Chronic hydroxymethylglutaryl coenzyme a reductase inhibition and endothelial function of the normocholesterolemic rat: comparison with angiotensin-converting enzyme inhibition

The purpose of the current study was to evaluate nifedipine-induced epicardial and microvascular response in human coronary arteries with and without endothelial dysfunction and intimal thickening. The investigation was performed in 70 patients 5 +/- 5 months after heart transplantation. Coronary vasomotor function was determined with intracoronary acetylcholine adenosine, and nifedipine, respectively. Intravascular ultrasound was used to detect significant intimal hyperplasia. In a subgroup (n = 38), coronary sinus and aortic endothelin concentrations were determined. Epicardial dilation to nifedipine was significantly enhanced in coronary arteries with endothelial dysfunction (p = 0.04), whereas adenosine-induced epicardial dilation was attenuated in segments with endothelial dysfunction (p = 0.002). In cases of intimal hyperplasia, nifedipine-mediated distal vasodilation was increased compared with normal segments (p = 0.03). Coronary flow index nifedipine was enhanced in patients with microvascular endothelial dysfunction (p = 0.037). A trend was observed between high endothelin plasma levels in the coronary sinus and an increased microvasodilation to nifedipine (p = 0.04). The study shows that epicardial and microvascular dilation to nifedipine is enhanced in the setting of coronary endothelial dysfunction, suggesting supersensitive dilator response. The association between microvascular response to nifedipine and endothelin levels in the coronary sinus needs further clarification.     

P-cresol,a uremic toxin,decreases endothelial cell response to inflammatory cytokines

BACKGROUND: Infectious diseases are among the most morbid events in uremia. The uremic toxin p-cresol may play a role in the immunodeficiency of uremia by depressing phagocyte functional capacity. Leukocyte adhesion to endothelium, a key event in the immune response, is mediated by endothelial adhesion molecules. These include intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, which are induced by various inflammatory cytokines. We asked whether p-cresol alters endothelial adhesion molecule expression and modifies endothelial/leukocyte adhesion. METHODS: Human umbilical vein endothelial cells (HUVEC) were incubated with p-cresol in the presence or absence of tumor necrosis factor (TNF) or interleukin-1beta (IL-1beta). Thereafter, the endothelial molecules ICAM-1, VCAM-1, and E-selectin were quantitated and the monocyte (THP-1) adhesion to HUVEC measured. RESULTS: P-cresol decreased cytokine-induced protein and mRNA expression of ICAM-1 and VCAM-1. In addition, p-cresol significantly decreased the adhesion of THP-1 to cytokine-stimulated HUVEC. CONCLUSIONS: P-cresol may play a role in the immune defect of uremic patients by inhibiting cytokine-induced endothelial adhesion molecule expression and endothelium/monocyte adhesion.     

Mechanisms of desflurane-induced preconditioning in isolated human right atria in vitro

BACKGROUND: The authors examined the role of adenosine triphosphate-sensitive potassium (K(ATP)) channels, adenosine A1 receptor, and alpha and beta adrenoceptors in desflurane-induced preconditioning in human myocardium, in vitro. METHODS: The authors recorded isometric contraction of human right atrial trabeculae suspended in oxygenated Tyrode's solution (34 degrees C; stimulation frequency, 1 Hz). Before a 30-min anoxic period, 3, 6, and 9% desflurane was administered during 15 min. Desflurane, 6%, was also administered in the presence of 10 microm glibenclamide, a K(ATP) channels antagonist; 10 microm HMR 1098, a sarcolemmal K(ATP) channel antagonist; 800 microm 5-hydroxy-decanoate (5-HD), a mitochondrial K(ATP) channel antagonist; 1 microm phentolamine, an alpha-adrenoceptor antagonist; 1 microm propranolol, a beta-adrenoceptor antagonist; and 100 nm 8-cyclopentyl-1,3-dipropylxanthine (DPX), the adenosine A1 receptor antagonist. Developed force at the end of a 60-min reoxygenation period was compared (mean +/- SD). RESULTS: Desflurane at 3% (95 +/- 13% of baseline), 6% (86 +/- 6% of baseline), and 9% (82 +/- 6% of baseline) enhanced the recovery of force after 60 min of reoxygenation as compared with the control group (50 +/- 11% of baseline). Glibenclamide (60 +/- 12% of baseline), 5-HD (57 +/- 21% of baseline), DPX (63 +/- 19% of baseline), phentolamine (56 +/- 20% of baseline), and propranolol (63 +/- 13% of baseline) abolished desflurane-induced preconditioning. In contrast, HMR 1098 (85 +/- 12% of baseline) did not modify desflurane-induced preconditioning. CONCLUSIONS: In vitro, desflurane preconditions human myocardium against simulated ischemia through activation of mitochondrial K(ATP) channels, adenosine A1 receptor, and alpha and beta adrenoceptors.     

