Arterial hypertension remains the world's leading mortality risk factor and despite overwhelming evidence that blood pressure-lowering strategies greatly reduce the cardiovascular risk, a substantial proportion of hypertensive individuals worldwide fail to achieve an optimal blood pressure control under treatment. Among the causes responsible for the gap existing between blood pressure lowering potential of the different antihypertensive treatments and real-life practice is the presence of drug-induced hypertension. Many therapeutic agents or substances may directly favour an increment of blood pressure values or counteract the blood pressure lowering effects of antihypertensive drugs. Excessive water and sodium retention, direct vasoconstriction or sympathomimetic activation are major mechanisms of action of such substances. The present manuscript will review medications and other substances that may increase blood pressure, also suggesting the choice of the more appropriate antihypertensive agents to employ when withdrawal of the substance or drug causing an elevation of blood pressure values is not possible.

BACKGROUND:Expression of inducible heme-oxygenase (HO-1) has been shown to be increased in various inflammatory disorders, which may confer a protective role. The aim of our study was to assess pulmonary expression of HO-1 after ischemia/reperfusion (I/R) of the lower limbs in rats. MATERIALS AND METHODS:We compared three groups of rats (n = 5/group): one Sham group, and two I/R groups (aorta cross-clamped for 2 h followed by 2 h of reperfusion), one of which pre-treated with Zn-protoporphyrin (Zn-PP), a competitive inhibitor of HO (50 micromol/kg, i.p.). At the end of experiment, lungs were harvested for determination of HO activity and HO-1 expression by Western blot and immunohistochemistry. Lung injury was assessed by bronchoalveolar lavage, histological study, and determination of the lung Evans Blue dye content, an index of microvascular permeability. RESULTS:I/R of the lower limbs was responsible for acute lung injury (ALI), characterized by neutrophilic infiltration (87 +/- 20 x 10(3) neutrophils/mm(3), Sham group versus 191 +/- 38 x 10(3) neutrophils/mm(3), I/R group; P < 0.002) and an increase in lung Evans blue dye content: (74 +/- 6 microg/g, Sham group versus 122 +/- 48 microg/g, I/R group; P < 0.05). Pre-treatment with Zn-PP further increases the Evans Blue content (122 +/- 48 microg/g, I/R group versus 179 +/- 23 microg/g Zn-PP group P < 0.05) and the neutrophilic infiltration. Pulmonary heme-oxygenase activity, and HO-1 content were increased after I/R. (10.5 +/- 12 pmol bilirubin/mg protein/h, Sham group versus 101.2 +/- 66 pmol bilirubin/mg protein/h, I/R group; P < 0.02). Immunohistochemistry revealed that the expression of HO-1 was mainly localized to inflammatory cells. CONCLUSIONS:ALI following I/R of the lower limbs in rats is associated with an increase of pulmonary expression of HO-1, inhibition of this expression increase the severity of ALI.

Background. Pulmonary expression of heme oxygenase has been observed in multiple studies. This expression has been found beneficial in decreasing the severity of acute lung injury (ALI) post ischemia-reperfusion (I/R). The aim of this study was to assess the role of exogenous administration of the end-products of heme oxygenase reaction, carbon monoxide, and bilirubin, in the severity of ALI.Study design. We compared five groups of rats (n = 7/group) including a sham group and four I/R of the lower extremities by clamping the abdominal aorta for 2 h followed by reperfusion for 2 h. The four I/R groups included a control group, one pretreated with bilirubin (50 mu mol/kg IV), another with inhaled carbon monoxide (CO) (250 ppm), and the last pretreated with both. The severity of ALI has been evaluated by a histological assay grading neutrophilic infiltration, as well as a study of the microvascular permeability using the Evans blue.Results. The administration of CO prevented pulmonary microvascular permeability alteration noted after I/R of the lower limbs (pulmonary content of Evans blue: 141 +/- 23 mu g/g of tissue in the isolated I/R group versus 68 +/- 34 mu g/g of tissue in CO group; P < 0.001). Histologically CO administration inhibited neutrophilic sequestration observed after I/R. On the other hand, treatment by bilirubin alone (50 mu mol/kg IV) did not modify the extent of pulmonary injury.Conclusion. Exogenous administration of carbon monoxide by inhalation at low doses prevented ALI post-I/R in this model. (c) 2007 Elsevier Inc. All rights reserved.

