Absence of histamine-induced nitric oxide release in the human radial artery: implications for vasospasm of coronary artery bypass vessels.

Radial artery (RA) bypass grafts can develop severe vasospasm. As histamine is known to induce vasospasm, its effect on RA was assessed compared with the classic bypass vessels internal mammary artery (MA) and saphenous vein (SV). The vessels were examined in organ chambers for isometric tension recording. Histamine induced contractions on baseline; the sensitivity was higher in RA and SV than MA. After precontraction with norepinephrine, histamine did not evoke relaxations of RA but induced relaxations of MA and less of SV at lower concentrations; it induced contractions at higher concentrations, reaching similar levels in all three vessels. Indomethacin did not affect the response of MA and RA but potentiated relaxations and reduced contractions of SV. Endothelium removal, N(omega)-nitro-L-arginine methyl ester (L-NAME), or the H2-receptor blocker cimetidine did not affect the response of RA, but inhibited relaxations and enhanced contractions in MA and inhibited relaxations in SV; in the latter, only L-NAME enhanced contractions. Real-time PCR detected much lower expression of endothelial H2-receptor in RA than MA or SV. Western blots revealed similar endothelial nitric oxide (NO) synthase expression in all three vessels. Relaxations to acetylcholine were identical in RA and MA. Thus histamine releases NO by activating the endothelial H2-receptor, the expression of which is much lower in RA than MA or SV. H2-receptor activation also releases prostaglandins in SV, partially antagonizing NO. The lack of histamine-induced NO production represents a possible mechanism of RA vasospasm.

Role of histone deacetylase inhibitors in the treatment of cancer (Review).

Acetylation and deacetylation of nucleosomal histones play an important role in the modulation of chromatin structure, chromatin function and in the regulation of gene expression. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two opposing classes of enzymes, which tightly control the equilibrium of histone acetylation. An imbalance in the equilibrium of histone acetylation has been associated with carcinogenesis and cancer progression. So far, a number of structurally distinct classes of compounds have been identified as HDAC inhibitors including the short-chain fatty acids, hydroxamates, cyclic tetrapeptides and benzamides. These compounds lead to an accumulation of acetylated histone proteins both in tumor cells and in normal tissues. HDAC inhibitors are able to activate differentiation, to arrest the cell cycle in G1 and/or G2, and to induce apoptosis in transformed or cancer cells. Attention is currently being drawn to molecular mechanisms involving histone deacetylases. An induction of p21(WAF/CIP1) and a suppression of angiogenic stimulating factors have been observed in tumor cells following exposure to HDAC inhibitors. In xenograft models, several HDAC inhibitors have demonstrated antitumor activity with only few side effects. Several clinical trials showed that HDAC inhibitors in well tolerated doses have significant antitumoral activities. A combination of HDAC inhibitors with differentiation-inducing agents and cytotoxic drugs is an innovative therapeutic strategy that carries the potential for significant improvements in the treatment of cancer.

[Influence of catecholamines on myocardium in experimental septic shock].

OBJECTIVE: To study the influence of catecholamine on myocardium in rats with septic shock and its mechanism by biochemical and pathophysiological methods to evaluate the underlying pathophysiologic mechanism of myocardial damage and the influence of catecholamine on the myocardial injury. METHODS: Septic shock was replicated in rats by cecal ligation and puncture (CLP). Dobutamine (DB), norepinephrine (NE) and combination of DB and NE were used in the lowest dose. The rats were randomly divided into sham operations, CLP control group, CLP+DB group, CLP+NE group and CLP+DB+NE group, 8 rats in each group. Troponin I (cTnI) and total creatine kinase (CK) were measured, and myocardial tissue was examined under light microscopy and electron microscopy. RESULTS: An significantly increased cTnI level was found in CLP septic shock rats, compared with sham rats (P<0.05). In the present study, the use of DB or NE alone, or the combination of the two drugs, was not found to influence the cTnI levels. But, the total CK levels in catecholamine-treated group were significantly increased (P<0.05). There was no statistically significant correlation between cTnI and CK levels. Morphological study confirmed the results of cTnI. Findings that were common in the myocardium of CLP septic shock rats included extracellular and intracellular edema as well as mitrochondrial injury. However, no conclusive evidence was found for the influence of catecholamine on myocardial damage. CONCLUSION: No evidence of the influence of catecholamine on myocardial damage is found. Pathological study suggests that myocardial injury is the result of ischemia.

Optimization of tumor-targeted gene delivery by engineered attenuated Salmonella typhimurium.

BACKGROUND: Attenuated Salmonella typhimurium has been demonstrated as a potential gene delivery vector. Previous findings induce the necessity to optimize tumor selectivity and bacterial dosing in relation to tumor volume and intratumoral therapeutic gene expression. MATERIALS AND METHODS: Attenuated Salmonella VNP20009 and VNP20047 (expressing cytosine deaminase) were systemically administered to tumor-bearing rats. The bacteria were quantified in tumor and normal organs. Conversion of 5-fluorocytosine to 5-fluorouracil was evaluated using thin layer chromatography. RESULTS: Tumor colonization efficiency was dependent on Salmonella density, administration route and tumor volume. Colonization of normal tissues gradually decreased with time, while intratumoral proliferation of bacteria remained high during the follow-up period. The Optimal Therapeutic Dose (OTD) was found to be 5.10(7) cfu/rat. Intratumoral VNP20047-expressed CDase leading to the conversion of 5-FC to 5-FU was detected in vivo. CONCLUSION: Our results indicate the need to define an OTD, probably for each species, when using genetically engineered Salmonella as a tumor- and species-selective vector in cancer therapy.