Improvement of aortic wall distensibility and reduction of oxidative stress by pioglitazone in pre-diabetic stage of Otsuka Long-Evans Tokushima fatty rats

We tested the hypothesis that pioglitazone (insulin sensitizer) reduces oxidative stress and improves aortic wall distensibility in the pre-diabetic stage of Otsuka Long-Evans Tokushima Fatty rats, type 2 diabetes mellitus (DM) model. 20 DM and 9 nonDM male rats were divided into 3 groups: treated-DM, untreated-DM, and untreated-nonDM. Pioglitazone (0.01%) was mixed in chow in the treated group from 15 to 20 weeks of age. At baseline and 20 weeks, plasma malondialdehyde (MDA) was measured. At 20 weeks, intravascular ultrasound images and aortic pressure were simultaneously recorded. Stiffness parameter was calculated from the cyclic variations of aortic diameter and pressure. From an excised thoracic aorta, aortic wall collagen was measured, and the morphology was histopathologically evaluated by hematoxylin-eosin staining. At 20 weeks, MDA (nmol/ml) in treated-DM (2.3 ± 0.3) was lower than in untreated-DM (3.2 ± 0.6, p < 0.0001). in treated-DM (0.53 ± 0.21) was smaller than that in untreated-DM (0.88 ± 0.26, p = 0.0067). Aortic wall collagen (mg/100 mg dry weight) did not decrease in treated-DM (22.3 ± 3.2 vs untreated-DM : 19.6 ± 4.7). Lumen/medial area ratio (L/M) increased in treated-DM (2.79 ± 0.40 vs untreated-DM : 2.22 ± 0.20, p = 0.0041, untreated-nonDM : 2.25 ± 0.55, p = 0.0075). MDA was significantly correlated with (r = 0.65, p = 0.0005) or L/M (r = –0.60, p = 0.0008). Pioglitazone may reduce oxidative stress and contribute to improvement of aortic wall stiffness without decrease in collagen content at an early prediabetic stage of type 2 DM.     

Feasibility of Induction Chemotherapy Using Bronchial Arterial Infusion for Locally Advanced Non-Small Cell Lung Cancer: A Pilot Study

Purpose: We examined the feasibility and effectiveness of bronchial arterial infusion (BAI) as induction chemotherapy before surgery for locally advanced non-small cell lung cancer (NSCLC). Methods: Eighteen patients with locally advanced NSCLC were given BAI consisting of cis-diamminedichloroplatinum (CDDP) (50–100 mg/m²) as induction chemotherapy before surgery (induction BAI). Six patients with clinical stage IIIA cancer had bulky N2 metastatic lymph nodes, and 12 patients with clinical stage IIIB cancer had T4 disease. Results: Of the 18 patients, 12 (67%) showed a partial response to the BAI therapy. Standard pulmonary resection was performed in 5 patients, pulmonary resection with the combined resection of adjacent organs was performed in 10 patients, and pulmonary resection with carinal resection and reconstruction was performed in 3 patients. Complete resection was possible in 14 patients (78%). There were no serious BAI therapy-related complications or postoperative deaths. The 5-year survival rate of the 18 patients was 35.7% and the median survival time (MST) was 19.4 months. Survival was better when complete resection was achieved after the induction BAI, especially in patients with stage IIIB (T4) disease. Conclusion: Based on our preliminary findings, BAI with CDDP as induction chemotherapy is feasible and may be an effective therapeutic modality for locally advanced NSCLC. Received: July 26, 2001 / Accepted: March 5, 2002     

Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivo

AIMS: To investigate the role of basal nitric oxide (NO) production in regulating large artery stiffness in vivo. METHODS: Incremental doses of the NO synthase inhibitor L-N(G)-monomethyl arginine (LNMMA: 0.1, 0.3, 1.0 and 3.0 mg kg-1 min-1) or placebo were infused in eight healthy men. Arterial stiffness was assessed noninvasively by pulse wave analysis. RESULTS: Compared with placebo, infusion of LNMMA led to a dose-dependent increase in mean arterial pressure, peripheral vascular resistance, and aortic and systemic arterial stiffness. There was an accompanying reduction in heart rate and cardiac index. The highest dose of LNMMA resulted in an increase of 25% in AIx (95% confidence limits; 12, 38) and of 16 mmHg in mean arterial pressure (9, 23) compared with infusion of saline. CONCLUSIONS: These data indicate functional regulation of large artery stiffness in vivo by NO, and may provide new therapeutic strategies for cardiovascular risk reduction.     