1. In the present study, the time-course, over a 1 year period, of postischaemic dilated cardiomyopathy and/or development of congestive heart failure was investigated in mice in terms of survival and cardiac functional and structural characteristics. 2. C57BL/6 mice with myocardial infarction (MI mice; coronary ligation n = 78) or sham-operated animals (n = 45) were used and echocardiographic, haemodynamic and histomorphometric parameters were assessed at 3, 6 and 12 months post-MI. 3. At 12 months, the survival rate was 70% in MI mice. Left ventricular dysfunction was evidenced by a strong decrease in ejection fraction (EF; -48 and -53% at 6 and 12 months, respectively; both P < 0.05) and an increase in left ventricular end-diastolic pressure (+100% at both 6 and 12 months; both P < 0.05). There was no major worsening in cardiac function between 6 and 12 months, suggesting strong compensatory mechanisms. Cardiac remodelling was observed, characterized by strong left ventricular hypertrophy (+38 and +62% at 6 and 12 months, respectively; both P < 0.05) and dilatation (+53% at 6 months; P < 0.05), but collagen was not significantly increased. Significant correlations were found between EF (echocardiography) and dP/dtmax, between end-diastolic volume (echocardiography) and left ventricular internal perimeter (histomorphometry) and between left ventricular mass (echocardiography) and weight. 4. In conclusion, despite a high survival rate, the MI mouse model displays most of the hallmarks of postischaemic dilated cardiomyopathy and/or congestive heart failure, thus affording the necessary background for the subsequent evaluation of gene manipulation and/or drug effects. In addition, two-dimensional echocardiography appears to be a suitable tool for the long-term follow up of cardiac function and remodelling in this model.

Objective: Expression of inducible heme oxygenase has been shown to be increased in various visceral inflammatory disorders, which may confer a protective role. The purpose of our study was to determine whether the expression of inducible heme oxygenase was up-regulated within lungs in a rat model of extracorporeal circulation.Methods: Wistar rats underwent either a partial femoro-femoral extracorporeal circulation in normothermia for 3 hours (n = 5) or a sham procedure (n = 5). Exhaled carbon monoxide concentration was monitored with an infrared analyzer. After the rats were killed, lungs were harvested for determination of heme oxygenase activity and inducible heme oxygenase expression (by Western blot and immunohistochemistry). Lung injury was also assessed by arterial blood gas analysis and microscopic study.Results: Extracorporeal circulation was responsible for a lung injury characterized by decreased arterial blood oxygen saturation and typical morphologic findings (marked alveolar neutrophil infiltration; interstitial edema). Exhaled carbon monoxide concentration remained stable throughout the experiment in all sham rats, whereas it increased after extracorporeal circulation (from 0.16 +/- 0.05 ppm at baseline to 0.7 +/- 0.2 ppm at end of experiment; P =.0001). Pulmonary heme oxygenase activity and inducible heme oxygenase content (assessed by Western blot) were increased within lungs of rats that underwent extracorporeal circulation. Immunohistochemistry revealed that the expression of inducible heme oxygenase was mainly localized to inflammatory cells.Conclusions: Post-extracorporeal circulation acute lung injury in rats was associated with an increased expression of inducible heme oxygenase, the functional significance of which remains to be determined.

We investigated in mice whether atherosclerosis exacerbates the development of post-ischemic heart failure and alters the beneficial effects of long-term angiotensin II type I receptor blockade in this model. ApoE-deficient (ApoE(-/-)) and C57BL/6J (C57) mice with myocardial infarction (coronary ligation) received vehicle (C57 and ApoE(-/-)) or irbesartan (Ir, 50mg/kg/d orally, C57-Ir and ApoE(-/-)-Ir). Ten months post myocardial infarction, survival rates were similar in C57 (58%) and ApoE(-/-) (62%). Atherosclerosis induced no significant alteration in blood pressure, cardiac output (fluospheres), total peripheral resistance, or shortening fraction (echocardiography) but increased renal resistance (+50%, P < 0.05). Chronic Ir treatment significantly improved survival to a similar extent in both C57-Ir (85%) and ApoE(-/-)-Ir (86%). It also decreased blood pressure to a similar extent in both strains (-16% and -18%, both P < 0.05). In C57-Ir mice, Ir did not modify cardiac output or total peripheral resistance, but it decreased renal resistance (-28%, P < 0.001) and left-ventricular weight (-28%, P < 0.05). In ApoE(-/-)-Ir mice, Ir limited atherosclerotic lesions (-13%, P < 0.05), increased cardiac output (+28%, P < 0.05) and shortening fraction (+24%, P < 0.05), and decreased total peripheral resistance (-33%, P < 0.01), renal resistance (-61%, P < 0.001), and left-ventricular weight (-27%, P < 0.001). In conclusion. atherosclerosis does not worsen heart failure development in mice and, although the beneficial cardiovascular effects of AT, receptor blockade are greater in ApoE(-/-) than in C57, reduction in mortality is similar in both strains.

