Outcomes of patients with chronic renal insufficiency in the bypass angioplasty revascularization investigation.

BACKGROUND: Although severe chronic kidney disease (CKD) is an independent predictor of mortality among patients with coronary artery disease, the impact of mild CKD on morbidity and mortality has not been fully defined. METHODS AND RESULTS: Morbidity and mortality for the 3608 patients with multivessel coronary artery disease enrolled in the Bypass Angioplasty Revascularization Investigation randomized trial and registry were compared on the basis of the presence and absence of CKD, defined as a preprocedure serum creatinine level of >1.5 mg/dL. Seventy-six patients had CKD. Patients with renal insufficiency were older and more likely to have a history of diabetes, hypertension, and other comorbidities. Among patients undergoing PTCA, patients with CKD had a greater frequency of in-hospital death and cardiogenic shock (P<0.05 and 0.01, respectively). There was a trend toward a larger proportion of patients with CKD experiencing angina at 5 years (P=0.079). Patients with CKD had more cardiac admissions (P=0.003 and <0.0001 for patients undergoing PTCA and CABG, respectively) and a shorter time to subsequent CABG after initial revascularization than patients without CKD (P=0.01). CKD was associated with a higher risk of death at 7 years, both of all causes (relative risk 2.2, P<0.001) and of cardiac causes (relative risk 2.8, P<0.001). CONCLUSIONS: CKD is associated with an increased risk of recurrent hospitalization, subsequent CABG, and mortality. This increased risk of death is independent of and additive to the risk associated with diabetes.

Spatial processing in the brain: the activity of hippocampal place cells.

The startling discovery by O'Keefe & Dostrovsky (Brain Res. 1971; 34: 171-75) that hippocampal neurons fire selectively in different regions or "place fields" of an environment and the subsequent development of the comprehensive theory by O'Keefe & Nadel (The Hippocampus as a Cognitive Map. Oxford, UK: Clarendon, 1978) that the hippocampus serves as a cognitive map have stimulated a substantial body of literature on the characteristics of hippocampal "place cells" and their relevance for our understanding of the mechanisms by which the brain processes spatial information. This paper reviews the major dimensions of the empirical research on place-cell activity and the development of computational models to explain various characteristics of place fields.

Hypercholesterolemia impairs myocardial perfusion and permeability: role of oxidative stress and endogenous scavenging activity.

OBJECTIVES: We intended to study the effect of hypercholesterolemia (HC) on myocardial perfusion and permeability response to increased cardiac demand. BACKGROUND: Hypercholesterolemia is associated with increased incidence of cardiac events and characterized by impaired coronary vascular function, possibly mediated partly through increased pro-oxidative conditions in plasma and tissue. However, it is yet unclear whether HC is also associated with impaired myocardial perfusion and vascular permeability responses in vivo. METHODS: For 12 weeks pigs were fed a normal, HC or HC diet supplemented daily with antioxidants (HC + AO, 100 IU/kg vitamin E and 1 g vitamin C). Myocardial perfusion and vascular permeability were measured in vivo using electron beam computed tomography before and after cardiac challenge with intravenous adenosine. Plasma and tissue oxidative status was determined ex vivo. RESULTS: Plasma cholesterol increased in all cholesterol-fed pigs but was associated with increased markers of oxidative stress only in HC pigs. Myocardial perfusion increased in response to adenosine in normal and HC + AO (+37 +/- 13% and +58 +/- 22%, respectively, p < 0.05 vs. baseline) but not in HC, whereas vascular permeability index increased only in HC pigs (+ 92 +/- 25%, p = 0.002). In HC animals, tissue endogenous oxygen radical scavengers and antioxidant vitamins were depleted and LDL oxidizability enhanced, but both were normalized in HC + AO pigs. Myocardial perfusion response was directly, and permeability inversely, associated with plasma and tissue vitamin concentrations. CONCLUSIONS: This study demonstrates that experimental HC is associated with blunted myocardial perfusion and increased vascular permeability responses in vivo to increased cardiac demand, which may be partly mediated by a shift in oxidative status.

Treatment with endothelin-receptor antagonists increases NOS activity in hypercholesterolemia.

