Insulin sensitivity index, acute insulin response, and glucose effectiveness in a population-based sample of 380 young healthy Caucasians. Analysis of the impact of gender, body fat, physical fitness, and life-style factors.

BACKGROUND: Insulin sensitivity and insulin secretion are traits that are both genetically and environmentally determined. AIM: The aim of this study was to describe the distribution of the insulin sensitivity index (Si), the acute insulin response, and glucose effectiveness (Sg) in young healthy Caucasians and to estimate the relative impact of anthropometric and environmental determinants on these variables. METHODS: The material included 380 unrelated Caucasian subjects (18-32 yr) with measurement of Si, Sg and insulin secretion during a combined intravenous glucose (0.3 grams/kg body weight) and tolbutamide (3 mg/kg body weight) tolerance test. RESULTS: The distributions of Si and acute insulin response were skewed to the right, whereas the distribution of Sg was Gaussian distributed. Sg was 15% higher in women compared with men (P < 0.001). Waist circumference, body mass index, maximal aerobic capacity, and women's use of oral contraceptives were the most important determinants of Si. Approximately one-third of the variation of Si could be explained by these factors. Compared with individuals in the upper four-fifths of the distribution of Si, subjects with Si in the lowest fifth had higher waist circumference, higher blood pressure, lower VO2max, and lower glucose tolerance and fasting dyslipidemia and dysfibrinolysis. Only 10% of the variation in acute insulin response could be explained by measured determinants. CONCLUSION: Estimates of body fat, maximal aerobic capacity, and women's use of oral contraceptives explain about one-third of the variation in Si in a population-based sample of young healthy Caucasians.

Receptor-ligand interactions measured by an improved spun column chromatography technique. A high efficiency and high throughput size separation method.

Size exclusion chromatography may under the right circumstances be an easy and powerful way to measure in solution the interaction between a receptor an dits ligand. Spun column chromatography is a fast size exclusion technique of increasing popularity, however, little information exists on the method development essential to obtain efficient separation in particular when used for analytical purposes. In this paper we describe a systematic approach to select the optimal parameters for spun column separation including a simple modification of the technique whereby the spun columns are eluted by high-speed gradient centrifugation. This modification is easy to implement and it considerably improves spun column performance. We hypothesize that the high-speed centrifugation step leads to the release of additional buffer which assists in the complete elution of excluded molecules while the gradient centrifugation helps to achieve equilibrium across the gel matrix during the elution. The new method has been used successfully for several different receptor-ligand interactions, and this paper describes a general approach on how to develop new applications of the technique.

BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age.

INTRODUCTION: A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carriers frequently have a positive family history of breast and ovarian cancer, are often diagnosed at a young age, and may have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general. OBJECTIVES: To estimate the prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish patients affected with bilateral or multifocal breast cancer and to determine the relationship of mutation status to family history of cancer. SUBJECTS: From the files of the Danish Breast Cancer Cooperative Group (DBCG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) disease. METHODS: DNA from the subjects was screened for BRCA1 and BRCA2 mutations using single strand conformation analysis (SSCA) and the protein truncation test (PTT). Observed and expected cancer incidence in first degree relatives of the patients was estimated using data from the Danish Cancer Registry. RESULTS: Twenty four mutation carriers were identified (20%), of whom 13 had a BRCA1 mutation and 11 carried a BRCA2 mutation. Two mutations in BRCA1 were found repeatedly in the material and accounted for seven of the 24 (29%) mutation carriers. The mutation frequency was about equal in patients with bilateral (22%) and multifocal breast cancer (18%). The incidence of breast and ovarian cancer was greatly increased in first degree relatives of BRCA1 and BRCA2 mutation carriers, but to a much lesser degree in relatives of non-carriers. An increased risk of cancer was also noted in brothers of non-carriers. CONCLUSIONS: A relatively broad spectrum of germline mutations was observed in BRCA1 and BRCA2 and most of the mutations are present in other populations. Our results indicate that a diagnosis of bilateral and multifocal breast cancer is predictive of BRCA1 and BRCA2 mutation status, particularly when combined with information on the patients' age at diagnosis and family history of breast/ovarian cancer.