We evaluated quantitative ultrasonic methods for assessment of carotid plaque content. In vitro measurements of fixed, carotid plaque specimens obtained by surgical endarterectomy were performed using a clinical Philips HDI 5000 imaging system connected to a radiofrequency (RF) signal-acquisition system. We acquired RF signals and grey-scale images from carotid specimens (n = 17) and a tissue-mimicking reference phantom. Imaged plaque sections were then classified according to histology. Parametric images were constructed from the integrated backscatter (IBS), and the midband, slope and intercept values of a straight-line fit to the apparent backscatter transfer function. Analysis was performed on 82 regions-of-interest (ROIs). The IBS values for collagen, lipid and hemorrhage plaques were 5.8 +/- 5.4, 3.9 +/- 3.7, 2.8 +/- 2.2 dB, respectively. Midband and IBS parameter images exhibited good agreement in morphology with histology, whereas the slope and intercept parameter images were noisy. Mean IBS, midband, and grey-scale values of complex plaques were found to be statistically different (p < 0.05) from lipid, hemorrhage and fibrolipid plaques. The bias and limits of agreement (1.3 +/- 4.9 dB) between the grey-scale and IBS methods, however, indicated that the two methods were not interchangeable. Results indicate necessary improvements, such as reduction of large measurement variances and identification of robust parameters, that will permit multiparametric characterization of carotid plaque under in vivo conditions. (E-mail: krwaters@boulder.nist.gov) (C) 2003 World Federation for Ultrasound in Medicine & Biology.

Exhaled nitric oxide (NO) concentration, a marker of pulmonary inflammation, has been shown to be elevated in various models of acute lung injury (ALI). This study was undertaken to evaluate the pulmonary NO production in a rat model of postextracorporeal circulation (ECC) ALI. Wistar rats underwent either a partial femorofemoral ECC in normothermia for 3 h (n = 10) or a sham procedure (n = 10). The extracorporeal circuit consisted of a roller pump and a membrane oxygenator. Exhaled NO concentration was monitored with a chemiluminescence analyzer. After sacrifice, lungs were harvested for microscopic studies and to analyze the inducible nitric oxide synthase (iNOS) activity and expression (Western blot). ECC was responsible for an ALI characterized by a decreased arterial blood oxygen saturation (88.9% [51.7-94.2] vs. 93.7% [91.4-98.6] P = 0.005) and pulmonary histological changes (marked alveolar neutrophil infiltration; interstitial edema; intraalveolar hemorrhage). The lung injury score was significantly higher in the ECC group (n = 5; 3.0 [2-4]) in comparison to the sham group (n = 5; 1.0 [0-2]). Exhaled NO concentration remained stable throughout the experiment in all sham rats whereas it significantly increased in the ECC group from baseline (2 ppb [1-5]) until the end of experiment (33.5 ppb [1-47]). Lung iNOS activity and expression were also significantly increased in the ECC group. An increase in exhaled NO, however, did not correlate with the decrease in arterial oxygen pressure. ECC was responsible for an ALI in rats and for an elevated pulmonary NO production. Determination of the relationship between exhaled NO and the severity of the inflammatory process in ALI will require further studies.

