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Serum levels of total and free testosterone and 17 beta-estradiol were determined in 144 men with acute ischemic stroke and 47 healthy male control subjects. Blood samples from patients were drawn a mean of 3 days after stroke onset and also 6 months after admission in a subgroup of 45 patients. Initial stroke severity was assessed on the Scandinavian Stroke Scale and infarct size by computed tomographic scan. Mean total serum testosterone was 13.8 +/- 0.5 nmol/L in stroke patients and 16.5 +/- 0.7 nmol/L in control subjects (P = .002); the respective values for free serum testosterone were 40.8 +/- 1.3 and 51.0 +/- 2.2 pmol/L (P = .0001). Both total and free testosterone were significantly inversely associated with stroke severity and 6-month mortality, and total testosterone was significantly inversely associated with infarct size. The differences in total and free testosterone levels between patients and control subjects could not be explained by 10 putative risk factors for stroke, including age, blood pressure, diabetes, ischemic heart disease, smoking, and atrial fibrillation. Total and free testosterone levels tended to normalize 6 months after the stroke. There was no difference between patients and control subjects in serum 17 beta-estradiol levels. These results support the idea that testosterone affects the pathogenesis of ischemic stroke in men.

This study assessed the short- and long-term effects of an energy-restrictive diet with or without exercise on plasminogen activator inhibitor-1 antigen (PAI-1 Ag) and PAI-1 activity, tissue-type plasminogen activator antigen (TPA Ag), and fibrinogen serum levels. Healthy, overweight postmenopausal women (age, 53.8+/-2.5 years; body mass index, 25 to 42 kg/m2; n=121) were randomly assigned to one of three groups: control, 4200-kJ/d diet, or 4200-kJ/d diet with combined aerobic and anaerobic exercise. PAI-1 activity and PAI-1 Ag, TPA Ag, and fibrinogen levels were measured at baseline, after a 12-week intervention, and after a further 6-month follow-up. PAI-1 Ag and activity and TPA Ag were positively correlated with serum triglyceride levels, the abdominal-to-total-body fat ratio (as assessed by total-body dual-energy x-ray absorptiometry), fasting blood glucose, and systolic BP and negatively with HDL cholesterol and sex hormone-binding globulin. The diet led to profound decreases and normalization of PAI-1 activity (approximately 50%), PAI-1 Ag (approximately 30%) and TPA Ag (approximately (29%), but exercise conferred no additional effect. Fibrinogen did not change. At follow-up there were no longer any significant changes (P>.05). In conclusion, PAI-1 Ag and activity as well as TPA Ag seem to be part of the metabolic syndrome X. The diet made the blood less thrombogenic in the short term with no effect of the added exercise.

The effects of isradipine and atenolol on platelet function and fibrinolytic activity were studied in 10 male patients with mild untreated hypertension. After a 2-week placebo run-in period, the volunteers were randomized to either isradipine 2.5 mg twice daily or atenolol 100 mg daily for a 6-month period. Those initially receiving isradipine then received atenolol and vice versa. After each therapy regimen, blood was drawn at rest and 1 h after exercise during a maximum exercise test. Platelet activity in vivo was estimated as release of B-TG and PF-4. Fibrinolytic activity was estimated as the fast-acting inhibitor against tissue plasminogen activator usually termed PAI-1. During atenolol and isradipine therapy, blood pressure (BP) was equally reduced (p < 0.05). Heart rate (HR) decreased during atenolol treatment but was not changed by isradipine. Platelet activity in vivo estimated as B-TG and PF-4 decreased irrespective of therapy (p < 0.02). During atenolol, as during placebo therapy, exercise resulted in a significant increase in platelet activity, as shown by an increase in B-TG (p < 0.02) and in PF-4 (p < 0.01). Such increase was not observed during isradipine treatment. Both treatments tended to improve fibrinolysis, as shown by a decrease in PAI, 1 h after exercise. Reducing BP with isradipine or atenolol results in a similar decrease in platelet activity and PAI-level, tested at rest and 1 h after rest, respectively. During exercise, platelet activity increased during atenolol treatment; such change did not occur during isradipine treatment.

