increased over the lungs. The fibrin formed in the microvasculature of the lungs started an endogenous fibrinolysis. This could be seen as reappearance of the 125I activity in the blood from fibrin degradation products accompanied by a decrease in the 125I activity over the lungs. When the rats were given tranexamic acid, the endogenous fibrinolysis was markedly decreased, measured as 125I activity in the blood, over the lungs and in lung parenchyma samples. The thrombin inhibitor DuP 714, which apparently inhibits not only thrombin but also plasmin and tissue plasminogen activator, completely prevented the fibrinolytic phase. The selective thrombin inhibitor argatroban, on the other hand, led to shortened lysis time. It is concluded that the present method provides a convenient and accurate means of studying pharmacological interventions with endogenous fibrinolysis. The differential effects of selective and nonselective thrombin inhibitors on endogenous fibrinolysis at comparable levels of thrombin inhibition are clearly demonstrated.

Animals↗

PubMed1996

Effects of inogatran, a new low-molecular-weight thrombin inhibitor, in rat models of venous and arterial thrombosis, thrombolysis and bleeding time.

Inogatran (MW 439 Da), a new, selective, active site inhibitor of thrombin, was evaluated in three rat models of thrombosis. In the venous thrombosis model, inogatran dose-dependently inhibited thrombus formation with a > 80% antithrombotic effect at a plasma concentration of 0.45 mumol l-1. In the arterial thrombosis model, inogatran dose-dependently inhibited thrombus formation, preserved vessel patency and the mean blood flow. Acetylsalicylic acid (ASA) potentiated the effects of low plasma concentrations of inogatran in the arterial thrombosis model. In the model of rt-PA-induced thrombolysis of a thrombus in the carotid artery, inogatran improved the patency time and the cumulative blood flow during the two hour thrombolysis period more than rt-PA alone. At high therapeutic plasma concentration of inogatran, there was only a moderate prolongation of bleeding time compared with the control value. It is concluded that inogatran is an effective antithrombotic agent both in the venous and arterial thrombosis models and also as adjuvant to rt-PA in the thrombolysis model.

Animals↗

PubMed1996

Significance of indoor environment for the development of allergic symptoms in children followed up to 18 months of age.

The development of symptoms possibly related to allergy or other forms of hypersensitivity was studied in a group of 638 children on two occasions: when the children were 3 and 18 months of age. Standardized questions were used to collect basic information about the child, technical characteristics of the home, and the mother's perception of the indoor climate. All reported exposure factors were analyzed in relation to the child's symptoms at 18 months of age, by logistic regression techniques. A family history of atopy was associated with a high incidence of most of the investigated symptoms. Attendance at a day nursery before 18 months of age increased the risk of recurrent colds and the need for several courses of treatment with antibiotics. If the mother smoked, the children more often suffered from protracted coughing episodes. If the child has a sibling, the risk of developing a wheeze, repeated colds, and the need for antibiotic treatment increased. No building factors, such as size of the home, heating and ventilation system, type of foundation, dampness, or presence of wall-to-wall carpets, showed a significant correlation to symptoms reported in the children. However, if the mothers reported symptoms that are often connected with "sick buildings", the children more often had eczema, dry skin, or reactions to food. The mothers' complaints about indoor air quality and climate and mucous membrane symptoms were significantly related to the type of building and presence of condensation on the windows in winter, a finding which may indicate that indoor climate factors also have some effect on the health of the children. This study reports the prevalences of symptoms until the age of 18 months. At this age, the allergic manifestations are usually nonspecific, and follow-up examinations to 4-5 years of age are needed before any definite conclusions can be drawn about the development of atopic diseases due to indoor climate factors.

Age Factors↗

PubMed1993

A new rat model of arterial thrombosis with a platelet-rich head and an erythrocyte-rich tail: thrombolysis experiments with specific thrombin inhibition.