Objective This study was undertaken to determine whether an increase in exhaled nitric oxide would reflect the severity of the acute lung injury caused by extracorporeal circulation. Design Prospective, controlled animal laboratory investigation. Setting University laboratory. Subjects Male, anesthetized, paralyzed, and mechanically ventilated Wistar rats (n = 34). Interventions Twenty-three Wistar rats underwent a partial (100 mL·kg−1·min−1) femoro-femoral extracorporeal circulation in normothermia for 90 mins. Eleven time-matched rats formed the sham group. Measurements and Main Results Exhaled nitric oxide was monitored with a chemiluminescence analyzer. Acute lung injury was assessed by blood gas analysis and lung water content. Lung Evans blue dye content, lung myeloperoxidase, and heme oxygenase activities were determined. Compared with the sham rats, extracorporeal circulation was responsible for acute lung injury characterized by an increased lung water content (82.4 ± 1.3% vs. 77.9 ± 1.1%;p < .05), an increased Evans blue dye content (191.8 ± 15.8 vs. 112.5 ± 16.8 mg/g tissue wet weight;p < .01), and an increased pulmonary heme oxygenase activity (332.9 ± 107 vs. 113.7 ± 46.5 pmol· hr−1·mg of protein−1;p < .05). Exhaled nitric oxide remained stable throughout the experiment in all sham rats. Among the 23 rats that underwent extracorporeal circulation, eight rats (35%) experienced an increase in exhaled nitric oxide concentration (16.9 ± 12.7 ppb). There was no significant difference between rats that did or did not experience an increase in exhaled nitric oxide regarding each index of acute lung injury. Conclusions An increase in exhaled nitric oxide did not reflect the severity of the acute lung injury caused by extracorporeal circulation. Its significance remains to be determined.

Oligodeoxynucleotides containing CpG motifs (CpG-ODN) are powerful immunostimulating agents that are currently entering clinical trials in various human diseases. Concerns exist about potential auto-immune diseases triggered by such treatment. We thus investigated whether tumor rejection induced by CpG-ODN treatment could lead to a harmful auto-immune reaction against the nervous system (neurological paraneoplastic disease) at the time of acute tumor rejection, or in long-term surviving animals. Mice bearing established neuroblastomas were treated with intra-tumoral injections of CpG-ODN, resulting in tumor inhibition and tumor rejection in one-third of the animals. Immunocytochemistry and Western blot studies revealed no specific anti-neuronal antibodies. None of the animals developed neurological disabilities and histological studies of the nervous system were normal. CpG-ODN can therefore trigger neuroblastoma rejection without inducing neurological paraneoplastic disease.

1. The aim of the present study was to investigate left and right ventricular (LV and RV, respectively) coronary vasodilatation reserve (CVR; fluorescent microsphere technique) in rats with hypertension (spontaneously hypertensive rats (SHR)) or congestive heart failure (CHF) and the effects of early and chronic renin-angiotensin system (RAS) blockade thereupon. 2. In adult SHR, both LV and RV CVR were impaired, especially in the non-hypertrophied RV, the main factor involved being coronary vascular remodelling. Blockade of the RAS normalized both LV and RV CVR, mainly through the prevention of hypertension and suppression of the resulting pericoronary fibrosis. 3. In postischaemic CHF rats, there was an early and severe degradation of LV and RV CVR that developed before any significant vascular remodelling and appeared to be linked to the deterioration of cardiac hypertrophy and haemodynamics. This degradation in CVR further worsened over the longer term due to late-developing pericoronary fibrosis and endothelial dysfunction. Blockade of the RAS had no early effects on LV and RV CVR, but improved RV CVR over the long term, mainly by limiting RV hypertrophy and by preventing the development of pericoronary fibrosis and coronary endothelial dysfunction. 4. In kallikrein-kinin system-deficient mice, CVR was not different from that of wild-type mice, suggesting that this system is not implicated in normal CVR regulation.

