Beta-thromboglobulin in urine and plasma: influence of coronary risk factors.

Blood platelet activation in vivo was evaluated by measuring beta-thromboglobulin in plasma and high molecular weight beta-thromboglobulin in urine in hypertensive smoking and nonsmoking middle-aged men (n=36) and in normotensive age-matched controls (n=40). We found no significant linear relationships between nocturnal or resting urinary high molecular weight beta-thromboglobulin and plasma beta-thromboglobulin in the combined hypertensive and normotensive groups. The excretion of high molecular weight beta-thromboglobulin correlated significantly with diastolic blood pressure when all subjects were pooled. After 60 minutes supine rest, nonsmokers had higher excretion of high molecular weight beta-thromboglobulin than smokers. Plasma beta-thromboglobulin levels tended to be higher in hypertensives. In multivariate analyses, resting high molecular weight beta-thromboglobulin excretion was positively related to diastolic blood pressure and negatively related to smoking, whereas plasma beta-thromboglobulin was positively related to diastolic blood pressure and inversely related to apolipoprotein A1 and B. We conclude that urinary high molecular weight beta-thromboglobulin and plasma beta-thromboglobulin are not closely related, but are complementary analyses, as there are methodological confounders for both variables.

Acute effects of cigarette smoking on platelet function and plasma catecholamines in hypertensive and normotensive men.

In this randomized controlled crossover study essential hypertensive men (n = 13) and matched normotensive controls (n = 18) were examined before and during cigarette and sham smoking to assess the acute effects of smoking on platelets and plasma catecholamines. Platelet activity in vivo was determined by measurements of the released alpha-granule constituent beta-thromboglobulin (beta-TG) in plasma and in urine. Urinary high molecular weight beta-TG and venous plasma epinephrine increased significantly during smoking in the hypertensive group, but not among the normotensive men. Thus, cigarette smoking induces a mild platelet release reaction and also elicits a significantly higher epinephrine response in hypertensive men compared to normotensive controls.

Monday and non-Monday concentrations of lifestyle-related blood components in the Oslo Diet and Exercise Study.

OBJECTIVE: We hypothesized that participants of intervention studies have an unfavourable lifestyle at the weekend compared with the rest of the week, thus affecting the concentrations of components in samples drawn on Mondays. DESIGN: The hypothesis was examined using data from the Oslo Diet and Exercise Study, a 2 x 2 randomized intervention trial on diet and exercise involving 209 participants. Each person chose which day of the week to attend for blood sampling, both before and after the 1 year of intervention. MAIN OUTCOME MEASURES: Comparison of mean concentrations of the components measured, in samples drawn on Mondays vs. non-Mondays, both at the start and at the end of intervention. RESULTS: At the start, nine components, from haemostasis, carbohydrate and lipid metabolism, showed a difference of more than 10% between Monday and non-Monday values, all Monday values differing from the non-Monday values in a cardiovascularly unfavourable direction. Participants starting and ending on a Monday showed the unfavourable profile both times, and those who were examined both times on a non-Monday showed a consistently favourable profile, whereas those who changed the day of examination at the start and end changed profile accordingly. CONCLUSION: The lifestyle-related components examined here showed differences between Monday and non-Monday values, which were not due to a selection bias. We suggest they may be related to a different lifestyle at the weekend compared with ordinary working days. If such effects are not recognized and properly taken into account, they may markedly affect the outcome of intervention studies.

Supplementary selenium influences the response to fatty acid-induced oxidative stress in humans.

