Investigation of distal aortic compliance and vasodilator responsiveness in heart failure due to proximal aortic stenosis in the guinea pig.
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Hypotension and syncope are recognized features of chronic aortic stenosis. This study examined vasomotor responses and dynamic compliance in isolated abdominal aortae after chronic constriction of the ascending aorta. Guinea pigs underwent constriction of the ascending aorta or sham operation. Sections of descending aorta were removed for studies of contractile performance and compliance. Dynamic compliance was measured using a feedback-controlled pulsatile pressure system at frequencies of 0.5, 1.5 and 2.5 Hz and mean pressures from 40 to 100 mmHg. Chronic (149+/-6 days) aortic constriction resulted in significant increases in organ weight/body weight ratios for left ventricle (58%), right ventricle (100%) and lung (61%). The presence of heart failure was indicated by increased lung weights, left ventricular end-diastolic pressure and systemic vascular resistance, reduced cardiac output and increased levels of plasma atrial natriuretic peptide (166%), adrenaline (x20), noradrenaline (106%) and dopamine (x3). Aortic rings showed similar constrictor responses to phenylephrine and angiotensin II, but maximal vasodilator responses to acetylcholine and isoprenaline were significantly increased (144% and 48% respectively). Dilator responses to sodium nitroprusside, forskolin and cromokalim were unchanged. Compliance of all vessels decreased with increasing pulsatile frequency and to a lesser extent with increased mean pressure, but were similar in aortic-constricted and control groups. Chronic constriction of the ascending aorta resulted in heart failure and increased vasodilator responses to acetylcholine and isoprenaline in the distal aorta while dynamic compliance was unchanged. We hypothesize that increased endothelium-mediated vasodilatation may contribute to hypotension and syncope in patients with left ventricular outflow obstruction. (+info)
Development of atherosclerotic lesions in cholesterol-loaded rabbits.
(2/1846)
To examine both of the target vessels and the optimal time of their endothelial denudation to study vascular restenosis after balloon injury in cholesterol-loaded rabbits, we made 36 atherosclerotic rabbits by feeding a hypercholesterol diet, and histologically examined the onset time and the development of atherosclerosis. Atheromatous changes were observed first after the 5th week in the thoracic aorta from the start of the diet, and then extended to the abdominal aorta, coronary artery with time. The atherosclerotic lesions in the thoracic aorta and the proximal portion of the coronary artery showed high-grade concentric intimal thickening with luminal stenosis. The abdominal aortic lesion mildly progressed. In the renal, carotid and femoral arteries, in contrast, slight atheroscleromatous changes developed during the diet period. These results suggest that the thoracic and abdominal aortas and the coronary artery would be suitable as target vessels to study vascular restenosis after balloon injury, and the endothelial denudation of these vessels should be performed between the 8th and 15th week in this diet protocol for an accurate analysis. (+info)
Regression of atherosclerosis: role of nitric oxide and apoptosis.
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BACKGROUND: We have recently found that administration of L-arginine to hypercholesterolemic rabbits induces regression of preexisting lesions. Others have previously shown that activation of the L-arginine/nitric oxide (NO) synthase pathway can induce apoptosis of vascular cells in vitro. Accordingly, the current study was designed to determine if dietary supplementation of L-arginine induces apoptosis of intimal lesions and if this effect is mediated through the NO synthase pathway. METHODS AND RESULTS: Male New Zealand White rabbits were fed a 0.5% cholesterol diet for 10 weeks and subsequently placed on 2.5% L-arginine HCl in the drinking water, and the cholesterol diet was continued for 2 weeks, at which time the aortas were harvested for histological studies. L-Arginine treatment increased the number of apoptotic cells (largely macrophages) in the intimal lesions by 3-fold (11.9+/-3.9 vs 3.9+/-1. 4 apoptotic cells/mm2, P<0.01). In subsequent studies, aortas were harvested for ex vivo studies. Aortic segments were incubated in cell culture medium for 4 to 24 hours with modulators of the NO synthase pathway. The tissues were then collected for histological studies and the conditioned medium collected for measurement of nitrogen oxides by chemiluminescence. Addition of sodium nitroprusside (10(-5) mol/L) to the medium caused a time-dependent increase in apoptosis of vascular cells (largely macrophages) in the intimal lesion. L-Arginine (10(-3) mol/L) had an identical effect on apoptosis, which was associated with an increase in nitrogen oxides released into the medium. These effects were not mimicked by D-arginine, and they were antagonized by the NO synthase inhibitor L-nitro-arginine (10(-4) mol/L). The effect of L-arginine was not influenced by an antagonist of cGMP-dependent protein kinase, nor was the effect mimicked by the agonist of protein kinase G or 8-BR cGMP. CONCLUSIONS: These results indicate that supplemental L-arginine induces apoptosis of macrophages in intimal lesions by its metabolism to NO, which acts through a cGMP-independent pathway. These studies are consistent with our previous observation that supplementation of dietary arginine induces regression of atheroma in this animal model. These studies provide a rationale for further investigation of the therapeutic potential of manipulating the NO synthase pathway in atherosclerosis. (+info)
The value of late computed tomographic scanning in identification of vascular abnormalities after abdominal aortic aneurysm repair.
