Physiological levels of beta-amyloid induce cerebral vessel dysfunction and reduce endothelial nitric oxide production.

beta-amyloid (A beta), the major component of senile plaques in Alzheimer's disease (AD), normally circulates in the blood at nanomolar levels but is elevated in AD. Previous studies have found that high concentrations (10(-5)-10(-4) M) of A beta result in neuronal cell death. Here we show that physiological levels of soluble A beta can induce dysfunction in perfused rat cerebral vessels and in cultured endothelial cells. At concentrations of 10(-9)-10(-6) M, A beta induced a significant concentration-dependent reduction of NO production in endothelial cells. At 10(-8) M, A beta significantly decreased the sensitivity of cerebral vessels to acetylcholine (ACh), an endothelium dependent vasodilator. At 10(-7) M and higher concentrations, A beta significantly reduced the maximum response of vessels to ACh, and induced significant endothelial cell death. A beta (10(-9)-10(-5) M) did not cause any detectable change in nitric oxide synthase levels. The results suggest that a modest increase in the concentration of A beta above its normal physiological level in the circulation, as found in the early stages of AD, results in decreased NO production and vessel sensitivity to endothelium-dependent vasodilation that could lead to constricted blood vessels and ischemia in the surrounding tissue. Further increases in A beta concentration, which may occur in the later stages of AD, result in cell death and decreased maximum vasodilator response of cerebral vessels.

Potassium channel openers prevent beta-amyloid toxicity in bovine vascular endothelial cells.

There is increasing evidence that the cerebrovasculture may be involved in the pathology of Alzheimer's disease. Here, we report that potassium channel openers (KCOs) inhibit dose and time dependent necrosis induced by beta-amyloid (Abeta) in cultured vascular endothelial cells. Cell proliferation rate was assayed by a colorimetric method. Abeta cytotoxicity and inhibition by the K(ATP) channel opener diazoxide and the K(Ca) channel opener NS1619 was correlated with changes in nitric oxide (NO) production. The protective effects were partly blocked by potassium channel blockers. Toxicity of Abeta and KCO protection was verified by histological examination of endothelial cells with scanning electron microscopy. eNOS levels in endothelial cells were not changed by any of the treatments. The results suggest that disruption of K(+) channels function may be a critical step in Abeta-induced cytotoxicity in endothelial cells by alteration of NO release.

Animal model of Alzheimer-like vascular pathology and inflammatory reaction.

This in vivo animal model of vascular inflammatory reaction facilitates morphologic and hemodynamic analyses of leukocyte-endothelial interaction and can be monitored by video microscopy and electron microscopy. The model has served as a rapid means to explore the deleterious vascular actions and inflammatory response to the cytokines tumor necrosis factor, interleukin-1 and amyloid-beta, as well as the protective effects of superoxide dismutase, estrogen, and cytokine antagonists.

Pulmonary endothelial and epithelial integrity and neutrophil infiltration after endotoxin in interleukin-1 receptor knockout mice.

Previously we found the structural integrity of the aortic endothelium was maintained after the administration of endotoxin in type 1 interleukin-1 (IL-1) receptor knockout mice. In this study, we investigated further the integrity of pulmonary vascular endothelium, airway epithelial, pulmonary microvasculature, and neutrophil infiltration into the microvasculature and respiratory air spaces. Adult male C57BL/129J wild-type mice and C57BL/129J knockout mice possessing a homozygous deletion of the type 1 IL-1 receptor received the following intraperitoneal injections; 1) Escherichia coli endotoxin (ENDT) (10 mg/kg), 2) ENDT (2 mg/kg given for 4 days), or (3) saline vehicle. Wild-type and knockout control animals receiving saline vehicle showed normal endothelial and epithelial ultrastructure with intact membranes. Pulmonary endothelial cell damage was found only in wild-type mice given a single 10 mg/kg endotoxin dose. Airway epithelial damage was found only in wild-type mice given a repetitive dose of endotoxin (2 mg/kg for 4 days). Neutrophil infiltration increased only in mice given a single dose of endotoxin (10 mg/kg) with the wild-type increasing by 32% and the knockouts by 6% compared with the saline control for that group respectively. Serum IL-6 and nitric oxide (indicators of septic shock severity and lethality) significantly increased only in the mice given 10 mg/kg of endotoxin. The maintenance of pulmonary endothelial and epithelial cell integrity and the decrease of neutrophil infiltration in the IL-1 knockout mice suggest that IL-1 contributes significantly to the severity of endotoxin-induced sepsis.