The mutual influences of wheat selenium (Se) and n-3 polyunsaturated fatty acids (n-3 PUFA) on plasma Se and indicators of increased oxidative stress were investigated in a randomized, double-blind study with 31 women (23.5 +/- 3.4 yr). Groups 1 and 2 ingested 5.4 g n-3 PUFA daily (as ethyl esters), whereas groups 3 and 4 received placebo capsules. Groups 2 and 3 received 3 slices of high-Se bread daily, providing 115 micrograms Se, in addition to the 77 +/- 26 micrograms Se in the diet. Groups 1 and 4 received placebo slices. Blood samples were drawn at baseline and at 3 and 6 wk. Serum Se concentrations increased in both groups given Se-enriched bread, but significantly less in subjects given n-3 PUFA (group 2). There were no changes in the plasma ratio alpha-tocopherol:mg cholesterol or plasma ascorbic acid levels. In group 1, plasma-conjugated dienes and thiobarbituric acid-reactive substances (TBARS) rose by 130% (p < 0.005) and 126% (p < 0.005), respectively. Two-way ANOVA showed significant interaction effects of Se and n-3 PUFA on changes in conjugated dienes (p = 0.03) and TBARS (p = 0.015), Se treatment apparently modifying the peroxidative effects of n-3 PUFA. In subjects receiving n-3 PUFA, changes in conjugated dienes and TBARS were negatively correlated with changes in serum Se. In summary, n-3 PUFA modified the effect of Se supplementation, whereas Se seemed to modify the peroxidative effects of n-3 PUFA.

Transdermal nitroglycerin: clinical and pharmacokinetic consequences of renewing the patch and the application site.

OBJECTIVE: We examined whether nitroglycerin (glyceryl trinitrate, GTN) patch treatment for 24 h could induce local cutaneous changes that impaired drug delivery and clinical efficacy. METHODS: Twenty angina patients were exercise-tested after 2 and 24 h of treatment and then 2 h after patch renewal. The patch was either renewed on a new skin location or on the previous application site in a randomised, double-blind, cross-over protocol. GTN plasma concentrations and finger plethysmography were obtained before and after each exercise test. RESULTS AND CONCLUSIONS: The clinical efficacy, the effect seen on plethysmography and the GTN plasma concentrations tended to increase after patch renewal, regardless of the application site of the renewed patch. Hence, cutaneous changes of clinical importance could not be demonstrated.

Mechanisms of tolerance during treatment with nitroglycerin patches for 24 h.

OBJECTIVE: We examined the relationship between tolerance development, counterregulatory responses and arterial vasodilating effects evaluated by digital pulse plethysmography. METHODS: Twenty patients with stable angina pectoris were exercise tested before, after 2 and after 24 h of open nitrate patch treatment. RESULTS: The effects observed after 2 h of treatment on exercise duration, ST-segment depression, blood pressure and heart rate were lost in most individuals after 24 h. In contrast, the effects on the arterial pulse curves persisted after 24 h, with a mean change from baseline of 29%, compared to 33% at 2 h. After 24 h, a significant decrease in haematocrit and an increase in body weight were observed. The haematocrit changes correlated with the loss of clinical efficacy (r = 0.57 for ST-segment depression, and r = 0.54 for exercise duration). CONCLUSION: Clinical nitrate tolerance may be observed despite maintenance of the arterial vasodilating effects, and tolerance is more related to plasma volume expansion as a counterregulatory mechanism.

Blood platelet responses to laboratory stress in young men. The effect of awareness of high blood pressure.

Healthy 19-year old males from the 95th percentile of mean arterial screening blood pressure were randomized to prolonged mental stress by receiving a letter informing of a high screening blood pressure (n = 13), or a neutral letter (n = 13). Blood platelet function in vivo was assessed by measurements of plasma concentrations of the platelet-specific protein beta-thromboglobulin, platelet counts, and mean platelet volumes before and during two laboratory stress tests (hand cold pressor test and arithmetic challenge). The cold pressor test caused a significant increase in beta-thromboglobulin concentrations in both groups, and significantly more in the uniformed group. Platelet count increased significantly in both groups during mental arithmetic with significantly higher counts in the uninformed group. Overall plasma beta-thromboglobulin responses were significantly larger in the uninformed group. This study demonstrates that laboratory stress is associated with blood platelet activation and that awareness of high blood pressure attenuates the platelet responses to such stress tests.