Stimulation of both humoral and cellular immune responses to HIV-1 gp120 by interleukin-12 in Rhesus macaques

The adjuvant effect of recombinant Rhesus macaque interleukin-12 (RhIL-12) on the induction of cellular and humoral immune responses elicited by the HIV-1 subunit vaccine protein gp120 in Rhesus macaques was examined. RhIL-12 in conjunction with gp120 was given at day 0, 28 and 84 intramuscularly. Coadministration resulted in an approximate 10-fold increase in plasma anti-gp120 antibody levels as compared to levels generated in control monkeys receiving gp120 alone. Potentiation of the humoral arm of the immune response was evident by both ELISA and an antiviral bioassay. In addition, RhIL-12 was found to produce a significant increase in gp120-specific proliferative responses and in the frequency of antigen-specific IFN-gamma and IL-2 producing T cells after restimulation of PBMC with gp120 in vitro indicating that RhIL-12 potentiates cell-mediated immune responses as well. A critical finding was that during the course of the study, RhIL-12 did not induce a neutralizing antibody response to the administered cytokine. The doses of RhIL-12 were well tolerated and no detectable adverse side-effects on hematopoietic and hepatic parameters were noted. The data revealed that IL-12, when coadministered intramuscularly, acts as a potent adjuvant which is able to enhance not only cellular but also humoral immune responses to gp120 in non-human primates and may have to be considered in future HIV vaccine strategies.     

Noscapine alters microtubule dynamics in living cells and inhibits the progression of melanoma

Cellular microtubules, polymers of tubulin, alternate relentlessly between phases of growth and shortening. We now show that noscapine, a tubulin-binding agent, increases the time that cellular microtubules spend idle in a paused state. As a result, most mammalian cell types observed arrest in mitosis in the presence of noscapine. We demonstrate that noscapine-treated murine melanoma B16LS9 cells do not arrest in mitosis but rather become polyploid followed by cell death, whereas primary melanocytes reversibly arrest in mitosis and resume a normal cell cycle after noscapine removal. Furthermore, in a syngeneic murine model of established s.c. melanoma, noscapine treatment resulted in an 85% inhibition of tumor volume on day 17 when delivered by gavage compared with untreated animals (P 相似文献   

The in vitro effects of remifentanil, sufentanil, fentanyl, and alfentanil on isolated human right atria

Because some clinical studies have suggested that opioids used in anesthesia may have different deleterious hemodynamic effects, we compared the direct myocardial effects of cumulative concentrations of remifentanil, sufentanil, fentanyl, and alfentanil on inotropic and lusitropic variables of isolated human myocardium in vitro. Human right atrial trabeculae, obtained from patients scheduled for coronary bypass surgery or aortic valve replacement, were suspended vertically in an oxygenated (95% oxygen/5% CO(2)) Tyrode's modified solution ([Ca(2+)](o) = 2.0 mM, 37 degrees C, pH 7.40, stimulation frequency 1 Hz). The effects of cumulative concentrations (10(-11), 10(-10), 10(-9), 10(-8), 10(-7), and 10(-6) M) of remifentanil (n = 8), sufentanil (n = 8), fentanyl (n = 8), and alfentanil (n = 8) on inotropic and lusitropic variables of isometric twitches were measured. Remifentanil, sufentanil, and fentanyl did not modify active isometric force and peak of the positive force derivative as compared with the Control group. Alfentanil induced a dose-dependent decrease in active isometric force and peak of the positive force derivative. This effect was abolished in the presence of [Ca(2+)](o) = 4.0 mM. None of these opioids altered lusitropic variables.     

Inhaled crocidolite mutagenicity in lung DNA

We used transgenic mice carrying the lacI reporter gene to study the mutagenesis potential of asbestos crocidolite. The animals were exposed by nose-only inhalation to an aerosol containing 5.75 mg/m(3) crocidolite dust for 6 hr/day and 5 consecutive days. After 1, 4, and 12 weeks, we examined four end points: the cytology of bronchoalveolar lavage, the lung load of crocidolite, the hydrophobic DNA adducts, and the mutations in the lacI reporter gene. Twelve weeks after exposure, nearly 10% of the inhaled fibers remained in the lung (227 +/- 103 ng/mg lung). There was evidence of a typical inflammatory response consisting of multinucleate macrophages at weeks 4 and 12, whereas immediately after the exposure, we observed numerous polymorphonuclear neutrophils. The mutant frequency significatively increased during the fourth week after the exposure: 13.5 [time] 10(-5) in the exposed group versus 6. 9 10(-5) in the control group. The induction factor, defined by the ratio of checked mutants of exposed mice to checked mutants of control mice, was 1.96. The mutation spectrum of control lung DNA and exposed lung DNA was similar, suggesting the possible involvement of a DNA repair decrease in crocidolite-treated animals. We used the (32)P-postlabeling method and did not detect any increase of either 5 mC or bulky adduct in treated mice. This is the first study that demonstrates asbestos mutagenicity in vivo after a nose-only inhalation.     

Phase II study of carminomycin in a human tumor cloning assay

Summary The anticancer activity of carminomycin was investigated in a human tumor cloning assay. No efficacy could be identified in the WiDr and the MCF7 cell lines which were highly responsive to doxorubicin. In addition, drug testing experiments were carried out in samples of various malignancies freshly obtained from 86 patients of whom 54 had not received prior anthracyclines. A reduction in the number of tumor colony forming units by 50% or more was seen in 1/26 breast cancers, 1/22 ovarian cancers and 1/7 melanomas. Cross-resistance studies indicated that eight tumors were responsive to doxorubicin only and one to carminomycin only whereas two were sensitive to both and 73 were resistant to both. This in vitro Phase II study corroborates the disappointing clinical results achieved with carminomycin.