A model for thrombolysis in rats was developed. Repeated, focal external heating was applied to the carotid artery which leads to the development of a cyclic blood flow with slow, steady decreases followed by abrupt increases. When this cyclic blood flow stops spontaneously, the entire arterial segment (approximately 10 mm) can be demarcated with snares to create an arterial thrombus of fixed size, with a platelet-rich head and an erythrocyte-rich tail. The usefulness of the model was tested by evaluating the thrombolysis induced by a low dose of recombinant tissue-type plasminogen activator (rt-PA) alone and rt-PA in combination with standard heparin and recombinant hirudin. Re-canalization of the artery was measured as blood flow and as the residual 125I-radioactivity in the artery at the end of the experiment, resulting from 125I-fibrinogen incorporated during the formation of the thrombus. Both blood flow and 125I-activity measurements show that hirudin, but not heparin in combination with rt-PA, significantly improves thrombolysis, which is in accordance with previous experimental findings. It is concluded that the model, with a thrombus resembling the thrombus found in man after coronary occlusion, enables complicated experiments with thrombolysis frequently performed only in large animals to be performed in rats.

Animals↗

PubMed1992

Noninvasive measurement of diameter changes in the distal abdominal aorta in man.

An ultrasound phase-locked, echo-tracking system was used to determine the dynamic properties of the distal abdominal aorta in 10 Caucasian male subjects (mean age, 25 years). Recordings were made at rest and during the blood pressure increase resulting from isometric exercise. The pressure diameter curve was nonlinear with an inflection at about 90-110 mmHg. Above this pressure range, the vessel was stiffer (less compliant), but the pressure diameter relationship was roughly linear above as well as below the inflection. Individual pressure diameter curves showed hysteresis, i.e., the aorta had a smaller diameter during expansion than during retraction at corresponding pressures. The pressure strain elastic modulus (Ep) and stiffness (beta) were at rest [Mean Arterial Pressure (MAP), 81 mmHg] 0.70 10(5) N/m2 and 6.0, respectively. During isometric exercise (MAP, 122 mmHg), Ep increased significantly by 91% and stiffness (beta) nonsignificantly by 27%. The variability of the compliance determinations was 5% when the ultrasonic system was combined with intra-arterial blood pressure measurements and less than 7% when combined with auscultatory blood pressure measurements. It is concluded that the phase-locked, echo-tracking system fulfills clinical requirements for routine measurements of vascular compliance.

Adult↗

PubMed1992

Diameter and compliance in the male human abdominal aorta: influence of age and aortic aneurysm.

In this study changes in the diameter and compliance of the distal abdominal aorta (76 healthy Caucasian males, 5-71 years old) were determined non-invasively and related to age by means of an ultrasound phase-locked echo-tracking system. The diameter of the aorta increased not only in the period between 5 and 25 years of age, but also by about 30% between the ages of 25 and 71. The pressure diameter curves at 25, 51 and 70 years were non-linear with flattening between 90 and 110 mmHg, and the slope of the curves declined with age. Thus, the pressure strain elastic modulus (Ep) and stiffness (beta) increased (i.e. compliance decreased) in an exponential manner according to age. A group of 37 males with aneurysmal widening of the distal abdominal aorta had a significant increase in Ep when compared to an age-matched control group. Furthermore, the ranges for both Ep and beta were much larger in the aneurysm group than in the control group, indicating diversity in the pathogenesis of the disease. The non-invasive ultrasonic method of phase-locked echo-tracking is an appropriate method for studying compliance in major arteries under a variety of pathophysiological conditions.

Adolescent↗

PubMed1992

Risk of developing atopic disease after early feeding with cows' milk based formula.

A follow up of a cohort of 736 healthy full term children with exposure to cows' milk based formula and breast milk from donors on the maternity ward was performed. The children were divided into three exposure groups according to the feeding patterns on the maternity ward. Group 1 received only mother's milk, group 2 mother's milk and human donors' milk, and group 3 received mother's milk, donors' milk and cows' milk based formula. The children were investigated at 7 years of age, by examining their medical files, and at 11 and 14 years, by questionnaires regarding symptoms of atopic disease. No significant differences between the three groups at follow up were found in the cumulative incidences of atopic diseases. The amount of formula given did not affect the risk of developing atopic disease. Children with a family history of such diseases ran the same risk of subsequent atopic disease whether they were fed formula or breast milk alone. Cows' milk based formula given on the maternity ward does not seem to increase the risk of developing atopic disease.

