Sun exposure rapidly reduces plasmacytoid dendritic cells and inflammatory dermal dendritic cells in psoriatic skin.

BACKGROUND: Interferon (IFN)-α-producing plasmacytoid dendritic cells (pDCs), inflammatory CD11c+CD1c- myeloid dendritic cells (mDCs) and macrophages have been found to contribute to the pathogenesis of psoriasis. Heliotherapy is a well-established treatment modality of this disease, although the details of how the effects are mediated are unknown. OBJECTIVES: To test the hypothesis that exposure to natural sun affects pathogenic DC subsets in lesional skin. METHODS: Skin biopsies were obtained from lesional and nonlesional skin in 10 patients with moderate to severe psoriasis subjected to controlled sun exposure on Gran Canaria. Biopsies were obtained at baseline, day 2 and day 16 and examined by immunohistochemistry. RESULTS: Sixteen days of heliotherapy had excellent clinical effect on patients with psoriasis, with significant reductions in Psoriasis Area and Severity Index (PASI) scores. In lesional skin pDC numbers and expression of MxA, a surrogate marker for IFN-α, were rapidly reduced. Inflammatory CD11c+CD1c- mDCs were significantly reduced whereas resident dermal CD11c+CD1c+ mDCs were unaffected. Expression levels of the maturation marker DC-LAMP (CD208) on mDCs were significantly reduced after sun exposure, as were the numbers of lesional dermal macrophages. A decrease of dermal DC subsets and macrophages was already observed after 1 day of sun exposure. An additional finding was that DC-SIGN (CD209) is primarily expressed on CD163+ macrophages and not DCs. CONCLUSIONS: The clinical improvement in psoriasis following sun exposure is associated with rapid changes in dermal DC populations and macrophages in lesional skin, preceding the clinical effect. These findings support the concept that these DC subsets are involved in the pathogenesis of psoriasis and suggest that sun-induced clinical benefit may partly be explained by its effect on dermal DCs.

Sun exposure induces rapid immunological changes in skin and peripheral blood in patients with psoriasis.

BACKGROUND: Ultraviolet (UV) radiation has immunosuppressive effects and heliotherapy is a well-described treatment modality for psoriasis. OBJECTIVES: To characterize early sun-induced immunological changes both local and systemic in patients with psoriasis. METHODS: Twenty patients with moderate to severe psoriasis were subjected to controlled sun exposure on Gran Canaria, Canary Islands, Spain. Psoriasis Area and Severity Index (PASI) scores were evaluated. Skin biopsies were obtained from lesional and nonlesional skin in 10 patients at baseline and on day 16 and from five additional patients on day 2. Specimens were examined with immunohistochemistry and polymerase chain reaction. Blood samples were obtained from all patients at the same time points and were examined for T-cell subsets and cytokine production. RESULTS: Significant clinical improvement was achieved during the study period. CD4+ and CD8+ T cells in lesional skin were significantly reduced in both the epidermis and dermis. In contrast, dermal FOXP3+ T cells were relatively increased. In the peripheral blood skin homing cutaneous lymphocyte-associated antigen (CLA)+ T cells were significantly decreased after only 1 day in the sun and in vitro stimulated peripheral blood mononuclear cells demonstrated reduced capacity to secrete cytokines after 16 days. CONCLUSIONS: Our data show that clinical improvement of psoriasis following sun exposure is preceded by a rapid reduction in local and systemic inflammatory markers, strongly suggesting that immune modulation mediated the observed clinical effect. We cannot completely rule out that other mechanisms, such as stress reduction, may contribute, but it is extensively documented that UV irradiation is a potent inducer of immunosuppression and we therefore conclude that the observed effect was primarily due to sun exposure.

Effect of climate therapy at Gran Canaria on vitamin D production, blood glucose and lipids in patients with psoriasis.