A morning increase in onset of acute myocardial infarction (MI) has been documented, but its association with wake time and possible triggering events is unclear. The community-based, ongoing Triggers and Mechanisms of Myocardial Infarction (TRIMM) study was designed to investigate the factors associated with the transition from chronic coronary artery disease to acute MI. During the pilot phase in 1989, 224 consecutive hospitalized MI patients (176 men and 48 women, aged 60.3 +/- 9.2 years) of the prospectively defined Monitoring of Trends and Determinates of Cardiovascular Disease (MONICA) Augsburg MI register were interviewed 16.8 +/- 6.5 days after the event. The frequency of onset of MI was significantly higher (p less than 0.01) during the morning from 6 to 9 AM compared with other times of day. After adjustment for individual wake times, the peak of onset of MI was markedly sharper; the relative risk of MI during the 3-hour peak interval (the 3 hours after awakening) compared with other times of day increased from 1.8 (95% confidence interval, 1.3-2.4) to 2.4 (95% confidence interval, 1.8-3.1). Sixty-seven percent of the patients reported possible acute triggers of MI and/or unusual life events; among those, 52% reported stress or emotional upset. The TRIMM pilot study demonstrated the feasibility of a community-based study of possible triggering events of MI. The circadian variation of MI appears to result primarily from increased onset after awakening. This narrowing of the time frame of increased risk of MI should facilitate study of pathogenic mechanisms and aid in the design of more effective preventive regimens.

Although the benefit of beta-adrenergic blocking agents in acute coronary ischemia has been well documented, it is unclear whether the responsible mechanisms include the modification of platelet function. In recent studies, metoprolol appeared to reduce the total number and duration of episodes of silent ischemia in patients with stable coronary artery disease throughout the day. This effect was not associated with a change in baseline or circadian variability of the platelet aggregability. Since the treatment caused significant decreases in heart rate and blood pressure, the drug effect is more likely to be based on reduction of myocardial oxygen demand. Metoprolol, however, prevented a platelet aggregability increase and intracellular cAMP decrease during exercise stress testing in patients with stable angina pectoris. We speculate that this effect of beta 1-adrenergic blockade may be due to hemodynamic and neurohormonal changes, or possibly also to an increase in synthesis or release of platelet inhibiting substances.

Sixteen patients with mild to moderate essential hypertension were randomly allocated to 6 weeks of treatment with nifedipine and captopril in a crossover trial. Nifedipine and captopril lowered blood pressure significantly both 2 and 12 h after the last dose. Apart from an increased heart rate 2 h after the last dose of nifedipine, the heart rate did not change. Platelet factor 4, thromboxane B2, 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and cyclic (c)AMP did not change during either therapy. There was no correlation between the plasma concentration of nifedipine measured 2 and 12 h after the last dose and the platelet variables described above. The findings show that nifedipine and captopril in therapeutic doses do not affect platelet activity in patients with mild to moderate essential hypertension.

Two groups of hypertensives and a group of migraine sufferers were tested during treatment with the nonselective beta-blocker propranolol and the beta 1-selective metoprolol. During treatment with propranolol, an increased platelet aggregability and a decrease in platelet content of cyclic AMP were seen when compared with metoprolol treatment. In addition, propranolol treatment increased the plasma level of adrenaline as well as the euglobulin clot lysis time.

The potential age-dependent antihypertensive responses to serotonin antagonists are critically reviewed with regard to the following considerations: Are they beneficial to the patient? Are they related to age-dependent changes in pharmacokinetics or pharmacodynamics? Are they necessarily true? The paper is focused on ketanserin, which is the only major serotonin (S2) antagonist that has yet been used to any extent in patients. Based on the available data in the literature, we conclude that the age-related antihypertensive effect of ketanserin is a beneficial phenomenon since it does not seem to be paralleled by a corresponding increase in side effects. Furthermore, the mechanism seems to be due to changes in the pharmacodynamics of the drug on the platelet or vascular smooth muscle since there is only negligible alteration in pharmacokinetics occurring with advanced age. Although multiple independent trials or pooled data strongly indicate that the efficacy of ketanserin increases with age, not all investigators agree. In our opinion, the interindividual variation in drug response is more characteristic to the drug than the relationship to age. Therefore, the selection of patients for ketanserin therapy should be based on individual testing in addition to age grouping.