Animals↗

PubMed1992

Raised plasma concentrations of endothelin-1 and -3 in marmosets with acute aortic stenosis: no relation to the renin-angiotensin system.

Plasma levels of endothelin (ET), plasma renin activity (PRA) and angiotensin II (Ang II) were measured in anaesthetized marmosets exposed to acute aortic stenosis proximal to the renal arteries. In vehicle experiments, ET rose from 5 +/- 2 to 38 +/- 4 pg ml-1, PRA from 5 +/- 2 to 99 +/- 21 ng ml-1 h-1 and Ang II from 21 +/- 4 to 213 +/- 76 pg ml-1. Administration of renin inhibitor and angiotensin converting enzyme inhibitor reduced PRA and Ang II to control levels, while the plasma levels of ET increased further (51 +/- 10 and 71 +/- 16 pg ml-1, respectively). During aortic stenosis the two isoforms ET-1 and ET-3 appeared in the circulation, while in conscious control animals only ET-1 was found. It is concluded that the increased plasma levels of ET in our primate model could not be ascribed to the increased circulating levels of PRA and Ang II.

Acute Disease↗

PubMed1991

Acute haemodynamic effects of felodipine, verapamil and hydralazine in the anaesthetized dog.

Felodipine, a potent dihydropyridine calcium antagonist with a pronounced vascular selectivity, was given intravenously (0.006-0.025 mumol kg-1) to anaesthetized, open-chest dogs with denervated hearts. The result was a dose-dependent decrease in mean arterial pressure (MAP) and total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and left ventricular end-diastolic pressure remained relatively unchanged. Cardiac tension work (TTI) and oxygen consumption (MVO2) were reduced, probably due to the decrease in afterload. The relative reduction of the coronary vascular resistance (CVR) was greater than that of TPR. The hypotensive effect of verapamil (0.05-0.20 mumol kg-1) was small and MAP decreased mainly via a decrease in HR and SV. Higher doses of verapamil which induced vasodilatation could not be given without the development of complete atrio-ventricular dissociation. Hydralazine (11-45 mumol kg-1) decreased TPR and CVR in parallel but the decrease in MAP was partly counteracted by a powerful increase in HR, SV and cardiac inotropy which was associated with elevated catecholamine levels in plasma. When MAP and HR were maintained constant by means of aortic balloon inflation and atrial pacing, felodipine markedly increased coronary blood flow and coronary sinus oxygen saturation while SV, TTI, inotropy and MVO2 remained relatively unchanged. It is concluded that felodipine markedly dilates peripheral resistance vessels, and in particular those in the coronary vascular bed, without any cardiodepressant effects.

Animals↗

PubMed1990

Effects of thiopental on resistance vessels in cat skeletal muscle.

Barbiturates are used clinically as anaesthetics and to reduce raised intracranial pressure. One side effect is hypotension, usually ascribed to a depression of cardiac contractility, while their effects on the resistance vessels are more controversial: both vasodilation and vasoconstriction have been described. This study analyzes the effects of thiopental on basal vascular tone in the cat skeletal muscle. We found that total resistance increased by almost 20% at low (50 mumol/l) and decreased down to about 50% of control at high (350 mumol/l) plasma concentrations of thiopental. The vasoconstriction dominated in the large arterioles (i.d. greater than 25 microns) and the vasodilation in the small arterioles (i.d. less than 25 microns). A dose-dependent inhibition of myogenic vascular reactivity (here defined as the maximum resistance increase to a transient rise in transmural pressure) coincided with the vasodilation. Autoregulation of blood flow was depressed by thiopental. During vasoconstriction there was a net transcapillary fluid absorption and during vasodilation a net fluid filtration. The fluid movements could be ascribed to variations in capillary hydrostatic pressure. If applicable to the cerebral circulation these results suggest that thiopental at high plasma concentrations might induce, instead of reduce, interstitial brain oedema.

Animals↗

PubMed1990

Regional haemodynamic effects of endothelin-1 in rat and man: unexpected adverse reaction.