The effectiveness of a standardized rose hip powder, containing seeds and shells of Rosa canina, on cell longevity, skin wrinkles, moisture, and elasticity.

OBJECTIVE: To evaluate the effects of a rose hip powder (Hyben Vital(®)) made from seeds and shells on cell senescence, skin wrinkling, and aging. METHODS: A total of 34 healthy subjects, aged 35-65 years, with wrinkles on the face (crow's-feet) were subjected to a randomized and double-blinded clinical study of the effects of the rose hip powder, as compared to astaxanthin, a well-known remedy against wrinkles. During the 8-week study, half of the participants ingested the standardized rose hip product, while the other half ingested astaxanthin. Objective measurements of facial wrinkles, skin moisture, and elasticity were made by using Visioscan, Corneometer, and Cutometer at the beginning of the study, after 4 weeks, and after 8 weeks. Evaluation of participant satisfaction of both supplements was assessed using questionnaires. In addition, the effect of the rose hip preparation on cell longevity was measured in terms of leakage of hemoglobin through red cell membranes (hemolytic index) in blood samples kept in a blood bank for 5 weeks. Significance of all values was attained with P≤0.05. RESULTS: In the double-blinded study, the rose hip group showed statistically significant improvements in crow's-feet wrinkles (P<0.05), skin moisture (P<0.05), and elasticity (P<0.05) after 8 weeks of treatment. A similar improvement was observed for astaxanthin, with P-values 0.05, 0.001, and 0.05. Likewise, both groups expressed equal satisfaction with the results obtained in their self-assessment. The rose hip powder further resulted in increased cell longevity of erythrocyte cells during storage for 5 weeks in a blood bank. CONCLUSION: Results suggest that intake of the standardized rose hip powder (Hyben Vital(®)) improves aging-induced skin conditions. The apparent stabilizing effects of the rose hip product on cell membranes of stored erythrocyte cells observed in this study may contribute to improve the cell longevity and obstructing skin aging.

Postmortem findings in cloned and transgenic piglets dead before weaning.

Important factors contributing to the well-known high mortality of piglets produced by SCNT are gross malformations of vital organs. The aim of the present retrospective study was to describe malformations found in cloned piglets, transgenic or not, dying or culled before weaning on Day 28. Large White (LW) embryos were transferred to 78 LW recipients, while 72 recipients received Göttingen embryos (67 transgenic and five not transgenic) and 56 received Yucatan embryos (43 transgenic and 13 not transgenic). Overall pregnancy rate was 76%, and there were more abortions in recipients with minipig embryos than in those with LW embryos (26% and 24% vs. 6%). Piglets (n = 815) were born from 128 sows with 6.5 ± 0.4 full-born piglets per litter. The overall rate of stillborn piglets was 21% of all born with the number of stillborn piglets ranging from one to nine in a litter. The mortality of the surviving piglets during the first month was 48%. Thus, altogether 58% of the full-born piglets died before weaning. In 87 of the 128 litters (68%), one to 12 of the piglets showed major or minor malformations. Malformations were found in 232 piglets (29.5% of all born). A single malformation was registered in 152 piglets, but several piglets showed two (n = 58) or more (n = 23) malformations (7.4% and 2.8% of all born, respectively). A significantly higher malformation rate was found in transgenic Göttingen and Yucatan piglets (32% and 46% of all born, respectively) than in nontransgenic LW (17%). There was a gender difference in the transgenic minipigs because male piglets had a higher rate of malformations (49.1%) than females (29.7%). The most common defects in the cloned piglets were in the digestive (12.2%), circulatory (9.4%), reproductive (11.3%), and musculoskeletal (9.1%) systems. Malformations of the musculoskeletal system were most frequent in Göttingen (16.3% vs. approximately 5.5% in the two other breeds), whereas abnormal cardiopulmonary systems were most frequent in Yucatan piglets (26.9% vs. 2.1% in LW and 5.3% in Göttingen). In conclusion, these results show that pig cloning results in a considerable loss of piglets and that many of these can be related to various malformations that all are also seen in noncloned piglets. Because approximately half of the cloned piglets still survive, even with eventual unknown minor malformations, use of pigs as models for human diseases is still realistic. However, continued efforts are needed to further reduce the level of malformations.