Effects of carvedilol and atenolol on arterial pulse curves (plethysmography) and finger temperature after hand cooling.

OBJECTIVE: In a double-blind, parallel study, the effects of 25 mg carvedilol and 50 mg atenolol on peripheral finger circulation and arterial pulse curve configuration were compared. METHODS: Healthy volunteers (n = 17) were examined at baseline and for 15 min after 60 s of hand cooling in ice-water. Finger temperature and digital plethysmography were recorded each minute from the cooled and the control hands. Measurements were also made before and 2 h after drug administration. RESULTS: Blood pressure declined from 120/86 to 108/74 mm Hg after atenolol (n = 9), and from 122/88 to 108/73 mm Hg after carvedilol (n = 8). In both groups, baseline finger temperature increased slightly after drug, and a more rapid rise in finger temperature was observed after cooling. There was no group difference in the drug effect on finger temperature, except in the first few minutes after cooling, when temperature recovery was greater after carvedilol. Carvedilol reduced the vasoconstrictor response to local cooling (digital plethysmography), compared both to the value before drug and after atenolol. At rest, carvedilol changed the pulse curves (control hand) towards vasodilatation and high compliance, expressed as a mean change in the relative height of the dicrotic notch of -10.3% versus 0.0% after atenolol. CONCLUSION: Future studies should clarify whether the vasoactive profile of carvedilol may translate into reduced occurrence of cold hands and feet amongst patients treated for hypertension.

Acute effects of low dose nicotine gum on platelet function in non-smoking hypertensive and normotensive men.

Twenty non-smoking middle-aged men with mild untreated essential hypertension were compared to age-matched controls (n = 22) in a double-blind placebo controlled study. Plasma and urinary concentrations of the platelet-specific protein beta-thromboglobulin (beta-TG), platelet count and mean platelet volume were measured before and after chewing 2 mg nicotine gum. The mean plasma nicotine concentration increased to 4.3 ng/ml in the hypertensive group and to 3.9 ng/ml in the normotensive group after 30 minutes of chewing the nicotine gum. Blood pressure and heart rate increased significantly, but there was no difference between the groups. Venous plasma catecholamine concentrations were unchanged. beta-TG concentrations in plasma and urine were similar in the two groups, and plasma beta-TG levels did not change after nicotine gum in either group. Urinary high molecular weight beta-TG decreased after nicotine compared to placebo. Platelet count and volume increased significantly in the hypertensive group, but not in the normotensive group. The response in platelet count was significantly higher in the hypertensive group. Thus, small amounts of nicotine increase platelet counts more in hypertensive than in normotensive non-smoking men, without inducing the platelet release reaction.

Does dietary arsenic and mercury affect cutaneous bleeding time and blood lipids in humans?

Fish species may contain considerable amounts of trace elements, such as selenium (Se), arsenic (As), and mercury (Hg). The present study investigated the relationships between dietary intake of these elements and cutaneous bleeding time and blood lipids in 32 healthy volunteers. For 6 wk, one group (n = 11) consumed approx 250 g Se-rich fish daily, providing them with an average Se intake of 115 +/- 31 micrograms Se/d, Hg intake of 18 +/- 8 micrograms/d, and As intake of 806 +/- 405 micrograms/d, all values analyzed in 4-d duplicate food collections. To study the effect of Se alone, one group (n = 11) included Se-rich bread in their normal diet, giving them a Se intake (135 +/- 25 micrograms/d) that was comparable to the fish group. A control group (n = 10) ate their normal diet, providing 77 +/- 25 micrograms Se/d, 3.1 +/- 2.5 micrograms Hg/d, and 101 +/- 33 micrograms As/d. The dietary As load strongly correlated both with bleeding times and changes in bleeding times (r = 0.48, p < 0.01 and r = 0.54, p < 0.002, respectively). Dietary Hg showed a positive correlation with LDL-cholesterol (r = 0.55, p < 0.01), whereas dietary Hg in the fish group showed a strong negative relationship with HDL-cholesterol (r = -0.76, p < 0.01). Selenium seemed to have only a modest effect on bleeding time. Our results suggest that mercury and arsenic from fish may be factors contributing to or modifying some of the known effects of fish ingestion.