Endothelin-1 was infused into the non-dominant brachial artery in two male subjects. We then monitored intra-arterial mean blood pressure, right atrial pressure, the heart rate and forearm blood flow (by plethysmography). Endothelin-1 at a dose of 5 x 10(-14) to 5 x 10(-9) mol, infused over 5 min periods, elicited no major changes in mean arterial pressure, heart rate and right atrial pressure. We observed an initial increase in forearm blood flow, followed by dose-dependent decreases of 25, 34 and 42% at 5 x 10(-11) to 5 x 10(-9) mol. A higher dose of endothelin-1, 5 x 10(-8) mol, given to only one of the subjects, elicited sweating and vomiting. In this subject, mean arterial pressure, right atrial pressure and the heart rate did not change, while forearm blood flow increased transiently. A deep muscular pain developed in the forearm receiving the endothelin-1 infusion after 30 min (maximum 2 h, duration 10 h), and this pain was intensified by touch and muscle contractions. The force of muscle contractions in the forearm was markedly reduced and a visible oedema developed. In order to investigate the mechanisms of oedema formation, endothelin-1 (10(-10) to 5 x 10(-8) mol/l) was given intra-arterially in a rat hindquarter preparation which was perfused at a constant flow rate. In the rat, endothelin-1 increased both pre- and postcapillary resistance, leading to an increase in capillary hydrostatic pressure and a marked net transcapillary fluid transfer from the perfusate to tissue. There was no sign of increased vascular permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Effects of felodipine on microvascular resting tone and responses to nerve stimulation and perfusion pressure reduction in rabbit skeletal muscle.

The effects of felodipine, a vasoselective dihydropyridine calcium antagonist, on microvascular dynamics were investigated in skeletal muscle. The diameters of the transverse (10-28 microns) and terminal (4-8 microns) arterioles, located at the immediate precapillary level in the rabbit tenuissimus muscle, were registrated by intravital microscopy. Topical application of felodipine (10(-7)-10(-5) M) induced a concentration-dependent vasodilation of both arteriolar generations. The steady state response at 10(-7) M revealed a relatively more pronounced dilatation of transverse (92 +/- 30% increase in diameter) than of terminal arterioles (44 +/- 12%). This is in contrast to muscle exercise, which elicits a more pronounced dilatation of terminal (260 +/- 39% increase) than of transverse arterioles (103 +/- 15%). Vasomotor nerve stimulation evoked a frequency-dependent constriction both in the absence and presence of felodipine (10(-6) M). However, the vasodilatory response elicited by graded perfusion pressure reductions was eliminated in the presence of felodipine (10(-7) M). Thus, the vasomotor nerve response was better preserved than the autoregulatory response in the presence of the calcium antagonist. The results indicate that felodipine dilates arterioles via an inhibition of myogenic vascular reactivity, which supports previous results obtained both in vivo and in vitro.

Animals↗

PubMed1990

Effects of noradrenaline and vasopressin analogues on resistance and capacitance vessels in the rat hindquarter preparation.

The isolated rat hindquarter preparation perfused at constant flow was used to determine resistance and capacitance responses from pressure and weight recordings. In response to noradrenaline at low concentrations, the capacitance effect was greater than the relative increase in total vascular resistance. 8-L-Arginine vasopressin showed capacitance responses only when the resistance vessel constriction was pronounced. Oxytocin and two synthetic analogues, 2-phenylalanine-8-ornithine vasopressin (Phe-Orn-VP) and 2-phenylalanine-8-ornithine oxytocin, showed varying potency for resistance vessel constriction but hardly any capacitance responses. However, when Phe-Orn-VP induced a small increase in total vascular resistance, a marked increase in post-capillary resistance was observed. The results are discussed in relation to a study in which the effects of vasopressin analogues were studied with intravital microscopy (Altura 1973).

Animals↗

PubMed1990

Effects of a behavioral treatment program on children with asthma.