BACKGROUND: Climate therapy (heliotherapy) of psoriasis is an effective and natural treatment. Ultraviolet radiation (UVB) from the sun improves psoriasis and induces vitamin D(3) synthesis. OBJECTIVE: The aim of the study was to investigate the effect of climate therapy on vitamin D(3) synthesis, blood glucose, lipids and vitamin B12 in psoriasis patients. METHODS: Twenty Caucasian patients (6 women and 14 men; mean age, 47.2 years; range, 24-65) with moderate to severe psoriasis [mean Psoriasis Area and Severity Index (PASI) score 9.8; range, 3.8-18.8] received climate therapy at the Gran Canarias for 3 weeks. Blood samples were drawn before and after 15 days of sun exposure. In addition, the patients' individual skin UV doses based on UV measurements were estimated. RESULTS: Sun exposure for 15 days lead to a 72.8% (+/- 18.0 SD) reduction in the PASI score in psoriasis patients. Although no direct correlation was observed between PASI score improvement and UVB dose, the sun exposure improved the vitamin D, lipid and carbohydrate status of the patients. The serum concentrations of 25-hydroxyvitamin D [25(OH)D] increased from 57.2 +/- 14.9 nmol/L before therapy to 104.5 +/- 15.8 nmol/L (P < 0.0001) after 15 days of sun exposure; the serum levels of 1,25-dihydroxyvitamin D [1,25(OH)(2)D] increased from 146.5 +/- 42.0 to 182.7 +/- 59.1 pmol/L (P = 0.01); the ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol decreased from 2.4 to 1.9 (P < 0.001); and the haemoglobin A(1)c (HbA(1)c) levels decreased from 5.6 +/- 1.7% to 5.1 +/- 0.3% (P < 0.0001). CONCLUSION: Climate therapy with sun exposure had a positive effect on psoriasis, vitamin D production, lipid and carbohydrate status.

Proinflammatory cytokines upregulate expression of calprotectin (L1 protein, MRP-8/MRP-14) in cultured human keratinocytes.

BACKGROUND: Normal skin contains no epidermal calprotectin. In biopsies from various inflammatory skin disorders, however, this antimicrobial protein occurs in the cytoplasm of keratinocytes. OBJECTIVES: To exclude the possibility of epidermal uptake of calprotectin from granulocytes and macrophages in diseased skin, we investigated whether cytokine-stimulated human keratinocytes can express calprotectin in vitro. METHODS: Keratinocytes from healthy individuals were cultured in serum-free keratinocyte medium. The cells were stimulated with different cytokines [interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-10 and IL-13], both separately and in various combinations. Cytoplasmic protein levels of calprotectin were measured by an enzyme-linked immunosorbent assay performed on fixed adherent keratinocytes, and mRNA expression was determined by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Calprotectin was produced by cytokine-stimulated keratinocytes, especially in response to combinations of the proinflammatory cytokines, which showed an additive upregulatory effect. When expression of mRNA for the light (MRP-8) and heavy (MRP-14) calprotectin chain was determined by RT-PCR, their respective levels were shown to be increased four- to ninefold and three- to fivefold after 24 h of combined stimulation with IFN-gamma and TNF-alpha. The time course of calprotectin production showed no significant elevation for the first 16 h but then increased and peaked after 36 h. CONCLUSIONS: Cultured human keratinocytes stimulated with proinflammatory cytokines produce calprotectin, suggesting that epidermal expression of this antimicrobial protein in diseased skin reflects compartmentalized synthesis rather than uptake from dermal inflammatory cells.

Dietary habits among patients with atopic dermatitis.

OBJECTIVE: To evaluate the dietary habits among adult patients with moderate to severe atopic dermatitis and relate intake to clinical symptoms. DESIGN: Data were obtained from a clinical trial. SETTING: Five departments of dermatology at Norwegian University hospitals. SUBJECTS: Outpatients, 46 men (median age 27 y) and 92 women (median age 28 y). METHOD: A quantitative food frequency questionnaire was filled in before attending the clinical trial. The results were compared to the diet of age- and sex-matched reference groups. RESULTS: Male patients had higher content of refined sugar in their diet than reference men (P=0.014). Among female patients, the intake of saturated fatty acids was higher (P=0.049), whereas the intake of very long-chain n-3 fatty acids was lower (eicosapentaenoic acid, P=0.032, docosahexaenoic acid, P=0.017) than in the reference group. In both genders, more patients than reference subjects had vitamin D intake below recommended level. Furthermore, the female patients had significantly lower intake of fruit compared to the reference group (P=0.002). No correlation was found between nutrient intake of the patients and their clinical scores. CONCLUSIONS: The patients's diet were fairly similar to the diet of reference groups. The intake of vitamin D and very long-chain n-3 fatty acids was low, especially among female patients. Furthermore, we could not detect any association between dietary habits and clinical status. European Journal of Clinical Nutrition (2000) 54, 93-97

Treatment of hypertensive and hypercholesterolaemic patients in general practice. The effect of captopril, atenolol and pravastatin combined with life style intervention.