Bleeding times related to serum triglyceride levels in healthy young adults.

A diet rich in fish tends to increase the bleeding time both in patients and healthy controls. Another effect of such a diet is a reduction in serum triglyceride levels in the individuals. It is not known whether these two effects are interrelated. In order to rule out effects of selenium in the fish diet, half of a control group consumed bread enriched with selenium while the other half had a normal diet. This combined control group (n = 21) was compared with healthy volunteers (n = 11) eating 250 g of fish daily for six weeks. Blood tests were performed at the start of the study, after three weeks and at the end. Changes in bleeding time were then related to changes in hemostatic variables and serum lipids. An inverse correlation (r = -0.41, p = 0.001) was present in the controls between serum triglyceride levels and bleeding times, but neither of the two variables changed in the course of the study. A negative correlation was observed in the fish eating group, and a change in the variables mentioned occurred in an orderly manner in the course of the study: a prolongation of the bleeding time from the start of the study to the end was only seen in individuals with low triglyceride levels, i.e. less than 1 mmol/L. Selenium in the diet, on the other hand, did not affect any of the observed variables.(ABSTRACT TRUNCATED AT 250 WORDS)

A new isosorbide dinitrate extended-release formulation: pharmacokinetic and clinical parameters in patients with stable angina pectoris.

In a double-blind, cross-over study the acute clinical efficacy and pharmacokinetic profile of a newly developed isosorbide dinitrate extended-release (ISDN-ER) formulation (10 mg immediate release and 60 mg slow release) were examined in eight angina patients. Exercise tests were done 1 h before and 1, 6 and 10 h after acute ISDN or placebo; similar testing was repeated after 14 days of open-labelled treatment. At 1, 6 and 10 h after administration, ISDN-ER significantly reduced the mean ST depression at highest comparable workload (HCWL) by 0.8, 0.6, and 0.6 mm, respectively. Total exercise duration increased significantly by 46, 42 and 72 s. The rate-pressure product at HCWL was not reduced significantly at any time, while digital plethysmography demonstrated a significant effect on arterial pulse curves throughout the 10 h. After 14 days of once-daily treatment, similar or somewhat attenuated clinical effects were observed. Pharmacokinetic measurements showed a first peak of ISDN at 1-2 h and a second peak at 4-5 h. The 5-isosorbide mononitrate (5-ISMN) metabolite peaked at 5-8 h and remained high at 10 h. After 14 days of treatment, the mean plasma concentrations of ISDN and 5-ISMN before drug were 0 and 69 ng.ml-1, respectively. Thus, satisfactory acute clinical efficacy and low nitrate levels during the night were observed. However, long-term clinical efficacy needs to be established in larger, placebo-controlled trials.

Effect of cold pressor test and awareness of hypertension on platelet function in normotensive and hypertensive women.

Plasma beta-thromboglobulin (beta-TG) concentration, reflecting platelet function in vivo, was compared in fertile women with untreated essential hypertension and age-matched normotensives, in two separate studies. In the first study, hypertensives and normotensives were aware of their blood pressure status. Blood was sampled through arterial and venous indwelling catheters, and no difference in beta-TG was found between the groups. Arterial beta-TG was significantly lower than venous concentration (p < or = 0.05). Cold pressor test increased arterial beta-TG significantly in both groups (p < 0.05). In the second study, both women and investigator were unaware of blood pressure status, and beta-TG concentration, platelet count, and mean platelet volume obtained by venipunctures were similar in the hypertensive and normotensive group. Thus, platelet function in vivo seems to be normal in fertile hypertensive women, in contrast to the platelet dysfunction previously reported in hypertensive men. In women, as in men, platelet release occurred during venous catheter blood sampling and during cold pressor test. However, at variance from men, platelet function was not influenced by awareness of blood pressure status in the hypertensive females.

