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Biomedical subjects

J Lundvall

Publications and source records attributed to J Lundvall.

At least 19 recordsLinked to original sources

Mechanisms in man for rapid refill of the circulatory system in hypovolaemia.

Compensatory, net fluid transfer across the capillaries was studied in the arm of man with plethysmographic technique during experimental hypovolaemia induced by lower body negative pressure (LBNP). Thirty, 60, and 110 cmH2O LBNP evoked rapid transfer of fluid from tissue to blood at average rates of 0.053, 0.088 and 0.147 ml min-1 100 ml-1 soft tissue, i.e. graded responses typical for a true homeostatic regulation. Other experiments demonstrated a net fluid absorption not only from the arm but also from a wide range of skeletal muscle and skin regions in the body during experimental hypovolaemia, i.e. the more or less generalized response required if the absorption process is to contribute importantly to plasma volume regulation. In a third series of experiments it was shown that gradually applied LBNP was a much less efficient stimulus for fluid gain into the circulation than rapidly instituted LBNP, tentatively explaining the fairly slow plasma volume refill in main in previous literature after experimental, true and necessarily slow blood loss. Taken together, the findings described warrant the conclusion that the described process of fluid gain into the circulation may be a very important component in the overall homeostatic circulatory regulation in states of hypovolaemia. The data in fact suggest that the process might be capable of increasing plasma volume by as much as 600 ml within only 10 min, suggesting that such plasma volume control might be much more potent than previously believed.

Adult

Large capillary fluid permeability in skeletal muscle and skin of man as a basis for rapid beneficial fluid transfer between tissue and blood.

Our previous studies strongly indicate that the capillary filtration coefficient (CFC) in skeletal muscle and skin of man is much larger than previously believed, or about 0.050 ml min-1 100 ml-1 mmHg-1. The hypothesis that this large capillary fluid permeability is a factor of primary importance for plasma volume control was approached. Experimental hypovolaemia induced by lower body negative pressure (LBNP of 70-95 cmH2O) was associated with a rapid net fluid gain from the studied upper arm into the circulation of 0.17 ml min-1 100 ml-1 tissue. The transcapillary driving force for this fluid transfer, probably caused by adrenergic adjustment of vascular resistance, with a decline of capillary pressure, was relatively small, or 1.7 mmHg on average. CFC was instead very high during LBNP, increasing from a control value of 0.054 +/- 0.004 (SE) to no less than 0.097 +/- 0.007 ml min-1 100 ml-1 mmHg-1, probably reflecting an increased number of effectively perfused capillaries. It is suggested that the large capillary fluid permeability in skeletal muscle and skin of man, with large tissue mass and fluid reservoir, may be of great functional importance for plasma volume control after blood loss and also in other (patho)physiological situations. As demonstrated, it can thus permit rapid transfer of large fluid volumes into the circulation and, perhaps of special importance, with only small transcapillary driving force (capillary pressure decline).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption

Very rapid net transcapillary fluid absorption from skeletal muscle and skin in man during pronounced hypovolaemic circulatory stress.

High levels (110-120 cmH2O) of lower body negative pressure (LBNP) were used in male volunteers (n = 7) to produce pronounced hypovolaemic circulatory stress in an attempt to reveal the potential in man for compensatory absorption of extravascular fluid from skeletal muscle and skin as studied in the upper arm by plethysmographic technique. LBNP evoked clear-cut hypovolaemic symptoms or even accidental syncope as well as a marked tachycardiac response and a significant fall in systolic blood pressure. In the studied arm there was concomitantly a very rapid net transcapillary absorption of extravascular fluid into the circulation at an average rate of 0.35 ml min-1 100 ml-1 soft tissue during 5 min of LBNP exposure. These data demonstrate an amazingly great potential to increase plasma volume by 'autotransfusion' of fluid from tissue to blood, as may be visualized by extrapolation of the data from the arm to apply to the whole mass of skeletal muscle and skin in the body. The observed absorption rate would then correspond to a total fluid gain of no less than 700 ml within a period no longer than 5 min. At present, however, there is no evidence to indicate that such impressive fluid volumes can be rapidly transferred from the extra-to the intravascular space after actual blood loss.

Adult

Much larger transcapillary hydrodynamic conductivity in skeletal muscle and skin of man than previously believed.