OBJECTIVE: To elucidate the effect on blood pressure and blood lipids of an angiotensin converting enzyme inhibitor (captopril), and a beta-receptor blocking agent (atenolol), given alone or in combination with a cholesterol reducing drug, the beta-hydroxy-methylglutaryl-coenzyme A reductase inhibitor pravastatin, in patients who were also encouraged to improve their lifestyle. DESIGN: A longitudinal study consisting of three phases. I: Lifestyle intervention alone. II: Continued lifestyle intervention combined with captopril or atenolol. III: Continued lifestyle intervention combined with the same drugs as in phase II and in addition pravastatin or placebo. SETTING: Fifty-four general practice surgeries in Norway. PARTICIPANTS: Hypertensive patients, 210 females and 160 males, treated or untreated with antihypertensive drugs with a sitting diastolic blood pressure between 95 and 115 mmHg and a serum total cholesterol between 6.5 mmol/l (7.0 for those age 60-67 years) and 9.0 mmol/l. RESULTS: The antihypertensive effect of captopril and atenolol was not influenced by concurrent administration of pravastatin. The effect of pravastatin was not limited by concurrent medication with captopril or atenolol. Improvement in lifestyle seemed to reduce the need for supplementary treatment with diuretics. CONCLUSION: Pravastatin can be used in combination with captopril or atenolol in the treatment of hypertensive and hypercholesterolaemic patients.

Plectin abnormality in epidermolysis bullosa simplex Ogna: non-responsiveness of basal keratinocytes to some anti-rat plectin antibodies.

Epidermolysis bullosa (EB) is a heterogeneous group of genetic bullous skin diseases. The EB simplex group (EBS) is characterized by intraepidermal blistering. EBS-Ogna was first described as a separate entity based on clinical studies. Later genetic linkage of EBS-Ogna to the GPT locus for glutamate pyruvate transaminase (alanine transaminase) was detected and GPT was assigned to chromosome 8, then to the terminal long arm band 8q24. Plectin is an abundant and widespread cytoskeletal protein which has been proposed as a general crosslinking element of intermediate filaments. Human plectin has recently been cloned and in situ hybridized to chromosome 8q24. To examine whether plectin could be associated with EBS-Ogna we performed an immunohistochemical study with a panel of mAbs to rat plectin. Interestingly, 2 of these mAbs showed strong intracellular staining of the suprabasal and basal layer of the epidermis in all control samples, whereas no reactivity of the basal layer was found in the Ogna group. These results strongly suggest that plectin is involved in the pathogenesis of EBS-Ogna.

The influence of atrioventricular conduction and heart rate on the pulmonary venous flow pattern.

The pulmonary venous flow (PVQ) pattern usually has two antegrade flow waves, corresponding to ventricular systole and diastole, respectively, and is used to assess left atrial pressure. To study the effects of atrioventricular conduction (AVD) and heart rate (HR) on the PVQ pattern, transthoracic pulsed Doppler recordings of pulmonary venous, transmitral, and aortic flow were made in five healthy subjects with dual-chamber pacemakers. Recordings were made at HRs of 80, 100, and 120 beats/min, with AVDs of 75, 150, and 220 msec at each HR. When the AVD was increased, the biphasic PVQ changed to a monophasic pattern in which a single flow wave covered the transition between ventricular diastole and systole. There was a shift of flow from ventricular systole to diastole. When HR was increased, the systolic fraction of the PVQ increased as a result of an increase in the relative duration of systole. In conclusion, AVD and HR influenced the PVQ pattern in subjects without signs of ventricular dysfunction. This may be a limitation to the use of the flow pattern to assess left atrial pressure.

Dietary supplementation with very long-chain n-3 fatty acids in patients with atopic dermatitis. A double-blind, multicentre study.