The protective effect of K+ channel openers on beta-amyloid induced cerebrovascular endothelial dysfunction.

Amyloid angiopathy is characterized by amyloid beta-peptide (A beta) deposition and may contribute to the cerebrovascular abnormalities that precede the onset of Alzheimer's Disease (AD). That aberrant potassium (K+) channel function occurs in AD patients is supported by deleterious effects of A beta on normal fibroblast K+ channels and prevention of A beta-induced toxicity by potassium channel openers (KCOs) in neuronal cell culture. We report here that KCOs protect cerebral and peripheral vessels against the endothelial damage induced by A beta. Pressurized posterior cerebral artery and aortic ring segments from the rat were constricted and then relaxed with the endothelium-dependent vasodilator acetylcholine before and after incubation with A beta (10(-6) M), or pre-treatment with KCOs before the addition of beta-amyloid. Vessels treated with A beta exhibited features of endothelial dysfunction: enhanced vasoconstriction and diminished endothelium-dependent vasodilation. Pre-treatment with KCOs significantly antagonized the A beta effect in both cerebral and aortic vessel segments. This protection was provided by both KCa and KATP channel openers. Endothelial damage by A beta and protection by KCOs was verified by electron microscopy. The K+ channel blocker, TEA, reversed the protective effect of KCO. The results suggest that potassium channel openers protect against A beta induced endothelial dysfunction and that KCOs may have a role in the treatment of degenerative cerebrovascular disease as seen in stroke, AD and aging.

Animal model of vascular inflammation.

Inflammatory mechanisms play a central role in the pathology of a variety of conditions ranging from atherosclerosis, arthritis, cancer and Alzheimer's disease. Under normal conditions the inflammatory response initiates protective actions, but triggers tissue damage under pathological conditions. Acute or chronic inflammation is mediated by nascent expression of a host of proteins such as the cytokines interleukins (IL), tumor necrosis factor (TNF), and interferons. Currently available in vitro or in vivo methods do not offer the specificity to probe the complex inflammatory cascade. We developed an animal model in which a single injection of the proinflammatory cytokines TNF-alpha and IL-1 beta in live rodents initiates a rapid inflammatory reaction which can be monitored by video microscopy and electron microscopy. This model exhibits the characteristic feature of inflammatory reaction such as adhesion and transmigration of leukocytes, and activation and degranulation of platelets and mast cells. This model is applicable to inflammatory processes in the peripheral and cerebral vasculature including the blood-brain barrier disruption in Alzheimer's disease. The animal model of inflammation reported here may prove to be a valuable tool in investigating the pathophysiology of a number of inflammatory diseases and identifying potential targets as well as agents for therapy.

Amyloid-beta peptide induced inflammatory reaction is mediated by the cytokines tumor necrosis factor and interleukin-1.

A chronic inflammatory response possibly mediated by amyloid-beta (A beta) is believed to be a major factor in the pathology of Alzheimer's disease (AD). Recently, we demonstrated that in vivo administration of A beta produces an inflammatory response and vascular disruption as seen in the brains of AD patients. In an inflammatory response, leukocyte activation and extravasation involves cytokine production. Previous studies have indicated that immune interactions exist between the central nervous system and the peripheral immune mechanisms in AD. Increased levels of interleukin-1 beta (IL-1 beta) have been detected in brain tissue, cerebrospinal fluid, and blood/serum from AD patients. In addition, A beta stimulated the production of tumor necrosis factor-alpha (TNF-alpha) in brain astrocytes and murine monocytes. Using an animal model we investigated the role of the cytokines, TNF-alpha and IL-1 beta, in the A beta-induced inflammatory response. Adult male rats were perfused via an intra-aortic cannula with either A beta alone, interleukin-1 receptor antagonist (IL-1 ra) plus A beta, tumor necrosis factor-binding protein (TNF-bp) plus A beta or sterile saline. Serum analysis for TNF-alpha, IL-1 beta, A beta and NO showed a significant increase in TNF-alpha and A beta but not in IL-1 beta or NO after the injection of A beta. Control values for serum A beta averaged 1.6 ng/ml and in rats injected with A beta, 99.6% of this peptide was removed from the blood within 30 min. The mesenteric arterioles and venules were video recorded for 1-2 h and then processed for electron microscopy (EM). In rats given A beta alone there was extensive vascular disruption, including endothelial and smooth muscle damage with leukocyte adhesion and migration. Animals receiving either IL-1 ra or TNF-bp before A beta showed no in vivo leukocyte extravasation or vascular damage under EM. Therefore, the cytokines TNF-alpha and IL-1 beta seem to mediate the vascular disruption and inflammatory response initiated by A beta. Antagonism of these pro-inflammatory cytokines may offer new avenues for AD therapy.