J Thorac Cardiovasc Surg 2001;122:197-8

BACKGROUND:Angiotensin I-converting enzyme inhibition (ACEI) and angiotensin II AT(1)-receptor blockade are effective at improving survival and limiting cardiac remodeling in the rat model of postischemic heart failure. Whether their combination yields additive/synergistic effects is unknown.METHODS AND RESULTS:Rats underwent coronary artery ligation and 7 days later were treated orally for 9 months with placebo (controls), 5 mg/kg valsartan, 1 mg/kg enalapril (doses submaximally effective at reducing mortality in the experimental model used), or 5 mg/kg valsartan and 1 mg/kg enalapril combined. Compared with controls, valsartan, enalapril, and their combination decreased mortality by 40% (P =.006), 21% (P =.065), and 33% (P =.032), respectively, but there was no significant difference between the 3 treatments. At the doses used, valsartan, but neither enalapril nor the combination, slightly limited cardiac hypertrophy and fibrosis development and reduced left ventricular end-diastolic pressure as assessed in the surviving animals at 9 months.CONCLUSIONS:In experimental chronic heart failure in rats, valsartan reduces mortality similar to other AT(1)-receptor blockers and a combination of AT(1)-receptor blockade (valsartan) and ACEI (enalapril) at submaximal doses does not exert additive/synergistic beneficial effects on mortality.

The goal of this work is to demonstrate the feasibility of objective noninvasive methods for in vivo characterization of carotid plaque content. Using a clinical ultrasonic imager connected to a radiofrequncy (RF) signal acquisition system, both RF signals and grayscale (GS) images were obtained from a tissue-mimicking reference phantom and from 26 independent segments of formalin-fixed human carotid endarterectomy specimens. Integrated backscatter (IBS) images of each segment were constructed from an FFT-based analysis on individual RF lines using a sliding Hamming window technique (32 point length, I point shift). For 82 matched ROIs, average IBS from parameter images was compared to average GS values normalized with respect to GS in the reference phantom. For 70 of the ROIs, plaque content was assessed by histology in terms of collagen, lipid, hemorrhage and calcification content. The current GS and IBS approaches were not found to be equivalent. The IBS values (mean standard error) for collagen, lipid and hemorrhage were 8.1 1.1, 5.3 +/- 1.0 and 4.9 +/- 0.7 dB, respectively. These measurements in carotid plaque which were obtained using an ultrasound imaging system represent an important step toward the transfer of quantitative plaque characterization to the clinic.

Tracheal reconstruction after extensive resection remains an unsolved surgical problem. Numerous attempts have been made using tracheal grafts or prosthetic conduits with disappointing results. In this study, we propose a new alternative using an aortic autograft as tracheal substitute. In a first series of experiments, a half circumference of two rings was replaced with an autologous carotid artery patch. In a second series, a complete segment of trachea was replaced with an autologous aortic graft supported by an endoluminal tracheal stent. No dehiscence or stenosis was observed. Microscopic examinations at 3 and 6 months showed the replacement of the aortic tissue by tracheal tissue comprising neoformation of cartilage and mucociliary or non-keratinizing metaplastic polystratified squamous epithelium. Although these results need to be confirmed by a larger series of experiments, they showed that a vascular tissue placed in a different environment with a different function can be submitted to a metaplastic transformation which tends to restore a normal structure adapted to its new function. These remarkable findings offer new perspectives in tracheal reconstruction in human.

The goal of this study was to develop methods for quantitative ultrasound imagery suitable for noninvasive assessment of carotid plaque composition prior to the selection of the technique for revascularization. Using two broadband transducers (5–12 MHz and 12–28 MHz), backscattered radio frequency signals were acquired from entire lengths of 15 carotid endarterectomy specimens. Spectral analysis methods with correction for system response and beam diffraction were applied to radio frequency signals from local volumes of plaque having a 2 mm slice thickness, 1 mm width and axial depth of 480 μm and 240 μm at 10 MHz and 20 MHz, respectively. From these spectra, local values of four ultrasound parameters (integrated backscatter, frequency dependence of backscatter, integrated attenuation and slope of attenuation) were estimated and used to construct quantitative images. To combine information from these different parameter images, a two-step approach was followed. First, in 59 independent quantitative images of highly stenotic plaque, the average parameter values in a central five-by-three pixel region were correlated with plaque composition as assessed by histology to investigate the relationship between parameter values, frequency bandwidth and plaque composition. Discriminant analysis of parameter values vs. plaque composition was made to find a set of predictive equations to classify sets of measurements. Correct classification was obtained for 100% of calcified, 75% of intraplaque hemorrhage and 71 % of lipidic plaques of the input data set. Second, each set of pixels from different parameter images was classified using the predictive equations, and a single, local tissue composition image was constructed. Examples of tissue composition images are presented in comparison with corresponding histologic sections. Both agreement and disagreement between image pairs are discussed.