The purpose of this study was to investigate whether fish oil and/or corn oil had a beneficial effect on the clinical state of atopic dermatitis, and to evaluate the dietary intake of nutrients in this group of patients. In a double-blind, multicentre study lasting 4 months, during wintertime, 145 patients with moderate to severe atopic dermatitis were randomly assigned to receive either 6 g/day of concentrated n-3 fatty acids, or an isoenergetic amount of corn oil. As local treatment, only an emollient cream or hydrocortisone cream was allowed. The fatty acid pattern in serum phospholipids, and the dietary intake of nutrients were monitored in a subgroup of patients, and the results were compared with a group of patients with psoriasis. The overall clinical score, as evaluated by the physicians, improved during the trial by 30% in the fish oil (P < 0.001) and 24% in the corn oil group (P < 0.001). This was also consistent with the results from a selected skin area, and it was further confirmed by the total subjective clinical score reported by the patients. There were no significant differences in the clinical scores between the two groups at baseline, and at the end of the study. In the fish oil group, the amount of n-3 fatty acids in serum phospholipids was significantly increased at the end of the trial, compared with pretreatment values (P < 0.001), whereas the level of n-6 fatty acids was decreased (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary supplementation with very long-chain n-3 fatty acids in man decreases expression of the interleukin-2 receptor (CD25) on mitogen-stimulated lymphocytes from patients with inflammatory skin diseases.

T-cell activation and cytokine production play an important role in several chronic inflammatory diseases. Because n-3 fatty acids exert beneficial effects on the clinical state of some of these diseases, we examined the effect of dietary supplementation of n-3 fatty acids on T-cell proliferation, expression of CD25 (interleukin-2 receptor alpha-chain), secretion of interleukin-2, interleukin-6 and tumour necrosis factor from T-cells from patients with psoriasis and atopic dermatitis. During 4 months, 21 patients supplied 6 g of highly concentrated ethyl esters of EPA and DHA in gelatin capsules daily to their diet. In the control group 20 patients supplied 6 g per day of corn oil in gelatin capsules to their diet. Eicosapentaenoic acid (20:5, n-3) of serum phospholipids increased from 14 (min 4-max 42) to 81 (min 59-max 144) mg l-1 (P < 0.01) in patients with atopic dermatitis receiving n-3 fatty acids, and from 25 (min 7-max 66) to 74 (min 46-max 142) mg l-1 (P < 0.01) in patients with psoriasis, whereas docosahexaenoic acid (22:6, n-3) increased from 65 (min 46-max 120) to 92 (min 54-max 121) mg l-1 (P < 0.05) and from 81 (min 38-max 122) to 92 (min 63-max 169) mg l-1 (NS) in atopic and psoriatic patients, respectively. The changes in the serum phospholipid fatty acid profile in the groups receiving n-3 fatty acids, correlate to the dietary intake of corresponding fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of dietary supplementation with very-long-chain n-3 fatty acids in patients with psoriasis.

BACKGROUND: In several studies dietary fish oil has been found to have beneficial effect on psoriasis, but the results are contradictory and based mainly on open studies or studies of small numbers of patients. METHODS: In a four-month double-blind, multicenter trial, we randomly assigned 145 patients with moderate-to-severe psoriasis to receive in their diet either highly purified ethyl esters of n-3 fatty acids ("fish oil"; 6 g of oil per day, containing 5 g of eicosapentaenoic and docosahexaenoic acid) or an isoenergetic amount of corn oil containing mainly n-6 fatty acids. All the patients were advised to reduce their intake of saturated fatty acids. A 48-hour dietary recall was performed, and the fatty-acid pattern in the serum phospholipids was monitored in a subgroup of patients. RESULTS: In the fish-oil group, n-3 fatty acids were increased in serum phospholipids (P < 0.001), the ratio of arachidonic acid to eicosapentaenoic acid decreased (P < 0.001), and the level of n-6 fatty acids decreased (P < 0.001). In the corn-oil group, only docosahexaenoic acid increased significantly (P < 0.05). The ratio of polyunsaturated to saturated fatty acids increased in both groups. Plasma concentrations of triacylglycerol decreased from base line in the fish-oil group (P < 0.05). The score on the Psoriasis Area and Severity Index, as evaluated by the physicians, did not change significantly during the trial in either group. This was also true of a total subjective score reported by the patients, but a selected area of skin in the corn-oil group showed a significant reduction in the clinical signs (P < 0.05). Scaling was reduced from base line in both groups (P < 0.01). The fish-oil group had less cellular infiltration (P < 0.01), and the corn-oil group had improvement in desquamation and redness (P < 0.05). There was no significant difference in clinical manifestations between the groups. Among the patients in the fish-oil group, an increase in the concentration of n-3 fatty acids in serum phospholipids was not accompanied by clinical improvement, whereas in the corn-oil group there was a significant correlation between clinical improvement and an increase in eicosapentaenoic acid and total n-3 fatty acids. CONCLUSIONS: Dietary supplementation with very-long-chain n-3 fatty acids was no better than corn-oil supplementation in treating psoriasis. Clinical improvement was not correlated with an increase in the concentration of n-3 fatty acids in serum phospholipids among the patients in the fish-oil group, whereas there was a significant correlation between clinical improvement and an increase in eicosapentaenoic acid and total n-3 fatty acids in the corn-oil group.