The capillary filtration coefficient (CFC) in the human forearm, determined with the 'venous occlusion' method, was found to be about 0.005 ml min-1 100 ml-1 soft tissue mmHg-1 when capillary pressure (Pc) was raised by about 30 mmHg, a finding in accordance with previous literature. With gradually smaller increments of Pc, however, the calculated CFC became gradually larger to reach maximal values of about 0.05 ml min-1 100 ml-1 mmHg-1 at increases in venous pressure that raised Pc by only 1.5-2 mmHg. It is suggested that these high CFC values, obtained at increases of intravascular pressure so low as to ensure minimal interference with the normal circulation, reflect the true prevailing transcapillary hydrodynamic conductivity in the tissue. The low CFC values during high increases in capillary (microvascular) pressure, on the other hand, seem to represent serious underestimations of the true CFC as a result of experimentally induced undesired active smooth muscle constrictor responses and/or passive deterioration of capillary exchange function. The conclusion is therefore reached that CFC in skeletal muscle and skin in man might be about 10 times higher than previously believed.

Adult

Transmission of externally applied negative pressure to the underlying tissue. A study on the upper arm of man.

The transmission to the underlying tissue of externally applied negative pressure (2-50 mmHg) was studied in 15 male volunteers on a segment of the upper arm 8 cm in length enclosed in a clear plastic cylinder sealed hermetically against the skin. Pressure recordings were obtained from the anterior and posterior tissue compartments from sites along the entire tissue segment exposed to negative pressure at depths from the skin surface ranging from 5 to 62 mm. Reduction of pressure in the cylinder caused rapid decline, and cessation of external negative pressure rapid recovery, of tissue pressure. In the steady-state phase of negative tissue pressure, the applied external pressure change was in the great majority of experiments transmitted fully or almost fully to the tissue, regardless of from which position along the tissue segment and from which tissue depth pressure was recorded and regardless of the magnitude of the applied negative pressure. The described findings suggest that a defined reduction of atmospheric pressure leads to a similar alteration of vascular transmural pressure and that the technique of external negative pressure can be used for not only qualitative but also quantitative studies of local circulatory reactions evoked by such transmural pressure changes.

Adult

Large capacity in man for effective plasma volume control in hypovolaemia via fluid transfer from tissue to blood.

Compensatory absorption of extravascular fluid from skeletal muscle and skin into the circulation in response to experimental hypovolaemia was studied by plethysmographic technique in the upper arm of man. Lower body negative pressure (LBNP) of 90 cmH2O, applied for 10 min, served to produce rapid and prominent hypovolaemic stress as indicated by prompt decrease in central blood volume (external recording of [99Tcm]erythrocyte activity) followed by marked tachycardia. The arm concomitantly showed an initial mobilization of regional blood, an increased vascular resistance, and a continuous net transcapillary fluid absorption, i.e. similar responses as reported in animals upon haemorrhage. The absorption of extravascular fluid, validated by simultaneous analyses of changes in tissue volume and in regional blood volume [99Tcm]erythrocyte activity), was rapid and averaged 0.13 ml min-1 100 ml-1 soft tissue during the 10 min of LBNP exposure. In some subjects with symptoms and signs of pronounced circulatory stress fluid was transferred twice as fast. Separate experiments indicated that the rapid fluid flux was causally linked to the existence in the studied tissue of a large transcapillary hydraulic conductance. It is concluded that man possesses a surprisingly great capacity for compensatory circulatory refill via fluid transfer from tissue to blood. The data in fact suggest that in true states of hypovolaemia as much as 500 ml might be gained into the circulation in only 10 min.

Adult

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

Myogenic mechanisms in the control of systemic resistance and transcapillary fluid exchange in man.

Myogenic reactions to raised vascular transmural pressure were studied in the forearm of healthy male volunteers. The study was designed to allow adequate comparative analyses of myogenic stimulus-effector response characteristics in the resistance vessels and in the precapillary sphincters, with no or minimal interference with systemic or local venous-arteriolar reflexes or with metabolic vascular control. Both vascular sections proved surprisingly sensitive to transmural pressure as a stimulus, showing graded constrictor responses when transmural pressure was raised 5-20 mmHg. There was a clearcut difference, however, in that the precapillary sphincters reacted very intensely even when transmural pressure was only slightly raised (5 mmHg). This potent myogenic regulation of precapillary sphincter tone may be an important factor in the control of transcapillary fluid exchange, and thereby in the control of plasma and interstitial fluid volumes, for instance in dependent regions on standing.

Adult

Application of external negative pressure to the extremities in man allows measurement of myogenic vascular reactions.