Twenty children with severe asthma using continual oral beta 2 agonists were randomized equally into either a behavioral intervention group or a control group. The behavioral intervention consisted of: symptom discrimination of asthma signals, self-management techniques of breathlessness, and contingency management of asthma-related behavior. The purpose of the study was to evaluate the effects of the behavioral treatment when superimposed on a regular medical treatment. The design consisted of a four-week baseline period, a four-week intervention period, and a four-week follow-up period. Results showed that the group receiving the behavioral intervention significantly reduced their use of beta 2 agonist spray doses and days of school absenteeism without increasing the number of asthma symptoms compared with the control group. It was concluded that children with severe asthma may benefit substantially from a behavioral program in addition to their regular medical treatment.

Absenteeism↗

PubMed1989

Derivation of haemodynamic information from ultrasonic recordings of aortic diameter changes.

An ultrasound phase-locked echo-tracking system was used for noninvasive measurements of diameter changes in the upper abdominal aorta of the anaesthetised cat. Comparisons were made between the noninvasively recorded diameter changes and central haemodynamic variables measured with inserted catheters and transducers. It was found that noninvasive observations of aortic diameter changes give reliable information on the direction and relative magnitude of the blood pressure change both in systole and in diastole. Indications of the direction of change of stroke volume, cardiac output, and aortic flow acceleration (a measure of cardiac inotropy) could also be gained. The information, taken together, comprises a pattern of response reflecting cardiovascular adjustments likely to have occurred. It is suggested that the technique is suitable for interpretation of (patho-) physiological changes in the foetus, as well as for determinations of great vessel compliance in man, i.e., in atherosclerosis research.

Animals↗

PubMed1989

Microvascular effects and oedema formation of felodipine in man.

The microvascular mechanisms responsible for oedema formation following the administration of calcium antagonists were studied in 10 healthy volunteers given intravenous felodipine and vehicle in a double-blind crossover trial. Plethysmography and laser Doppler flowmetry were used to measure microvascular parameters. Felodipine increased both skin and forearm blood flow. Due to a more pronounced inhibition of vascular tone in pre- than in postcapillary resistance vessels, capillary hydrostatic pressure increased and caused a net fluid filtration from blood to tissue. No evidence for increased vascular permeability was found. Under control conditions, a hydrostatic load led to fluid filtration despite constriction of resistance vessels and precapillary sphincters. Felodipine increased this fluid filtration and impaired the local vasoconstrictor responses. It is concluded that oedema formation induced by felodipine and other calcium antagonists can partly be ascribed to the vasodilatory effect of the drug (increased capillary pressure) and partly to interference with the local vascular control (probably the myogenic component) that protects dependent vascular regions from enhanced fluid filtration.

Adult↗

PubMed1988

The role of sympathetic activity in atherogenesis: effects of beta-blockade.

Clinical and experimental evidence points to potential antiatherosclerotic effects of certain beta-adrenoreceptor antagonists. Long-term treatment with metoprolol resulted in significant reductions of total and cardiovascular mortality or morbidity due to decreased incidence of coronary and cerebrovascular complications both in a primary prevention trial in hypertensive patients and in a secondary prevention trial in patients surviving myocardial infarction. The observations suggest that a retardation of atherosclerosis development might have contributed to the reduced incidence of cardiovascular complications. An antiatherosclerotic effect of beta-blockers has been directly demonstrated in animal studies. In cholesterol-fed rabbits, metoprolol significantly reduced the development of atherosclerotic plaques in the aortic intima in the absence of any changes in blood lipids. Similar findings were reported for propranolol, which prevented psychosocial stress-induced atherosclerosis of the coronary artery in monkeys. Furthermore, beta-blockers have been shown to prevent stress-induced endothelial injury and platelet accumulation to intima at atherosclerotic predilection sites in animal models. These antiatherogenic effects may be due to biochemical and hemodynamic factors. Two biochemical effects of beta-blockade may lead to reduced cholesterol accumulation in arterial intima at unchanged serum cholesterol levels. One is a beta-blocker-induced increase of prostacyclin biosynthesis, and the other a metabolic change of low-density lipoprotein, reducing its potential for deposition in the arterial wall. The antiatherogenic effect of these factors may be reinforced by beta-blocker-induced hemodynamic changes leading to reductions of arterial flow aberrations and pressure-related wall stress.

Adrenergic beta-Antagonists↗