Very long chain n-3 and n-6 polyunsaturated fatty acids inhibit proliferation of human T-lymphocytes in vitro.

The effect of marine n-3 polyunsaturated fatty acids on proliferation of human T-cells in vitro was compared to other polyunsaturated, monounsaturated and saturated fatty acids. Monoenes and saturated fatty acids had little effect on T-cell proliferation. Eicosapentaenoic acid and docosahexaenoic acid exerted a strong dose-dependent inhibitory effect on proliferation of mitogen- or antigen-stimulated T-cells, similar to that observed for arachidonic acid. Sixty microM of albumin-bound eicosapentaenoic acid or arachidonic acid promoted 25-40% inhibition of proliferation of T-cells stimulated with mitogen, whereas the same concentration of albumin-bound docosahexaenoic acid promoted 60% inhibition. When epidermal cells (Langerhans cells) were used as antigen-presenting cells, 100 microM of albumin-bound eicosapentaenoic acid or arachidonic acid caused 40% inhibition on T-cell proliferation. Low density lipoprotein (LDL), isolated after four months of dietary intake of fish oil or corn oil, inhibited mitogen-stimulated T-cell proliferation in a dose-dependent manner. Fish oil- and corn oil-enriched LDL showed similar ability to inhibit T-cell proliferation. Epidermal cells preincubated with docosahexaenoic acid, and extensively washed before adding purified T-cells and antigen, resulted in a strong inhibition of T-cell proliferation, whereas preincubation of purified T-cells with docosahexaenoic acid did not cause any inhibitory effect. Cyclooxygenase and lipoxygenase inhibitors (indomethacin, acetylsalicylic acid, nordihydroguaertic acid) did not affect the antiproliferative effect of eicosapentaenoic acid and arachidonic acid, neither did the antioxidants butylated hydroxytoluene or alpha-tocopherol. Eicosanoids, (PGE2, PGE3, LTB4, LTB5 and lipoxin A or lipoxin B) added directly to mitogen-stimulated peripheral blood mononuclear cells (PBMC) did not influence T-cell proliferation significantly. Decreased viability was observed when mitogen-stimulated lymphocytes were cultured with essential polyunsaturated fatty acids, whereas the viability of unstimulated lymphocytes was hardly influenced by the same fatty acids. We conclude that; (a) pharmacological albumin-bound concentrations of the highly unsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid promote a strong antiproliferative effect on mitogen- and antigen-stimulated human T-cells: (b) docosahexaenoic acid can suppress accessory cell function and consequently suppress T-cell activation; (c) physiologic concentration of LDL particles rich in n-3 and n-6 fatty acids, both promote a dose-dependent antiproliferative effect on mitogen-stimulated PBMC; (d) the inhibition is independent of eicosanoid metabolites; and (e) lipid peroxidation seems unlikely to be responsible for the antiproliferative effect.

Oral magnesium supplementation improves metabolic variables and muscle strength in alcoholics.