Estrogen protects peripheral and cerebral blood vessels from toxicity of Alzheimer peptide amyloid-beta and inflammatory reaction.

Due to increases in life expectancy, women are living 30 years or more beyond menopause. This has led to an increasing interest in the association between postmenopausal estrogen deficiency and degenerative diseases associated with aging such as cardiovascular disease, osteoporosis and dementia. Women are two times more likely to develop late-onset Alzheimer's disease (AD) than age-matched men. A large number of observational reports and a few randomized clinical trials have indicated that estrogen replacement therapy (ERT) may retard the development and severity of dementia in postmenopausal women. The mechanism underlying the protective action of estrogen in AD is under active investigation. A chronic inflammatory reaction mediated by abnormal deposition of proteins such as amyloid-beta (A beta) is central to the pathology of AD. We investigated the effect of low doses of conjugated estrogen (Premarin) in an animal model of A beta-induced vascular disruption and inflammatory reaction. This rodent model allows live videomicroscopic recording and electron microscopic analysis of peripheral vascular disruption and inflammatory reaction triggered by A beta. Estrogen prevented vascular deposition of A beta, endothelial and vessel wall disruption with plasma leakage, platelet and mast cell activation, and characteristic features of an inflammatory reaction: adhesion and transmigration of leukocytes. The beneficial effect was lost when estrogen treatment was discontinued. Estrogen also protected the cerebral blood vessels from endothelial dysfunction induced by A beta. This novel protective effect of estrogen against A beta cytotoxicity in peripheral and cerebral vasculature may contribute to the therapeutic efficacy of estrogen in AD and coronary vascular disease.

beta-Amyloid induces cerebrovascular endothelial dysfunction in the rat brain.

beta-Amyloid toxicity plays a central role in the pathology of Alzheimer's disease. Contraction and relaxation responses of pressurized rat posterior cerebral artery were studied before and after in vitro exposure to beta-amyloid. The peptide-induced characteristic features of endothelial dysfunction including enhanced vasoconstriction with serotonin and diminished relaxation to endothelium-dependent vasodilators acetylcholine and bradykinin. Response to the endothelium-independent vasodilator nitroprusside was not affected by beta-Amyloid. beta-amyloid inhibition of acetylcholine-induced vasodilation was prevented by the oxygen radical scavenging enzyme superoxide dismutase. Endothelial destruction and the protective effect of superoxide dismutase was verified by electron microscopy. The results suggest that beta-amyloid peptide produces endothelial dysfunction in cerebral microvessels through reactive oxygen species.

beta-Amyloid-induced cerebrovascular endothelial dysfunction.

Cerebrovascular effects of beta-amyloid were investigated using bovine mid-cerebral arteries. beta-amyloid-induced endothelial damage was evidenced by increased vasoconstriction, diminished vasodilation and was evident on electron microscopy. The endothelial dysfunction was mediated by reactive oxygen radicals. Vascular damage by beta-amyloid may be an early event in the development of the pathology of Alzheimer's disease.

Beta-amyloid-induced coronary artery vasoactivity and endothelial damage.

Amyloid beta-peptide (A beta) deposition has been associated with coronary heart disease and neurodegenerative diseases. A link between A beta and free radical generation has been explored in neuronal tissue. We report here on the effect of A beta on pressurized segments of coronary resistance arteries and the role of free radicals. A small oscillatory response to A beta (10[-6] M) that consisted of a relaxation followed by constriction and a return to the basal diameter was observed in all vessels. The thromboxane A2 analog U46619 produced a significantly greater constriction compared with the response before treatment with A beta. The presence of the antioxidant enzyme superoxide dismutase (SOD) reduced both the response to A beta alone and the enhanced response to U46619. Vasodilation responses to acetylcholine (10[-9]-10[-5] M) were virtually eliminated at all concentrations by A beta. We confirmed endothelial cell damage by A beta with electron microscopy. The results suggest that A beta deposition in coronary resistance arteries causes endothelial damage that is mediated through superoxide radicals.