Differential effects of non-specific beta-blockade and calcium antagonism on blood-clotting mechanisms.

The effects of non-selective beta-blockade (timolol, 5 mg twice daily) and calcium antagonism (isradipine, 2.5 mg twice daily) on heart rate, blood pressure, platelet aggregation, fibrinolytic activity, and platelet cyclic adenosine monophosphate content were investigated in 10 patients with mild hypertension in a randomized, placebo-controlled, double-blind study. Each patient served as his or her own control, taking each drug in turn for two weeks. Both drugs lowered blood pressure to the same degree. During timolol treatment, however, platelet aggregation increased whereas isradipine resulted in a shortening of the euglobulin clot lysis time (p less than 0.05), indicating increased fibrinolytic activity. Platelet aggregation and fibrinolytic activity are modified by cyclic adenosine monophosphate. Since beta-adrenoceptors are present on platelets and endothelial cells, the differences in platelet behavior and fibrinolytic activity may reflect a decreased cyclic adenosine monophosphate production caused by non-selective beta-adrenoceptor blockade.

Platelet function in surgical stress.

Ten patients for elective cholecystectomy were studied pre-, per-and postoperatively. All had neurolept anesthesia. Plasma concentrations of beta-TG, TXB2 and 5-HT and intraplatelet 5-HT were measured. Aggregation to ADP was recorded. Serum cortisol concentration was used as index of the stress response, showing peroperative increase and postoperative decrease. Closely related to this we observed a significant increase in P--beta-TG and P-TXB2 with postoperative normalization in 6 patients without complications. P--5-HT had a peak peroperatively and remained elevated postoperatively. A negative correlation between P--5-HT and decreasing intraplatelet 5-HT postoperatively was observed. High postoperative levels of P--5-HT seem to be related to low arterial PO2 and pulmonary dysfunction. In 3 patients with complications a second increase in P--beta-TG, P-TXB2 and partly in P--5-HT was found. Platelets were temporarily refractory to ADP immediately following surgery and showed increased aggregability postoperatively. We conclude that platelets are activated in surgical stress.

Effects on platelet aggregation and fibrinolytic activity during upright posture and exercise in healthy men.

The circadian variation of acute myocardial infarction suggests that daily activities such as assuming the upright posture and performing different daily activities may trigger the onset of coronary thrombosis. Such triggering may result from unfavorable alterations in the balance between the prothrombotic and antithrombotic properties of the blood. The present study compares the effects of 2 common daily activities, assuming the upright posture and exercise, on platelet aggregation and fibrinolytic activity. In healthy male subjects, assuming the upright posture in the morning significantly increased platelet aggregation and produced only a moderate increase in fibrinolytic activity within 10 minutes. These changes were still present after 90 minutes in the upright posture. Supine posture for 45 minutes resulted in levels of fibrinolytic activity and platelet aggregation comparable to that observed before initially assuming the upright posture in the morning. Return to the supine posture for 45 minutes resulted in levels of fibrinolytic activity and platelet aggregation comparable to that observed before the initial assumption of upright posture. The changes recurred when upright posture was taken later in the day. Exercise did not increase platelet aggregation to levels beyond that produced by the upright posture, but was associated with a marked increase in fibrinolytic activity. Thus, exercise and upright posture produce distinctive alterations in the thrombogenic potential of the blood that may influence the timing of clinical vascular events.

Rapidity and duration of platelet suppression by enteric-coated aspirin in healthy young men.

