Monocyte-associated tissue factor is suppressed by phorbol myristate acetate

The monocyte is the only normal circulating cell type capable of initiating blood coagulation through the expression of tissue factor. Recently isolated peripheral blood monocytes that contain no demonstrable tissue factor activity can be induced to express tissue factor activity by a number of stimulatory agents. Monocyte-associated tissue factor activity transiently increases in response to adherence to tissue culture plates and, consistent with other reports, markedly increases after the isolated monocytes are treated with endotoxin. Phorbol myristate acetate (PMA) induced an increase in tissue factor activity at low doses (10(-11) to 10(-12) mol/L). Conversely, concentrations of PMA that stimulate release of oxygen metabolites or that cause the cytosol-to-membrane translocation of protein kinase C (PKC) (10(-9) to 10(-7) mol/L) resulted in a rapid decrease in both adherence-induced and endotoxin-induced monocyte tissue factor activity. The effects of PMA on monocytes were time- and dose-dependent with respect to PKC translocation, release of oxygen metabolites, and changes in tissue factor activity. Immunofluorescent staining of monocytes with monoclonal antibody (MoAb) HTF1-7B8, directed against human tissue factor, revealed that tissue factor antigen was induced concurrently with tissue factor activity by adherence and endotoxin and that tissue factor antigen decreased after PMA stimulation.     

薤白中两种新甾体皂甙成分

从中药薤白(Allium macrostemon Bunge)鳞茎中分得两种流的甾体皂甙,薤白甙甲(macrostemonoside A,1)和薤白甙丁(macrostemonoside D,2),通过光谱(IR,MS,¹HNMR,¹³CNMR,¹H-¹H COSY和NOESY等)分析和衍生化研究,分别确定为:tigogenin-3-O-β-D-glucopyranosyl(1→2)[β-D-glucopyranosyl(1→3)]-β-D-glucopyranosyl(1→4)-β-D-galactopyranoside(1)和tigotenin-3-O-β-D-glucopyranosyl(1→2)[β-D-glucopyranosyl(1→3)(6-O-acetyl-β-D-glucopyranosyl)](1→4)-β-D-galactopyranoside(2)。     

Glucocorticoid modulation of muscarinic and β-adrenergic receptors in guinea pig lung

Summary— We investigated the effect of the in vivo treatment of guinea pigs with methylprednisolone, 10 mg/kg daily, on lung muscarinic and β-adrenergic receptors. Receptor densities were assessed by saturation experiments of tritiated N-methylscopolamine and dihydroalprenolol binding to lung membranes. After 3 h of treatment, methylprednisolone induced a decrease of 19.2% ( P < 0.05) of muscarinic receptors but was without effect on β-adrenergic receptor density. After 24 h, an increase of 39.7% ( P < 0.01) and 16.9% ( P < 0.05) was observed for muscarinic and β-adrenergic receptors, respectively. For muscarinic receptors, this increase reached 53.4% ( P < 0.01) within 48 h and stayed at this level until 96 h. The increase of β-adrenergic receptors was maximal (24.9%) after 72 h and returned to the control value after 96 h. The dissociation constant (K_d) values of both ligands were not affected by the glucocorticoid treatment. Functional studies showed that the 96 h treatment did not affect the contractile response of guinea pig lung parenchymal strips to carbachol since the 50% concentration value (EC₅₀) and the maximal contraction value (E_max) were not significatively different from control values. These data show that glucocorticoids control the expression of both muscarinic and β-adrenergic receptors in guinea pig lung but with different time courses and to a larger extent for muscarinic receptors. The glucocorticoid treament did not modify the contractile response of lung strips to carbachol, confirming the absence of effect on the affinity of muscarinic receptors and suggesting that the receptor reserve exceed the increase of their density by the steroid.     

The uterotonic action of the aqueous extract of Bridelia atroviridis in the rat

The effects of the aqueous extract of leaves of Bridelia atroviridis (Bridelia), a small African tree, on the mechanical activity of rat uterus were studied. The aqueous extract of leaves of B atroviridis administered in a concentration-dependent manner (5 x 10(-6)-1.2 x 10(-3) g/ml) induced contractions that were antagonized by various calcium entry blockers (nifedipine, diltiazem, manganese chloride). In absence of external calcium ions, repeated applications of a supramaximal concentration of Bridelia (1.2 x 10(-3) g/ml) evoked sustained and repeated contractions the amplitude of which was congruent to 20% of those obtained in the physiological external calcium concentration. Bridelia-induced contractions in calcium-free medium were inhibited by isoprenaline (8 x 10(-7) M), caffeine (15 x 10(-3) M) and trifluoperazine (10(-5) M). Contractile responses induced by Bridelia in both calcium-containing and calcium-free media were antagonized by prior incubation of uterus with phorbol 12, 13-dibutyrate (6 x 10(-7) M), cholera toxin (6 x 10(-8) M) or pertussis toxin (5 x 10(-7) g/ml). These results show that Bridelia has a potent uterotonic action in the rat. The cellular basis of this action appears to be complex, and involves various mechanisms including calcium mobilization from both intra and extracellular compartments and activation of phospholipase C through a G-protein.     

Lack of effect by nifedipine on hepatic mixed function oxidase in man

Nifedipine (NF), a calcium channel blocker, is often prescribed in association with other drugs. Therefore, it was interesting to know whether or not, nifedipine, which is metabolized by the cytochrome P-450NF, was able to induce or to inhibit in vivo the activity of the hepatic mixed function oxidase system. The study was conducted in ten young healthy male volunteers receiving 20 mg NF slow release bid for 15 days. Due to the small number of subjects, comparison of the NF pharmacokinetics at dose 1 and 26 failed to show a bimodality in the frequency distribution of its area under the plasma concentration-time curve (AUC 274.5 to 317.1 ng ml-1 h, NS). Hepatic microsomal autoinduction (t1/2 2.87 to 3.06 h, NS) was not found. No statistically significant effect was seen on the aminopyrine breath test and on the debrisoquine metabolic molar ratio performed before and at the end of the treatment. Unlike what has been suggested by in vitro studies, NF treatment did not modify significantly the urinary excretion of 6 beta-hydroxycortisol (318 to 265 micrograms/d, NS). After the last dose, the total oral clearance of NF was highly correlated with the metabolic clearance to 4-hydroxyantipyrine (r = 0.88; P = 0.005) but the other parameters of antipyrine biotransformation remained unchanged. We conclude that repeated nifedipine oral intake does not modify enzymatic activities of hepatic P-450 cytochromes involved in the biotransformation of antipyrine, aminopyrine, debrisoquine and cortisol.     

Mortality in Systemic Sclerosis (Scleroderma)

Two hundred and thirty-seven patients with systemic sclerosiswere followed prospectively in a scleroderma clinic. The overall3, 6, and 9-year survival rates were 86, 76 and 61 per centrespectively. Renal, cardiac and pulmonary disease, and olderage at enrolment were adverse prognostic factors associatedwith reduced survival. There were no significant differencesin survival between males and females or in patients with restrictedcompared to those with diffuse skin thickening. Death from systemicsclerosis was most frequently due to pulmonary hypertension,with fewer than expected deaths from renal or cardiac causes.Twenty-eight per cent of deaths were due to causes unrelatedto systemic sclerosis, most commonly cancer and ischaemic heartdisease, and in older patients