Cannabinoids inhibit pre- and postjunctionally sympathetic neurotransmission in rat mesenteric arteries

The effects of cannabinoids on sympathetic neurotransmission in the rat isolated perfused mesenteric arterial bed, were investigated. Electrically evoked sympathetic neurogenic vasocontraction was inhibited by the cannabinoid receptor agonists 11-hydroxy-dimethylheptyl-Delta(8)-tetrahydrocannabinol (HU210), (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]trans-4-(3-hydroxypropyl)-cyclohexanol (CP55,940) and methanandamide, and by (+)-11-hydroxy-Delta(8)-tetrahydrocannabinol (HU211), a (+)-stereoisomer of HU210. The inhibition was unaffected by cannabinoid CB(1) and CB(2) receptor antagonists. Electrically evoked release of endogenous noradrenaline from sympathetic nerves was inhibited by HU210, but not by HU211. Inhibition was blocked by a cannabinoid CB(1), but not a CB(2), receptor antagonist. HU210 attenuated contractions to noradrenaline, and all of the cannabinoids blocked contractions to KCl. Capsaicin pre-treatment had no significant effect on HU210- and CP55,940-mediated inhibition of sympathetic neurogenic contraction, but partly blocked inhibition mediated by methanandamide. These data show that cannabinoids can inhibit, by distinct pre- and postjunctional actions, sympathetic neurotransmission in the rat mesenteric arterial bed. The pre-junctional action is mediated by a cannabinoid CB(1)-like receptor, but the postjunctional action does not appear to involve either cannabinoid CB(1) or CB(2) receptors.     

Enhanced effects of central angiotensin II on cardiovascular and drinking responses in inbred polydipsic (STR/N) mice

STR/N, an inbred strain of mice, is known to exhibit extreme polydipsia and polyuria. The objective of this study was to investigate the possible reasons for polydipsia. First, comparisons were made between STR/N mice and control mice from the Institute of Cancer Research (ICR) concerning daily drinking, urinary excretion, and basal cardiovascular function. Then, since angiotensin II (ANG II) is a potent stimulus for drinking behavior, we investigated the effects of intracerebroventricular (i.c.v.) administration of ANG II on cardiovascular and water intake responses. Daily water intake, food intake, urinary volume, and urinary electrolytes (Na and K) excretion were larger in STR/N mice than in ICR mice, and the basal blood pressure was significantly lower in STR/N mice than in ICR mice. The i.c.v. administration of ANG II (10 pmol/per mouse) resulted in increased mean arterial blood pressure (MAP) and water intake in both STR/N and ICR mice, but the changes in MAP were significantly larger in STR/N mice than in ICR mice. These results suggest that polydipsia in STR/N mice is at least partially attributable to high sensitivity of central ANG II receptors and low MAP.     

Low-density lipoprotein apheresis in the treatment of peripheral arterial disease

Low-density lipoprotein (LDL) apheresis is performed in patients with homozygous familial hyper-cholesterolemia who lack LDL receptors and with heterozygous familial hypercholesterolemia who are LDL receptor deficient with documented, symptomatic coronary artery disease who are resistant to diet changes and maximum drug therapy. LDL apheresis can reduce or abolish anginal symptoms and improve coronary lesions. Several reports reveal the improvement of insufficient peripheral blood flow. By extensively removing blood LDL and changing coagulation factors and various vasoactive substances, LDL apheresis improves blood rheology and thereby peripheral circulation. It seems worth trying on all patients with arteriosclerotic lesions, even if they are normocholesterolemic.     