The recent demonstration of aspirin's ability to prevent and reduce the severity of myocardial infarction has led to a marked increase in its use and to a need for information regarding the time-course of onset and offset of its antiplatelet effect. A study of healthy men was conducted to determine (1) the rapidity of onset of inhibition of platelet aggregation in response to adenosine diphosphate, and thromboxane A2 production after chewed enteric-coated aspirin (325 mg, n = 10); and (2) the duration of platelet inhibition after cessation of enteric-coated aspirin (325 mg) every other day for 14 days (n = 10). When chewed, enteric-coated aspirin greatly inhibited platelet aggregation response to adenosine diphosphate and thromboxane A2 production within 15 minutes. Complete recovery of platelet aggregation occurred in half of the subjects by day 3, and in 80% of the subjects by day 4; the platelet response was not affected by exercise. This study demonstrates a rapid onset of aspirin's antiplatelet effect and provides information relevant for optimal timing of initiation of aspirin for acute conditions such as myocardial infarction and unstable angina, and cessation of aspirin before surgery.

Platelet function and fibrinolytic activity in hypertensive and normotensive sleep apnea patients.

Platelet function and fibrinolytic activity was studied during rest and after ergometric exercise in 13 hypertensive or normotensive patients with obstructive sleep apnea (OSA) and in 10 sex- and weight-matched controls. All patients had undergone a complete polysomnography for the diagnosis of OSA. The controls did not undergo any sleep investigation but had no history of snoring or witnessed apneas during sleep. On antihypertensive drug wash-out, two of the patients were normotensive, whereas 11 had mild to moderate hypertension. Platelet aggregation measured by adenosine 5'-diphosphate- or adrenaline-induced aggregation, platelet factor-4 or beta-thromboglobulin did not differ between patients and controls. During exercise beta-thromboglobulin decreased significantly in both OSA patients and controls. Plasma tissue plasminogen activator activity was similar in OSA patients and controls and increased significantly in both groups after exercise. Plasminogen activator inhibitor type 1 (PAI-1) was 18.4 +/- 3.6 IU/ml in OSA patients compared with 8.2 +/- 1.7 IU/ml in controls (p < 0.029) during rest, indicating decreased fibrinolytic activity. The difference between groups remained after exercise (p < 0.017). Blood pressure elevation was more common and body mass index (BMI) was higher in patients with OSA, but there was no direct relation between blood pressure level or BMI and PAI-1. Nevertheless, differences between groups were smaller when blood pressure and obesity were accounted for. It is concluded that patients with OSA may exhibit decreased fibrinolytic activity. Low fibrinolytic activity may represent a confounding pathophysiological mechanism behind the high incidence of myocardial infarction and stroke in patients with OSA.

Inhibition of human platelet aggregation by dihydropyrano- and dihydrofuranocoumarins, a new class of cAMP-phosphodiesterase inhibitors.

Certain esters of dihydropyranocoumarin and dihydrofuranocoumarin alcohols have previously been shown to inhibit the cAMP-phosphodiesterase from bovine heart. We now report that these naturally occurring coumarins inhibit the high affinity (Km = 1.1 microM) cAMP-phosphodiesterase from human platelets with activities that closely correlate with those obtained using phosphodiesterase from bovine heart tissue. Additionally the coumarins inhibit the aggregation of human platelets induced with ADP, adrenaline and collagen with activities comparable to those of dipyridamole. A lack of significant correlation between these metabolic and functional activities indicates that there exist, besides cAMP-phosphodiesterase inhibition, additional mechanisms of action for the platelet aggregation inhibitory effect of dihydropyrano- and dihydrofuranocoumarins.

Intestinal and extra-intestinal cancer in Crohn's disease: follow-up of a population-based cohort in Copenhagen County, Denmark.