Platelet selenium as indicator of wheat selenium intake.

The effect of an increased intake of wheat selenium (Se) on platelet Se, serum Se, whole-blood Se, and glutathione peroxidase (GSH-Px) levels was investigated in 14 healthy Norwegian females (age 21-53 years). The intake of 60 micrograms Se per day as wheat Se, for six weeks, significantly increased the platelet Se (mean +/- SEM) from 9.1 +/- 1.1 mumol/L to 11.4 +/- 0.9 mumol/L, the serum Se from 1.43 +/- 0.18 mumol/L to 1.63 +/- 0.25 mumol/L, and the whole blood Se from 1.77 +/- 0.18 mumol/L to 2.01 +/- 0.18 mumol/L. The increase in percent of initial Se values was twice as high for platelets as for serum and whole blood. The GSH-Px levels were not altered during the experiment. Platelet Se was not significantly correlated to the Se intake initially. At the end of the experimental period, the Se in platelets reflected the total Se intake, but not with a simple linear correlation. No significant correlation between the total Se intake and the Se concentration in whole blood or serum was found.

Effects of fish oil, nifedipine and their combination on blood pressure and lipids in primary hypertension.

In a double-blind, crossover, placebo-controlled study the effects of four weeks' treatment with 4.55 g/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on BP and serum lipids were assessed in 18 males with hypertension (WHO stage I-II). At the end of the double-blind phase, eight patients on placebo (olive oil) and ten patients on fish oil treatment were given nifedipine 20 mg twice daily added to their regimens for four weeks. Four weeks' fish oil treatment slightly reduced BP values; however, compared with placebo no changes were found. VLDL-cholesterol and triglycerides were significantly reduced by 24%, whereas total and LDL-cholesterol remained unchanged. Placebo did not change BP and lipid values. When nifedipine was added to fish oil/placebo, BP in the two groups was reduced to almost the same extent. When nifedipine was added to fish oil, total cholesterol was significantly reduced by 12% in comparison with baseline value and LDL-cholesterol was reduced by 15%, albeit insignificantly. Placebo plus nifedipine was lipid neutral. A significant correlation was found between the nifedipine-induced changes in supine mean arterial pressure and total, LDL- and VLDL-cholesterol, respectively, in those patients with and without fish oil treatment. In conclusion, the combined administration of fish oil and nifedipine possesses favourable antihypertensive and metabolic properties in hypertensive males with elevated lipid levels.

The sympathetic nervous system may modulate the metabolic cardiovascular syndrome in essential hypertension.

The association between blood pressure and coronary artery disease may be caused by a concurrence of atherogenic biochemical abnormalities in hypertensive patients, i.e., the metabolic cardiovascular syndrome (increased total cholesterol, triglycerides, and insulin; decreased high-density lipoprotein (HDL) cholesterol; and insulin resistance, glucose intolerance, and blood platelet dysfunction). There are numerous reports of sympathetic nervous system overactivity in hypertensive subjects that could be of importance for the pathophysiology of the high blood pressure. Plasma catecholamines have metabolic hormonal effects at concentrations slightly above low normal resting levels. Even transiently and certainly chronically raised plasma catecholamine levels may cause biochemical abnormalities. Catecholamines may raise total cholesterol, triglycerides, and insulin, decrease HDL cholesterol, and cause insulin resistance and glucose intolerance, and recent evidence supports an in vivo influence of epinephrine on blood platelets, causing dysfunction in hypertensive subjects. Thus, the sympathetic nervous system may modulate the metabolic cardiovascular syndrome in essential hypertension. Hypertensive subjects may respond to environmental stimuli with larger sympathoadrenal responses than normal subjects. Furthermore, emotional stress has been associated with coronary artery disease. Thus, the metabolic hormonal effects of catecholamines, by causing the metabolic cardiovascular syndrome, may be the crucial link between "stress" and cardiovascular disease.