Temporary unilateral microembolization of the lung-a new approach to regional chemotherapy for pulmonary metastases

BACKGROUND: Except in patients with resectable disease, treatment of pulmonary metastases is still disappointing. Regional chemotherapy may be a suitable method for delivering more effective doses to regionally confined tumors while minimizing systemic toxicity. We propose an unilateral chemoembolization of the lung applicable by endovascular method. MATERIALS AND METHODS: An unilateral microembolization of the lung with degradable starch microspheres (DSM) alone (group 1) and combined with carboplatin (group 2) was performed on Sprague-Dawley rats (n = 12). Microcirculatory parameters were studied by in vivo videomicroscopy and radiological pattern on pulmonary angiogram. RESULTS: After injection of DSM, mean embolization time in subpleural capillaries was 7.1 +/- 2.3 min, followed by a mean flow retardation of 14.3 +/- 4.6 min; 21.4 +/- 4.7 min after embolization, original flow of erythrocytes was observed demonstrating reperfusion and reversibility of microembolization. After reperfusion relative fluorescence measured in subpleural alveoli was 0.13 +/- 0.049 in group 1, 0.105 +/- 0.016 in group 2, and 0.11 +/- 0.036 in control group (NS). Alveolar septal diameter was 17.3 +/- 1.13 microm in group 1, 16.8 +/- 1.25 microm in group 2, and 16.6 +/- 1.08 microm in control group (NS), demonstrating neither altered permeability nor pulmonary edema. Pulmonary angiogram confirmed patency of the central pulmonary artery. CONCLUSION: For the first time unilateral microembolization of the lung could be established in an experimental model. By injection of DSM, reversible embolization on arteriolar and capillary level could be demonstrated without occlusion of the main branches of the pulmonary arteries. Alveolar-capillary membrane disorder as symptom of early toxicity could not be detected even with additional application of carboplatin.     

Chronic left heart catheterization for microvascular blood flow determination in the rabbit: a minimally invasive technique using specially designed port devices.

BACKGROUND: This study describes a modified catheterization technique with subcutaneously implanted port catheters to be inserted in a retrograde manner across the aortic valve into the left heart ventricle through the right carotid artery to measure organ perfusion. MATERIALS AND METHODS: The specially designed arterial port catheters were implanted in New Zealand rabbits (n = 11, 3.7 +/- 0.1 kg [mean +/- SEM]) under iv anesthesia (medetomidine/ketamine) and single-shot perioperative antibiotic therapy. Hemodynamics were registered continuously during the operation via an ear artery catheter. RESULTS: Implantation of ports was performed in all animals (11/11) without major complications (mean operation time: 70 +/- 3 min). We did not observe catheter-associated arrhythmia, fall in mean arterial pressure (MAP before and post OP: 70 +/- 2 and 68 +/- 2 Torr, respectively), or change in arterial oxygen saturation (SaO2 before and post OP: 89 +/- 3 and 95 +/- 2%, respectively). With a specifically modified microsurgical insertion technique, cerebral blood supply was effectively preserved as evidenced from postmortem histological examinations, cerebral blood flow determination with fluorescent microspheres, and measurement of S-100b protein serum concentrations, a specific marker of neuronal damage. The positioning of the catheter tip in the left ventricle was found to be correct in 10/11 animals. CONCLUSIONS: Repeated and atraumatic microsphere injections into the left ventricle have become feasible by transcutaneous puncture of subcutaneous port systems over several weeks under light sedation. Hence, this new approach (i) avoids the necessity of repeated intracardiac injections and port insertions via thoracotomy, thus reducing the perioperative stress for the animals, and (ii) allows for the first time minimally invasive repetitive and chronic measurements of regional organ blood flow under various experimental settings.     