AIM: To determine the long-term risk of intestinal and extra-intestinal malignancies in Crohn's disease patients in Copenhagen County, Denmark. METHODS: In Copenhagen County, a strictly population-based cohort of 374 patients with Crohn's disease diagnosed between 1962 and 1987 was followed until 1997 in order to determine the long-term risk of intestinal and extra-intestinal malignancies. Information on cancer occurrence was provided by the Danish National Cancer Registry and confirmed by the examination of hospital files. The observed number of cases was compared with the expected number, calculated from individually computed person-years at risk and 1995 cancer incidence rates for the background population. RESULTS: The risk of small bowel adenocarcinoma was significantly increased, independent of age and gender (standardized morbidity ratio, 66.7; 95% confidence interval, 18.1-170.7). The risk of colorectal cancer was not increased, either in the total group of patients or in patients with colonic Crohn's disease exclusively (standardized morbidity ratio, 1.64; 95% confidence interval, 0.20-5.92). Extra-intestinal cancer did not occur more frequently than expected. CONCLUSIONS: This population-based study of patients with Crohn's disease revealed no increase in colorectal cancer risk, possibly due to maintenance treatment with 5-aminosalicylic acid preparations and surgery in treatment failure. In contrast, the risk of small bowel cancer was increased more than 60-fold, but the numbers were small. The risk of extra-intestinal cancer was not increased and no lymphomas were observed.

Decreased fibrinolytic activity and increased platelet function in hypertension. Possible influence of calcium antagonism.

Twelve patients with mild hypertension were compared, after 14 days of placebo, with an age- and gender-matched group of 12 healthy volunteers for platelet aggregability and fibrinolytic activity. Following this, 10 of the 12 hypertensives were treated with the calcium antagonist isradipine for 12 months. Blood was drawn for determinations of platelet aggregation and fibrinolytic activity after two weeks and 12 months of treatment. Platelet aggregation tended to increase in the hypertensives compared with controls, indicated by a lowering of the adenosine diphosphate (ADP) threshold value for irreversible aggregation. Tissue-plasminogen activator (t-PA) activity was significantly decreased in hypertensives compared to controls (P less than .05). During therapy, platelet aggregation decreased and t-PA activity increased (P less than .05). The present data suggest that fibrinolytic activity is decreased and platelet aggregation increased in mild hypertension. Besides the blood pressure-lowering effect, isradipine may protect against thromboembolic diseases by modifying platelet function and fibrinolytic activity.

Beneficial effect of isradipine on the development of left ventricular hypertrophy in mild hypertension.

The objective of this study was to analyze the long-term hemodynamic effects of the calcium antagonist isradipine in mild hypertension compared with those of the beta 1-selective adrenoceptor antagonist atenolol, focusing in particular on the development of cardiac hypertrophy. Ten male patients with mild essential hypertension were entered into a double-blind crossover study. Examinations were carried out after 2 weeks of placebo run-in, and after 6 and 12 months of active treatment. Mean resting blood pressure was reduced from 115 +/- 12 mm Hg to 106 +/- 12 mm Hg with atenolol, and to 107 +/- 8 mm Hg with isradipine. The increase in the product of heart rate times blood pressure was significantly greater during isradipine treatment, as was the maximum exercise capacity. Left ventricular mass was increased from 228 +/- 36 g to 305 +/- 68 g with atenolol whereas it remained unchanged with isradipine (254 +/- 55 g). The results indicate that antihypertensive treatment with isradipine as monotherapy may prevent the development of left ventricular hypertrophy whereas treatment with atenolol as monotherapy does not appear to offer this possibility.

Lewis phenotypes and the insulin resistance syndrome in young healthy white men and women.