In vivo vascular damage, leukocyte activation and inflammatory response induced by beta-amyloid.

beta-amyloid toxicity is central to the pathology of Alzheimer's disease. Recent evidence implicates vascular dysfunction as a contributing factor to the dementia of Alzheimer type. Using intravital microscopy we demonstrate that in vivo administration of beta-amyloid produces extensive vascular disruption including endothelial and smooth muscle damage, adhesion and migration of leukocytes across arteries and venules. Amyloid angiopathy with vascular damage and inflammatory changes are hallmarks in the brains of Alzheimer disease victims. The vascular actions of beta-amyloid are distinct from the neurotoxic properties of the peptide and were prevented by the free radical scavenging enzyme superoxide dismutase. Oxygen radical mediated vascular dysfunction may induce ischemic and inflammatory responses leading to neurodegeneration as seen in Alzheimer's disease.

Cerebrovascular endothelial dysfunction mediated by beta-amyloid.

beta-Amyloid (A beta) toxicity has a critical role in the pathology of Alzheimer's disease (AD) but its function in the neurodegenerative process is not clearly established. Recently, we demonstrated a novel action of beta-amyloid on peripheral blood vessels: endothelial dysfunction through reactive oxygen species. Here we report the direct effect of A beta on cerebrovascular endothelium. Following treatment with A beta 1-40, bovine cerebral arteries showed characteristic features of endothelial dysfunction such as increased contraction to vasoconstrictor and diminished relaxation to endothelium-dependent vasodilators. Electron microscopy revealed significant damage to the endothelium by A beta. Pretreatment with the antioxidant superoxide dismutase (SOD) and PBN (n-tert-butyl-alpha-phenylnitrone) antagonized the effects of A beta. Endothelial damage induced by A beta could produce ischemic and inflammatory changes contributing to the pathology of AD.

Endothelial structural integrity is maintained during endotoxic shock in an interleukin-1 type 1 receptor knockout mouse.

The derangement of arterial endothelial cell morphology is a good indicator of a severe shock state. Because interleukin (IL)-1 has been implicated in this process, we examined the structural integrity of aortic endothelial cells in conjunction with serum IL-6 concentrations and nitric oxide levels, which are known to increase during endotoxemia in animals genetically devoid of the type 1 IL-1 receptor. Endotoxin (10 mg/kg Escherichia coli, injected intraperitoneally) (LD100) or saline vehicle was administered to adult male C57BL/129J wild-type control mice and C57BL/129J knockout mice possessing a homozygous deletion of the type 1 IL-1 receptor. The integrity of the aortic endothelium was determined by comparisons of ultrastructure. Mice injected with sterile vehicle showed normal endothelial ultrastructure with intact membranes. Wild-type and knockout control animals receiving saline vehicle showed a complete aortic endothelium (29.11 +/- .27 and 30.85 +/- .21 intact endothelial cells per millimeter of internal elastic lamina (IEL), respectively, p = N.S.). Endotoxin-treated wild-type animals showed extensive endothelial damage with most sections showing only denuded IEL on the luminal surface (1.83 +/- .38 cells/mm IEL, p < .001 vs. control). Knockout animals treated with endotoxin showed complete maintenance of endothelial structural integrity (34.08 +/- .57 cells/mm IEL, p < .001 vs. endotoxin-treated wild type) with ultrastructural morphology appearing identical to those given saline vehicle. Also, no apparent correlation was observed between serum IL-6 concentrations or serum nitric oxide levels and aortic endothelial damage. The maintenance of endothelial integrity in animals devoid of the IL-1 receptor confirms earlier observations of endothelial cell protection with IL-1 receptor antagonism and suggests that IL-1 contributes significantly to sepsis-induced endothelial damage.

beta-amyloid-induced endothelial necrosis and inhibition of nitric oxide production.

Deposits of amyloid beta-peptide (A beta) in senile plaques and cerebral blood vessels is the prominent feature of Alzheimer's disease (AD), regardless of genetic predisposition. The cellular origin of cerebral deposits of A beta or its precise role in the neurodegenerative process has not been established. Recently we demonstrated a novel action of beta-amyloid on blood vessels--vasoactivity and endothelial damage through superoxide radicals. Since endothelial dysfunction is associated with vascular degenerative diseases, we examined the direct action of A beta on endothelial cells in culture. Cells treated with A beta displayed characteristics of necrotic cell death which was prevented by the free radical scavenging enzyme superoxide dismutase. Stimulation of endothelial nitric oxide (NO) production by the calcium ionophore, A23187, or bradykinin was inhibited by beta-amyloid. We conclude that an imbalance of NO and oxygen radicals may mediate the A beta-induced endothelial damage on endothelial cells in culture and may also contribute to a variety of pathophysiological conditions associated with aging: hypertension, cerebral ischemia, vasospasm, or stroke.