Interleukin-10 fails to modulate low shear stress-induced neointimal hyperplasia.

INTRODUCTION: Overexpression of the anti-inflammatory cytokine interleukin-10 (IL-10) blocks atherosclerotic events in vivo, and IL-10 has been recently hailed as an "immunologic scalpel" for atherosclerosis. Alternatively, mice lacking IL-10 receiving atherogenic diets have increased occlusive lesions. It remains unclear whether such IL-10 modulation broadly applies to other forms of occlusive arterial remodeling. We hypothesized that lack of IL-10 would exacerbate, and exogenous or overexpression of IL-10 would abrogate low shear stress-induced neointimal hyperplasia (NIH). METHODS: Wild-type (WT) and IL-10-deficient (IL-10-/-) mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated artery results in remodeling and formation of neointima containing BrdU and SMC alpha-actin-positive cells. Additional groups of WT mice underwent CCA ligation and were treated daily with intraperitoneal saline or 1 microg of human IL-10. Chronic delivery gene therapy approaches were also utilized to define the role of IL-10 signaling. WT mice were treated adventitially with 1 x 10(10) adenovirus/green fluorescent protein (Ad/gfp) and an Ad/empty control to confirm the veracity of adventitial delivery. Then, Ad viral IL-10 (vIL-10), Ad/empty, and virus buffer alone were applied directly to the adventitia of the CAA immediately following ligation. In separate experiments, 1 x 10(10) Ad/empty or Ad/vIL-10 was injected intramuscularly. CCAs were perfusion fixed 28 days postligation, the time at which NIH is near maximum. RESULTS: IL-10-/- mice developed identical NIH areas compared to WT controls. Mice receiving IL-10 demonstrated NIH equivalent to saline controls. Mice receiving intramuscular or adventitial Ad/IL-10 developed high serum levels of IL-10 yet formed NIH areas similar to those of controls. Serum IL-10 levels were significantly higher (P = 0.04) with adventitial delivery. Mice treated adventitially with Ad/gfp showed reliable transfection of cells within the adventitia of CAA. No antibody to human IL-10 was found in the sera of intraperitoneal IL-10-treated mice, which failed to attenuate NIH. CONCLUSION: Under the conditions of this experiment, lack of IL-10 does not exacerbate low shear stress-induced NIH, nor does exogenous administration or overexpression of IL-10 attenuate it. Despite high serum levels of vIL-10 in mice treated with ad/vIL-10 adventitially, there appears to be no therapeutic effect despite the confirmed transfection of adventitial cells. Discrepancies between these findings and previous research may be related to IL-10 dosing, inflammation induced by the adenoviral vector, or disparities between the NIH models.     

Mixing during Intravertebral Arterial Infusions in an in vitro Model

Regional delivery of drugs can offer a pharmacokinetic advantage in the treatment of localized tumors. One method of regional delivery is by intra-arterial infusion into the basilar/vertebral artery network that provides local access to infratentorial tumors, which are frequent locations of childhood brain cancers. Proper delivery of drug by infused solutions requires adequate mixing of the infusate at the site of infusion within the artery lumen. Our mixing studies with an in vitro model of the vertebral artery network indicate that streaming of drug solution is likely to occur at low, steady infusion rates of 2ml/min. Streaming leads to maldistribution of drug to distal perfused brain regions and may result in toxic levels in some regions while concurrently yielding subtherapeutic levels in adjacent regions. According to our model findings, distribution to both brain hemispheres is not likely following infusion into a single vertebral artery even if the infusate is well-mixed at the infusion site. This outcome results from the unique fluid flow properties of two converging channels, which are represented by the left and right vertebral branches converging into the basilar. Fluid in the model remains stratified on the side of the basilar artery served by the infused vertebral artery. Careful thought and planning of the methods of intravertebral drug infusions for treating posterior fossa tumors are required to assure proper distribution of the drug to the desired tissue regions. Improper delivery may be responsible for some noted toxicities or for failure of the treatments.