An increased risk of ischemic heart disease in men with the Lewis blood group phenotype Le(a-b-) has been reported. It has been suggested that the Le(a-b-) phenotype is a genetic marker of the insulin resistance syndrome. To examine whether Le(a-b-) confers the insulin resistance syndrome, we studied a random sample of unrelated healthy young white men and women living in Copenhagen (n = 380, 18 to 32 years). All individuals had their insulin sensitivity estimated using Bergman's minimal model (intravenous glucose in combination with tolbutamide) and systolic blood pressure (SBP) was measured with a London School of Hygiene Sphygmomanometer. A number of anthropometric measurements including body mass index (BMI, kilograms/meters squared) and biochemical characteristics were performed. The Lewis blood group typing was carried out on erythrocytes. Twenty-one men had the Le(a-b-) phenotype. Compared to all other men (N = 165), the Le(a-b-) men had a significantly higher SBP (6 mm Hg, P = .0024). They also had higher values of BMI (8%, P = .016), total body fat mass (25%, P = .015), fasting values of serum insulin (32%, P = .006), serum C-peptide (20%, P = .029), and plasma glucose (8%, P = .003). The fasting values of serum lipids, plasminogen activator inhibitor (PAI-1) activity, tissue plasminogen activator (t-PA) antigen, and insulin sensitivity did not differ between Le(a-b-) men and men with other Lewis phenotypes. Altogether 194 women participated in the study of which 21 women had the Le(a-b-) phenotype. Except for a lower PAI-1 activity (45%, P = .044), no values differed between Le(a-b-) women and women with other Lewis phenotypes. The women were also stratified according to use of oral contraceptives. Le(a-b-) women using oral contraceptives (N = 8) had a significantly lower plasma level of fasting PAI-1 activity (P = .029) and t-PA antigen (P = .004) compared to women using oral contraceptives without the Le(a-b-) phenotype (N = 42). Our data support the hypothesis that Le(a-b-) men exhibit features of the insulin resistance syndrome, including higher levels of BMI, SBP, and fasting levels of serum insulin and plasma glucose. In young women no signs of the insulin resistance syndrome were found in subjects with the Le(a-b-) phenotype.

Aging and platelet beta-adrenoceptor function.

Ten young volunteers (mean age 20 years) and ten elderly volunteers (mean age 89 years), including equal numbers of healthy men and women, were tested regarding adrenaline-induced platelet aggregation in vitro, platelet cyclic AMP content before and after beta-adrenoceptor stimulation with isoprenaline, as well as binding by platelet membranes of 125I-hydroxybenzylpindolol. In the aged patients there was a highly significant decrease in the concentration of adrenaline needed to produce irreversible platelet aggregation, as compared with the young. Platelet basal cyclic AMP content did not differ but the response to isoprenaline stimulation, expressed as the percentage rise of cyclic AMP content above the unstimulated level, was significantly decreased in the old subjects. The beta-adrenoceptor number was unchanged but the affinity decreased significantly in the old group. The data suggest that the increased aggregation response to adrenaline in old people could be due in part to a diminished functional capacity of the platelet beta-adrenoceptor.

Time course of platelet alpha granule release in acute myocardial infarction treated with streptokinase.

OBJECTIVE: To determine the time course of platelet alpha granule release in patients with acute myocardial infarction treated with streptokinase. DESIGN: A prospective study. SETTING: Coronary care unit. PATIENTS: Nine with myocardial infarction treated with both streptokinase and aspirin, and nine with acute chest pain but without myocardial infarction, who were treated with aspirin only. METHODS: All patients received 250 mg aspirin on admission and 150 mg once daily thereafter. All patients who fulfilled the indications for streptokinase received 1.5 megaunits, in a single infusion. After the initial medication, serial measurements of plasma beta thromboglobulin and plasma platelet factor 4 were performed at fixed intervals after the onset of chest pain. The primary endpoint sought was the peak value of beta thromboglobulin and platelet factor 4 in each individual. RESULTS: The median peak plasma beta thromboglobulin in the infarction group was substantially higher than in those without infarction, at 37 (range 12 to 210) v 15 (9 to 36) mg/litre, P < 0.01. The corresponding values for plasma platelet factor 4 were 4.6 (2.4 to 60.0) v 2.2 (< 2 to 8.5) mg/litre, P < 0.01. Increased values were seen only within the first 12 h after onset of chest pain, and after 12 h there was no difference between the patients with myocardial infarction and those without. Aspirin treatment did not abolish alpha granule release. CONCLUSIONS: In patients with acute myocardial infarction treated with streptokinase the content of the alpha granules is released within the first 12 h after the onset of chest pain. Aspirin apparently does not abolish this release.