Effect of Brugia malayi on the growth and proliferation of endothelial cells in vitro.

Athymic mice (C3H/HeN) parasitized by Brugia malayi develop massively dilated lymphatics. The lymphatic endothelial lining is perturbed, and numerous mononuclear and giant cells are closely apposed to the endothelium. The hyperplastic endothelial cells and low opening pressure of the lymphatics suggest abnormal multiplication of these cells may be important in the dilation. We studied the in vitro growth rate of human umbilical vein endothelial cells cultured with adult worms and microfilariae of B. malayi. The tetrazolium salt reduction assays were used to quantify possible direct mitogenic or inhibitory effects. The growth factor-induced proliferation of endothelial cells was significantly suppressed by 44-51% on day 1, 46-81% on day 3, and 45-79% on day 5 in cultures containing adult female worms, which had greater suppressor activity on endothelial cell proliferation than male worms, microfilariae, or soluble adult worm extract. Culture supernatant containing female worm excretory-secretory products significantly inhibited the growth and multiplication of cells, suggesting that adult female worms release antigens or proteins that have inhibitory activity on growth factors necessary for endothelial cell proliferation in vitro. Excess human recombinant epidermal growth factor and bovine brain extract partly reversed the inhibitory activity of worms in culture and restored the endothelial cell proliferation when incubated with worm culture supernatant. Indomethacin and BW 775Hcl failed to restore normal endothelial proliferation in the presence of female worms, suggesting that parasite-derived prostanoids and cyclooxygenase products did not cause the inhibition. Lymph from dilated lymphatics, but not serum from infected mice, increased the proliferation of cells in vitro. Together, these data demonstrate that excretory-secretory products of B. malayi parasites suppress vascular endothelial proliferation in vitro. Furthermore, increases in the number of these cells in vitro in the presence of lymph suggest that parasite-induced host factors may be important in modulating the degree of proliferation.

Mechanism of anoxia-induced atrial natriuretic peptide release in the isolated rat atria.

Our laboratory has recently shown that locally produced endothelin (ET) is involved in the atrial natriuretic peptide (ANP) response to a physical stimulus, stretch. The aim of this study was to determine if factors locally produced in the atria were involved in the ANP response to a chemical stimulus, anoxia. Reduced oxygen tension is a potent stimulus of ANP release, and our results show that, when isolated perfused atria were exposed to anoxic conditions, the ANP secretion rate increased by a maximum of 129 +/- 8% of the baseline. Exposure to anoxia caused neither an elevation in perfusate creatinine phosphokinase, a change in atrial morphology detectable by electron microscopy, nor interfered with the return toward the baseline ANP secretion rate with reoxygenation, suggesting that this response was not due to myocyte damage. When the atria were pretreated with either 3 microM BQ-123, an endothelin receptor inhibitor, or 10 microM indomethacin, a cyclooxygenase inhibitor, the ANP response to anoxia was nearly abolished. To clarify the association between ET and prostaglandins, we showed that the ANP response to 50 nM ET-1 was totally blocked at both high and low pressure by 10 microM indomethacin, but the increased contractility response to ET was unaffected. Therefore, we have concluded that the anoxia-induced ANP response is mediated by locally produced ET, which, in turn, stimulates the production of prostaglandins. Prostaglandins appear to be responsible for the increased ANP secretion rate.

Effect of Brugia malayi infections on endothelial cells: a morphological study.