Transmission to tissue of externally applied negative pressure (10-100 mmHg) was studied in male volunteers in the upper arm. When the negative pressure was applied there was a rapid decline in tissue pressure and when the negative pressure stopped tissue pressure recovered rapidly. Negative pressure was transmitted fully or almost fully to the entire anterior and posterior tissue compartments, regardless of tissue depth and of the magnitude of the negative pressure applied. Regional venous pressure decreased as the negative pressure was applied but soon returned to the control level. Arterial pressure and the heart rate were unaffected. These findings indicate that external negative pressure can be used to produce graded and defined alterations in vascular transmural pressure in all parts of the exposed tissue, with few passive flow changes and without interference to systemic reflexes. External negative pressure may therefore represent the most convenient method for investigation of the stimulus-effector response characteristics of myogenic reactions in different consecutive sections of the vasculature.

Adult

Human cellular retinol-binding protein gene organization and chromosomal location.

The gene encoding the human cellular retinol-binding protein (CRBP) has been isolated from genomic libraries and its structure determined. Only one copy of the gene is present in the human genome. We have located the CRBP gene to segment 3p11-3qter on human chromosome 3 using hybridizations to mouse-human, rat-human and hamster-human cell hybrids. The gene harbors four exons encoding 24, 59, 33, and 16 amino acid residues respectively. The second intervening sequence alone occupies 19 kb of the 21 kb of the CRBP gene. The nucleotide sequence of the gene has been determined with the exception of the second intron. The positions of the introns agree with those in the rat CRBPII, the rat liver fatty-acid-binding protein and the mouse adipose P2 protein genes encoding molecules belonging to the same protein family as CRBP. In contrast to the other sequenced members of this family the promoter of the CRBP gene resembles those found in the 'housekeeping' genes in that it is (G + C)-rich, contains multiple copies of the CCGCCC sequence and lacks TATA box. A 9-bp homology containing the core sequence of the simian virus 40 enhancer repeat was found in the 5' upstream region. A genomic Southern blot probed with CRBP cDNA revealed hybridizing bands in restricted chicken and frog DNA.

Amino Acid Sequence

Ketanserin in intermittent claudication: effect on walking distance, blood pressure, and cardiovascular complications.

In a 7-center Scandinavian double-blind placebo-controlled study of 179 patients with intermittent claudication, the effect of the serotonin antagonist ketanserin was evaluated on walking distance, brachial and ankle blood pressure, and symptoms. For all centers together, pain-free walking distance was significantly increased after 6 months with both ketanserin (+65%; 71 patients) and placebo (+42%; 78 patients), with no significant difference. However, there was large variability among centers. Classification of "responders" (doubling of walking distance) and patients who deteriorated (decrease of walking distance or dropout for inefficacy) showed significantly more patients responding and significantly fewer patients deteriorating with ketanserin than with placebo. Systemic blood pressure was significantly decreased by ketanserin in hypertensive, but not normotensive, patients, while ankle pressure was unaffected. The incidence and nature of side effects were equal with ketanserin and placebo, but there were more side effects causing dropout in the ketanserin group. An unexpected and possibly important observation was the occurrence of six serious cardiovascular events (myocardial infarction, cerebrovascular complications, and development of rest pain) in the placebo group but none in ketanserin-treated patients. Moreover, there were four additional similar complications in the placebo run-in period. Ketanserin appears to be beneficial in a subgroup of patients with intermittent claudication. A fortuitous finding of this study is that ketanserin might possess a protective effect against thrombovascular complications in patients with intermittent claudication.

Adult

Cellular retinoid binding proteins.

The cellular retinol-binding protein (CRBP) and the cellular retinoic acid binding protein (CRABP) have similar physicochemical characteristics. The amino acid sequences of rat CRBP and bovine CRABP have been elucidated and they display 40% sequence identity. Both protein sequences appear to be evolutionarily highly conserved. The amino acid sequence of human CRBP, deduced from a cDNA-clone, is 96% identical to the rat CRBP sequence. CRBP and CRABP are members of a protein family, all members of which may bind hydrophobic ligands and interact with membrane components. All members of the protein family are probably related in tertiary structure and might interact with membrane components through two regions with a high probability for alpha-helix. The tissue distribution of CRBP and CRABP, together with their relation to lipid transporting proteins suggests that CRBP and CRABP are cellular transporting proteins for retinol and retinoic acid, respectively.

Amino Acid Sequence

Cloning and sequencing of a full length cDNA corresponding to human cellular retinol-binding protein.

We have isolated and sequenced a cDNA clone corresponding to the human cellular retinol-binding protein (CRBP). The deduced amino acid sequence, which encompasses 134 amino acid residues, shows significant homology with several low molecular weight proteins which bind hydrophobic ligands. No homology to the plasma retinol-binding protein was observed. Southern and Northern blot analyses suggest that the CRBP gene is present in a single copy in the haploid genome and that it is transcribed in a single mRNA species.

Amino Acid Sequence