Platelet alpha-adrenoceptor function and aging.

The effect of aging on platelet alpha-adrenoceptor binding of 3H-dihydro-alpha-ergocryptine (3H-DHE) and alpha-adrenoceptor response expressed as cAMP decrease, after the addition of noradrenaline 10 microM to intact platelets in vitro were examined and correlated with adrenaline induced platelet aggregation in a group of twelve young volunteers (mean age 21 years), and twelve old volunteers (mean age 88 years). The binding by platelets of 3H-DHE was considerably higher in the young than in the old group (mean 292.70 +/- 40.79 and 167.90 +/- 18.30 fmol/mg protein respectively, p less than 0.02). The affinity (Kd) was also influenced with values of 1.49 +/- 0.21 in the young and 3.32 +/- 0.45 nM in the old, p less than 0.01). Stimulation of platelets with noradrenaline caused a greater decrement of cAMP in the old than in the young group (mean 4.44 +/- 0.87 as compared with 0.32 +/- 0.75 pmol/10(9) platelets. Platelet sensitivity to adrenaline, when expressed as aggregation increased in the old group. These data suggest that the enhanced sensitivity to adrenaline as observed in old people is not the result of increased alpha-adrenoreceptor number of affinity, but related to changes in the platelet membrane possibly not related to the alpha-adrenoceptors.

Characterization of human platelet beta-adrenoceptors.

The widespread use of beta-adrenoceptor antagonists against hypertension, angina pectoris and migraine or as a preventive treatment after myocardial infarction has encouraged us to investigate the effects of these drugs on platelet function. The aim of this study was to examine whether beta-blocking drugs interfere with platelet beta- adrenoceptors and whether this dependency is related to their selectivity for beta-adrenoceptor subtypes. Beta-adrenoceptor stimulation of human platelets with isoprenaline increased cyclic AMP (cAMP), which is known to inhibit platelet aggregation. Furthermore, our studies showed that cAMP formation in vitro was stimulated by non-selective and beta 2-selective agonists, but not by the predominant beta 1-agonist prenalterol. Isoprenaline- stimulated cAMP formation was blocked by the non- selective beta-adrenoceptor antagonists propranolol, timolol, and alprenolol, while the beta 1-selective antagonists atenolol and metoprolol had no influence on an isoprenaline-induced cAMP formation. Receptor binding studies using (3H)-dihydroalprenolol revealed an IC50 value for propranolol of 85 nM, while metoprolol only displaced the bound (3H)-dihydroalprenolol at far higher concentrations (IC50, 20 microM). We conclude that the human platelet beta-adrenoceptors are mainly of the beta 2- subtype and that beta-adrenoceptor antagonists, especially the non-selective antagonists interfere with platelet function assessed as platelet cAMP formation.

The impact of static work on fibrinolysis and platelet function.

Brief stress such as dynamic work protects against thrombosis by enhancing blood fluidity. The effect of isometric work on blood fluidity, however, is not known. The aim of the present study therefore was to test the effect of isometric work on heart rate (HR), blood pressure (BP), platelet function and fibrinolytic activity. Twelve healthy male volunteers were tested before and after isometric work. Isometric work resulted in an increase in HR from 62.4 to 110.0 beats/min and in systolic BP from 118.3 to 134.5 mmHg (p < 0.01). No significant change occurred in platelet release estimated as plasma levels of B-TG and PF-4, or platelet aggregation induced by ADP. Fibrinolytic activity increased, as evidenced by a decrease in ECLT from 136.7 + 10.5 to 72.3 + 9.8 min) (p < 0.01) and an increase in t-PA of 400%. No significant change was observed in PAI. The present data suggest that isometric work increases fibrinolytic activity significantly, but leaves platelet function unchanged.