An association between plasma free protein s concentration and risk of coronary heart disease in middle-aged men.

Protein S is a vitamin K-dependent protein with anticoagulant properties. Case series have reported reduced plasma concentrations in patients with arterial thromboses, while other studies have reported increased levels in patients with coronary heart disease (CHD). The present study sought to clarify the relation between free protein S and risk of CHD. A prospective survey was conducted of 3000 men aged 50 to 61 years, free of clinical CHD at baseline. Free protein S was measured by commercial immunoassay. End-points recorded were sudden coronary death, first nonfatal and fatal myocardial infarction (MI), surgical intervention for symptomatic, angiographically demonstrated CHD, and all-causes mortality. Statistical analysis employed univariate incidence rate ratios followed by Cox proportional hazards regression. There were 168 CHD events recorded during 21,000 person-years of risk. Mean free protein S concentration was 6% higher in those who developed CHD than in the remainder, the crude hazard ratio (HR) for a one standard deviation (S.D.) increase in free protein S being 1.25 (95% CI, 1.08-1.25). Free protein S was associated with cholesterol concentration and other conventional CHD risk factors. In multivariate regression analysis, after adjustment for conventional CHD risk factors a 1 S.D. increase in free protein S was associated with a HR of 1.15 (0.98-1.35) for CHD, of borderline conventional statistical significance. This association of free protein S with risk of CHD may reflect effects of plaque-destabilising inflammatory activity on protein S levels.

An abnormal plasma distribution of protein S occurs in functional protein S deficiency.

Protein S is a natural anticoagulant present in the plasma that serves as a cofactor for activated protein C. Patients deficient in protein S are subject to recurrent venous thrombotic disease. Protein S deficiency differs from other plasma protein deficiencies in that deficient patients often have normal or only mildly reduced levels of protein S in their plasma as detected by conventional immunologic methods but have markedly reduced functional protein S levels. This apparent discrepancy is due to the presence of two forms of protein S in plasma. The protein S is present free and in a complex with C4b-binding protein. The free form is functionally active, whereas the bound form is not. Examination by crossed immunoelectrophoresis of 31 functionally protein S-deficient individuals from seven families reveals that 29 of the 31 have all or most of their protein S complexed to C4b-binding protein with little or no free protein and have correspondingly low levels of protein S functional activity (type I deficiency). Two related protein S-deficient individuals show a different type of distribution with little or no protein S, either bound or free (type II deficiency). The detection and classification of protein S-deficient individuals requires the application of both a functional assay and an assessment of protein S distribution between bound and free forms.

The effect of althesin on plasma corticosterone levels.

Althesin in doses which produced anesthesia (4 and 6 ml kg-1, i.p.) produced biphasic changes in plasma corticosterone levels. Plasma corticosterone showed an increase (p less than 0.05) due to the stress of injection but returned to basal levels by 30 min. Subsequent to the anesthetic effect (approximately 30 min) corticosterone levels increased markedly (p less than 0.01). Althesin's effectiveness showed time of day effects, i.e., Althesin was more effective in the A.M. Rats given 6 ml kg-1 Althesin showed graded plasma corticosterone responses to stresses of varying intensity. Blood withdrawal and surgical stress evoked significant increases in plasma corticosterone but a 2-min holding stress had no effect on plasma corticosterone levels. Instrumented rats receiving supplemental injections (i.p.) presented patterns of plasma corticosterone which were different from those receiving supplemental infusions (i.a.). Whereas plasma corticosterone levels of rats receiving the continuous infusion of Althesin remained relatively constant, corticosterone levels of those which received supplemental injections tended to increase. Collectively, these data suggest that Althesins usefulness as an experimental anesthetic is limited to those studies which are not compromised by stress-induced pituitary-adrenal activity.

The effect of urethane on pituitary-adrenal function of female rats.

Urethane anaesthesia resulted in rapid and sustained increase in plasma corticosterone levels of adult female rats both in the (a.m.) AM and (p.m.) PM. Initial corticosterone levels of non-injected control rats showed marked AM-PM differences (i.e., 28.3 micrograms/dl and 52.6 micrograms/dl, respectively), but by 10 min post-injection, the morning corticosterone levels were increased (76.2 micrograms/dl) such that AM-PM differences were not observed. By 30 min post-injection, PM plasma corticosterone levels had increased significantly (88 micrograms/dl) but were not different from AM values for the remainder of the 2 h experiment. Saline injected controls showed the expected response to stress; plasma corticosterone levels were increased (P less than 0.01) at 10 min but were back to baseline by 45 min (9.0 micrograms/dl). Dexamethasone (100 micrograms/kg, sc) markedly suppressed both AM and PM urethane-stimulated corticosterone levels. However, diurnal differences in dexamethasone suppression were noted; whereas morning plasma corticosterone levels averaged 24.8 micrograms/dl over the five sampling times corresponding PM values averaged 54.3 micrograms/dl. Plasma corticosterone levels of non-anaesthetized, hypophysectomized ACTH-primed and injected rats were not different from those similarly treated and anaesthetized with urethane and urethane-induced increases in corticosterone were not abolished by hypothalamic isolation (HI). However, plasma corticosterone levels of HI rats were less than those of sham-operated controls (i.e., 58 micrograms/dl and 74 micrograms/dl, respectively). Collectively, these data indicate that urethane evokes a sustained increase in pituitary-adrenal activity, that the increased activity is dexamethasone sensitive and that a site of action for pituitary-adrenal activation is, at least in part, at the level of the hypothalamo-hypophyseal complex.