Magnesium deficiency is common among chronic alcoholics, but the knowledge of oral magnesium supplementation to this group is limited. We, therefore, randomized 49 chronic alcoholics, moderate to heavy drinkers for at least 10 years to receive oral magnesium or placebo treatment for 6 weeks according to a double-blind protocol. Effects on metabolic variables and muscle strength were analyzed. Significant reduction of aspartate-aminotransferase (ASAT), alanine-aminotransferase (ALAT) and gamma-glutamyl-transpeptidase (GGT) were seen after magnesium, whereas no change was observed with placebo. Bilirubin decreased in both groups. Serum Na, Ca, and P increased significantly during magnesium therapy compared with no statistically significant change in the placebo group. Serum K and Mg increased slightly after magnesium supplementation and decreased in the placebo group, resulting in a significant difference between the two groups at the end of the study. Muscle strength increased significantly during magnesium treatment, contrasting to no change with placebo. Blood pressure, heart rate, hematological variables, serum lipids (cholesterol, HDL, TG), glucose tolerance, and creatinine were unchanged in the two groups after treatment. Alcohol consumption was similar before and during the trial and does not explain the differences between the two groups The results shows that short-term oral magnesium therapy may improve liver cell function, electrolyte status, and muscle strength in chronic alcoholics.

Effect of dietary supplementation with n-3 polyunsaturated fatty acids on physical properties and metabolism of low density lipoprotein in humans.

The effects of marine n-3 polyunsaturated fatty acids were investigated in relation to the chemical and physical properties of low density lipoprotein (LDL) and how these changes affected LDL metabolism in humans. The subjects received supplements of six capsules daily, each capsule containing 1 g of either highly concentrated ethyl esters of n-3 fatty acids (85% eicosapentaenoic acid and docosahexaenoic acid) (n = 12) or corn oil (56% linoleic and 26% oleic acid) (n = 11). After 4 months of oil supplementation, the following changes were observed in the lipid moiety of the n-3-enriched LDL particles compared with LDL from the corn oil group: LDL cholesteryl ester, as well as the amount of total lipids of LDL, was significantly lower (0.97 +/- 0.12 versus 1.19 +/- 0.23 mg/mg protein and 1.88 +/- 0.40 versus 2.45 +/- 0.31 mg/mg, respectively; mean +/- SD, n = 6, p less than 0.05); the amount of eicosapentaenoic and docosahexaenoic acids and the unsaturation index increased (104.0 versus 29.4 micrograms/mg protein and 6.64 versus 5.49, respectively); and differential scanning calorimetry showed that LDL cholesteryl ester melting temperature was lowered by 2 degrees C (27.6 +/- 0.8 degrees versus 29.5 +/- 0.2 degrees C). The only effect observed on the protein moiety was an increase in the ratio of apolipoprotein (apo) B to cholesterol (0.66 +/- 0.17 versus 0.82 +/- 0.14 mg/mg cholesterol; p less than 0.05). Circular dichroism spectra of LDL indicated an alpha-helix content of 46 +/- 5% in apo B from both groups. No difference was observed by 13C nuclear magnetic resonance spectroscopy in the ratio of "active" to "normal" lysine residues of apo B. No detectable differences in the size of n-3 fatty acid-enriched LDL particles versus control LDL could be measured by either electron microscopy of negatively stained LDL (24.5 +/- 2.0 versus 25.0 +/- 1.5 nm) or dynamic light scattering (24.9 +/- 0.9 versus 24.9 +/- 0.4 nm). LDL from the fish oil and corn oil groups showed similar susceptibility to Cu(2+)-catalyzed lipid peroxidation, as indicated by the amount of lipid peroxides formed during the oxidation time, and degradation of oxidatively modified LDL in J774 macrophages as a function of Cu2+ oxidation time. No effect of n-3 fatty acids was observed on LDL metabolism. Specific uptake and degradation of n-3 fatty acid-enriched LDL were similar to those for control LDL in HepG2 cells as well as in human skin fibroblasts, and they showed the same ability to stimulate cholesteryl ester synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

[Beta blockaders and physical performance. Limiting factors]. / Betablokkere og fysisk arbeidstoleranse. Begrensende faktorer.

Beta blockers are known to cause reduced exercise performance in hypertensive and healthy subjects. Additive effects of selective blockade of beta-1 and beta-2 receptor subtypes seems to account for the total reduction in exercise capacity observed with non-selective beta-1,2 blockade. The mechanism is as yet undefined. The magnitude of the reduction is dependent of type of exercise and level of fitness. Hemodynamic parameters, substrate delivery to the working muscles, mental factors, and interference with potassium homeostasis may be involved.