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PURPOSE: The purpose of this study was to determine the prevalence of late arterial abnormalities after aortic aneurysm repair and thus to suggest a routine for postoperative radiologic follow-up examination and to establish reference criteria for endovascular repair. METHODS: Computed tomographic (CT) scan follow-up examination was obtained at 8 to 9 years after abdominal aortic aneurysm (AAA) repair on a cohort of patients enrolled in the Canadian Aneurysm Study. The original registry consisted of 680 patients who underwent repair of nonruptured AAA. When the request for CT scan follow-up examination was sent in 1994, 251 patients were alive and potentially available for CT scan follow-up examination and 94 patients agreed to undergo abdominal and thoracic CT scanning procedures. Each scan was interpreted independently by two vascular radiologists. RESULTS: For analysis, the aorta was divided into five defined segments and an aneurysm was defined as a more than 50% enlargement from the expected normal value as defined in the reporting standards for aneurysms. With this strict definition, 64.9% of patients had aneurysmal dilatation and the abnormality was considered as a possible indication for surgical repair in 13.8%. Of the 39 patients who underwent initial repair with a tube graft, 12 (30.8%) were found to have an iliac aneurysm and six of these aneurysms (15.4%) were of possible surgical significance. Graft dilatation was observed from the time of operation (median graft size of 18 mm) to a median size of 22 mm as measured by means of CT scanning at follow-up examination. Fluid or thrombus was seen around the graft in 28% of the cases, and bowel was believed to be intimately associated with the graft in 7%. CONCLUSION: Late follow-up CT scans after AAA repair often show vascular abnormalities. Most of these abnormalities are not clinically significant, but, in 13.8% of patients, the thoracic or abdominal aortic segment was aneurysmal and, in 15.4% of patients who underwent tube graft placement, one of the iliac arteries was significantly abnormal to warrant consideration for surgical repair. On the basis of these findings, a routine CT follow-up examination after 5 years is recommended. This study provides a population-based study for comparison with the results of endovascular repair. (+info)
Suppression of experimental abdominal aortic aneurysms by systemic treatment with a hydroxamate-based matrix metalloproteinase inhibitor (RS 132908).
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BACKGROUND: Abdominal aortic aneurysms (AAAs) are associated with chronic inflammation, disruption of medial elastin, and increased local production of elastolytic matrix metalloproteinases (MMPs). The purpose of this study was to investigate how treatment with a hydroxamate-based MMP antagonist (RS 132908) might affect the development of experimental AAAs. METHODS: Male Wistar rats underwent intraluminal perfusion of the abdominal aorta with 50 units of porcine pancreatic elastase followed by treatment for 14 days with RS 132908 (100 mg/kg/day subcutaneously; n = 8) or with vehicle alone (n = 6). The external aortic diameter (AD) was measured in millimeters before elastase perfusion and at death, with AAA defined as an increase in AD (DeltaAD) of at least 100%. Aortic wall elastin and collagen concentrations were measured with assays for desmosine and hydroxyproline, and fixed aortic tissues were examined by light microscopy. RESULTS: AAAs developed in all vehicle-treated rats, with a mean AD (+/- SE) that increased from 1.60 +/- 0.03 mm before perfusion to 5.98 +/- 1.02 mm on day 14 (DeltaAD = 276.4 +/- 67.7%). AAAs developed in only five of eight animals (62.5%) after MMP inhibition, with a mean AD that increased from 1.56 +/- 0.05 mm to 3.59 +/- 0.34 mm (DeltaAD = 128.1 +/- 18.7%; P <.05, vs vehicle). The overall inhibition of aortic dilatation attributable to RS 132908 was 53.6 +/- 6.8%. Aortic wall desmosine fell by 85.4% in the vehicle-treated rats (1210.6 +/- 87.8 pmol/sample to 176.7 +/- 33.4 pmol/sample; P <.05) but only by 65.6% in the animals treated with RS 312908 (416.2 +/- 120.5 pmol/sample). In contrast, hydroxyproline was not significantly affected by either elastase perfusion or drug treatment. Microscopic examination revealed the preservation of pericellular elastin and a greater degree of fibrocollagenous wall thickening after MMP inhibition, with no detectable difference in the extent of inflammation. CONCLUSIONS: Systemic MMP inhibition suppresses aneurysmal dilatation in the elastase-induced rodent model of AAA. Consistent with its direct inhibitory effect on various MMPs, RS 132908 promotes the preservation of aortic elastin and appears to enhance a profibrotic response within the aortic wall. Hydroxamate-based MMP antagonists may therefore be useful in the development of pharmacologic approaches to the suppression of AAAs. (+info)
Experimental assessment of proximal stent-graft (InterVascular) fixation in human cadaveric infrarenal aortas.