Athymic mice (C3H/HeN) parasitized by Brugia malayi develop gross lymphatic dilations at the chronic stage of infection. The hyperplastic endothelial cells and low fluid pressure of the lymphatics, characteristic of these infections, suggest that abnormal changes in these cells may play an important role in the dilation. We studied the lymphatic and vascular endothelium of parasitized mice for morphological changes by scanning and/or transmission electron microscopy. The lymphatic endothelium of dilated lymphatics was perturbed, scalloped, bulbous and highly indented. Numerous mononuclear and giant cells were closely apposed to the endothelial wall. Endothelial cells of both the lymphatics and the adjacent venules revealed no focal cytoplasmic lesions. Growth factor-dependent cell proliferation was significantly suppressed in vitro in endothelial cell cultures containing adult female worms, male worms or microfilariae. The actin cytoskeletal network appeared intact in these cells, and no gross changes in distribution were evident. Although the lymphatic walls were highly tortuous, our examination revealed no significant alterations in their morphology. Perivascular infiltration of activated mast cells, lymphocytes and monocytes/macrophages indicated polarization of inflammatory cells into the lymphatic tissue. It is possible that these inflammatory cells might induce temporal functional changes in the lymphatics of infected athymic mice.

Arteriolar reactivity of endotoxin-tolerant rats after hemorrhage and reinfusion.

Adrenergic and endothelium-dependent arteriolar reactivity are greatly reduced in hemorrhagic shock. However, development of tolerance to endotoxin may prevent the decrease. The reactivity of cremaster muscle arterioles was tested in pentobarbital-anesthetized endotoxin-tolerant (ENDT-T) and nontolerant control rats. Tolerance was developed by sublethal intraperitoneal injections of Escherichia coli endotoxin for 4 days (n = 9). Controls received saline (n = 9). Mean arterial pressure (MAP), arteriolar diameter-response curves to topical norepinephrine (NE) (10-9M to 10-3M) and responses to 10-3M acetylcholine (ACh) were obtained as follows 1) at control, 2) following hemorrhage to 40 mmHg. 3) after uptake of 25% of bled volume with the remainder infused, and 4) at 240 min post-hemorrhage. The A1, A2, and A3 arterioles were constricted following hemorrhage in the ENDT-T group and in the saline group. After reinfusion and in late shock, vessel diameters remained constricted. MAP increased to control levels (106 +/- 5 and 101 +/- 4 mmHg, respectively) following re-infusion in both groups but in late shock it decreased until death in the nontolerant group and decreased only minimally (96 +/- 4 mmHg) in the ENDT-T group. The nontolerant group NE ED50 increased from pre-hemorrhage to late shock (p < .05). The ENDT-T group ED50 was unchanged. The bleeding volumes of the two groups were not different. The survival time of the nontolerant group was 234 +/- 36 min, whereas the ENDT-T group all survived and were sacrificed at 427 +/- 30 min. The response to endothelium-dependent ACH vasodilation in late shock was significantly reduced in the saline group but was unchanged in the ENDT-T group. Alpha 1 receptor activity was maintained in both groups. Alpha 2 receptor activity was attenuated pre-hemorrhage and at 240 min post-hemorrhage in ENDT-T rats. In late shock, alpha 2 receptor activity was attenuated in nontolerant rats. The development of endotoxin tolerance prevents the loss of arteriolar responsiveness to NE and ACh. ENDT-T rats have attenuated alpha 2 receptor activity but not alpha 1 receptor activity.

Maintenance of dynamic microvascular function and structure in a rat model of endotoxic shock by blockade of the interleukin-1 receptor.

The microvascular and macrovascular effects of IL-1 receptor antagonist (IL-1ra) were examined in rat cremaster muscle A1, A2, and A3 arterioles by videomicroscopy to better define its protective effects during endotoxemia. Mean arterial pressure (MAP), arteriolar diameters, and responses to norepinephrine (NE) and acetylcholine (ACh) were examined hourly after the administration of Escherichia coli endotoxin (6 mg/kg intravenously). Animals received saline (Control) or IL-1ra (.2 mg/kg/min intravenously) beginning 1 h prior to endotoxin. Serum tumor necrosis factor-alpha (TNF-alpha) and nitrate/nitrite (NO) were determined terminally. Aortic endothelium was examined by electron microscopy (EM). All Control animals, but no IL-1ra animals, died within 6 h (p < .01).IL-1ra significantly attenuated endotoxin-induced vasoconstriction of A1 and A2 arterioles (p < .01), while MAP and NE threshold remained at baseline (p < .01 vs. Control). Serum TNF and NO were elevated following endotoxin (p < .001), but only TNF was decreased (p < .005) in animals receiving IL-1ra. Aortic endothelium was damaged in all Control animals but was spared with IL-1 antagonism. IL-1ra increases survival during endotoxic shock and attenuates production of TNF but not NO. IL-1ra maintains MAP, arteriolar diameters, reactivity of arterioles to NE and ACh, and the integrity of the aortic endothelium.