Awareness of high blood pressure increases arterial plasma catecholamines, platelet noradrenaline and adrenergic responses to mental stress.

Thirty-six, 19-year-old men within the 95th percentile of mean blood pressure (110 mmHg) at a routine medical screening were randomized into two groups and requested to return for a follow-up visit in 2 weeks. One group was sent a neutral letter, while the other was sent a letter conveying the information that their blood pressures were elevated. After 15 min sitting in the laboratory, there was a significantly higher heart rate (P less than 0.05) in the informed group. Thirteen informed and 13 uninformed subjects were examined further by intra-arterial blood pressure recording and serial sampling of arterial catecholamines during cold pressor and mental stress tests. The study was undertaken examiner-blind. Informing the subjects of high blood pressure increased both baseline plasma noradrenaline (P less than 0.01) and adrenaline (P less than 0.05) and intraplatelet noradrenaline (P less than 0.05). Blood pressure (P less than 0.05) and heart rate (P less than 0.05) increased significantly more in the informed group when the subjects were told of the cold pressor test. In addition, there were exaggerated adrenaline (P less than 0.05) and diastolic blood pressure (P less than 0.05) responses to mental stress in the informed group. Thus, awareness of high blood pressure in young men may increase sympathetic tone and responses as measured in the laboratory. Conclusions from studies on early pathogenesis of essential hypertension should therefore be drawn with more caution when patients are aware of their high blood pressure.

Gradient centrifugation to isolate platelets for determination of trace elements by neutron-activation analysis.

A nonionic iodinated compound, Nycodenz, was used for density-gradient isolation of platelets before analysis for trace elements by instrumental neutron activation. The platelet samples were almost free from plasma and erythrocytes, and the trace element contribution from additives was insignificant for the elements investigated. The reproducibility of the trace element analysis in platelets attests to the usefulness of density-gradient separation. Platelet samples were obtained twice, three weeks apart, from 10 healthy young women (ages 24 +/- 2 years). The mean (SD) concentrations were as follows: Se, 0.62 (0.16) mg/L and 4.7 (1.4) ng/10(9) platelets; Zn, 44 (10) mg/L and 333 (80) ng/10(9) platelets; Rb, 3.0 (0.5) mg/L and 23 (5) ng/10(9) platelets; and Cs, 24 (5) micrograms/L and 0.18 (0.04) ng/10(9) platelets.

Awareness of high blood pressure stimulates platelet release reaction.

The present study aimed at testing the hypothesis of a link between mental stress and blood platelet function. Twenty-nine 19-year-old men were recruited from the 98th percentile of mean blood pressure (116 mmHg) at a routine medical screening. They were not informed about their elevated blood pressures at the time of the screening. One year later they were randomized into two groups. Group 1 (n = 16) was exposed to mental stress by a letter informing them about their high blood pressure, while group 2 (n = 13) was sent a neutral letter. At an examination 2 weeks later, heart rate (p less than 0.05) and plasma adrenaline (p less than 0.05) responses to a cold pressor test were exaggerated in the informed group. The plasma beta-thromboglobulin (beta TG) concentration was elevated in the informed group (p less than 0.05) as was mean blood pressure (p less than 0.05). beta TG correlated positively with hematocrit (r = 0.59, p less than 0.005) and mean blood pressure (r = 0.43, p less than 0.05), and negatively with plasma HDL (r = -0.61, p = 0.001). The study shows that awareness of hypertension induces a hyperadrenergic state which is associated with the platelet release reaction. Under these circumstances platelet release seems to be correlated to established coronary heart disease risk factors.