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OBJECTIVES: This paper investigates the radial deformation load of an aortic endoluminal prosthesis and determines the longitudinal load required to cause migration in a human cadaveric aorta of the endoprosthesis. DESIGN AND METHODS: The endovascular prosthesis under investigation was a 24 mm diameter, nitinol, self-expanding aortoaortic device (InterVascular, Clearwater, Florida, U.S.A.). Initially, a motorised digital force gauge developed an incremental load which was applied to the ends of five stent-grafts, to a maximum of 10 mm (42%) compression. Secondly, using a simple bench model, each ends of four stent-grafts were deployed into 10 cadaveric experimental aneurysm necks and a longitudinal load applied to effect distraction. RESULTS: Increasing load produced increasing percentage deformation of the stent-grafts. The mean longitudinal distraction load for an aneurysm neck of 20 mm was 409 g (200-480 g), for 15 mm was 277 g (130-410 g) and for 10 mm was 218 g (130-340 g). The aneurysm diameter and aortic calcification had p values of 0.002 and 0.047, respectively, while the p value for aneurysm neck length was less than 0.00001. CONCLUSIONS: These results suggest that there is a theoretical advantage of oversizing an aortic prosthesis and that sufficient anchorage is achieved in an aortic neck of 10 mm to prevent migration when fully deployed. (+info)
Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death.
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Inflammation is a major feature of human atherosclerosis and is central to development and progression of the disease. A variety of proinflammatory cytokines are expressed in the atherosclerotic plaque and may modulate extracellular matrix remodeling, cell proliferation, and cell death. Little is known, however, about the expression and potential role of anti-inflammatory cytokines in human atherosclerosis. Interleukin-10 (IL-10) is a major anti-inflammatory cytokine whose expression and potential effects in advanced human atherosclerotic plaques have not been evaluated. We studied 21 advanced human atherosclerotic plaques. IL-10 expression was analyzed by use of reverse transcription-polymerase chain reaction and immunohistochemical techniques. Inducible nitric oxide synthase expression was assessed by using immunohistochemistry, and cell death was determined by use of the TUNEL method. Reverse transcription-polymerase chain reaction identified IL-10 mRNA in 12 of 17 atherosclerotic plaques. Immunohistochemical staining of serial sections and double staining identified immunoreactive IL-10 mainly in macrophages, as well as in smooth muscle cells. Consistent with its anti-inflammatory properties, high levels of IL-10 expression were associated with significant decrease in inducible nitric oxide synthase expression (P<0.0001) and cell death (P<0. 0001). Hence, IL-10, a potent anti-inflammatory cytokine, is expressed in a substantial number of advanced human atherosclerotic plaques and might contribute to the modulation of the local inflammatory response and protect from excessive cell death in the plaque. (+info)
Rat sarcoma model supports both "soil seed" and "mechanical" theories of metastatic spread.
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Following injection into the portal venous or vena caval systems, tumour cells are held up almost exclusively in the liver or lung respectively, and subsequent outgrowth of tumour only occurs in these organs. Following systemic arterial injection, cells are distributed, and subsequently grow, in a variety of organs. However, the adrenal gland supports tumour growth from much fewer cells than the lung, and this is partly due to the fact the rate of tumour cell loss in the initial 48 h is very high in the latter compared to the former organ. (+info)