In experimental hypercholesterolemia, endothelium-dependent relaxations decrease, as does endothelial immunoreactivity for nitric oxide (NO) synthase (NOS; eNOS) in coronary arteries. Systemic levels of NO also decrease with concomitant elevations in systemic circulating levels of endothelin (ET)-1. Chronic treatment of hypercholesterolemic pigs with ET-receptor antagonists increases circulating NO and improves endothelium-dependent relaxations. Mechanisms causing these increases are not known. Therefore, experiments were designed to test the hypothesis that chronic administration of ET-receptor antagonists to hypercholesterolemic pigs increases NO production through increases in NOS activity. Female juvenile pigs were fed a 2% cholesterol atherogenic diet and were randomly allocated to receive no treatment (controls), a selective ET(A)-receptor antagonist (ABT-624), or a combined ET(A) + ET(B)-receptor antagonist (RO-48-5695) daily for 12 wk. After 12 wk, endothelial cells from thoracic aorta were prepared for measurement of eNOS mRNA or eNOS activity. Total cholesterol, low-density-lipoprotein cholesterol, and concentrations of ET-1 were significantly higher in all three groups at 12 wk compared with baseline levels. Circulating plasma-oxidized products of NO (NOx) increased with ET-receptor blockade. NOS mRNA was similar among groups. Total and Ca-dependent NOS activity was significantly higher in aortic endothelial cells from the ET(A) + ET(B)-treated pigs compared with those treated with ET(A) antagonist alone. These results suggest that changes in systemic NOx after chronic inhibition of ET(A) + ET(B) receptors in hypercholesterolemia may result from posttranscriptional changes in NOS.

Simvastatin preserves coronary endothelial function in hypercholesterolemia in the absence of lipid lowering.

Recent evidence suggests that some benefit from the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may occur independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary endothelial function, endothelial NO synthase (eNOS) expression, and oxidative stress in experimental hypercholesterolemia (HC) in the absence of cholesterol lowering. Pigs were randomized to 3 experimental groups: normal diet (N group), high cholesterol diet (HC group), and HC diet with simvastatin (HC+S group) for 12 weeks. Low density lipoprotein cholesterol was similarly increased in the HC and HC+S groups compared with the N group. In vitro analysis of coronary large- and small-vessel endothelium-dependent vasorelaxation was performed. The mean vasorelaxation of epicardial vessels to bradykinin was significantly attenuated in the HC group compared with the N group (32.3+/-1.2% versus 42.9+/-1.6%, respectively; P<0.0001). This attenuation was significantly reversed in the HC+S group (38.7+/-1.5%, P<0.005 versus HC group). The maximal vasorelaxation to substance P was significantly attenuated in the HC group compared with the N group (50.5+/-11.9% versus 79.3+/-5.3%, respectively; P<0.05). This attenuated response was normalized in the HC+S group (74.9+/-4.1%, P<0.05 versus HC group). The maximal arteriolar vasorelaxation to bradykinin was also significantly attenuated in the HC group compared with the N group (71.9+/-4.9% versus 96.8+/-1.34%, respectively; P<0.005). This was reversed in the HC+S group (98.4+/-0.6%, P<0.0001 versus HC group). Western blotting of coronary tissue homogenates for eNOS demonstrated a decrease in protein levels in the HC group compared with the N group, with normalization in the HC+S group. Elevation of plasma F(2)-isoprostanes and thiobarbituric acid-reactive substances, markers of oxidative stress, occurred in the HC compared with the N group. These changes were reversed in the HC+S group. In summary, simvastatin preserves endothelial function in coronary epicardial vessels and arterioles in experimental HC (in the absence of cholesterol lowering) in association with an increase in coronary eNOS levels and a decrease in oxidative stress. These alterations may play a role in the reduction in cardiac events after treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

Altered myocardial microvascular 3D architecture in experimental hypercholesterolemia.

BACKGROUND: Experimental hypercholesterolemia (HC) impairs intramyocardial microvascular function. However, whether this is associated with alterations in microvascular architecture remained unknown. Using a novel 3D micro-CT scanner, we tested the hypothesis that HC is associated with an alteration in the microvascular architecture. METHODS AND RESULTS: Pigs were euthanized after 12 weeks of either normal (n=6) or 2% HC (n=6) diet. The hearts were excised and the coronary arteries injected with a radiopaque contrast material. Myocardial samples were scanned with micro-CT, and 3D images were reconstructed with 21-microm cubic voxels. The myocardium was tomographically subdivided into subepicardium and subendocardium, and microvessels (<500 microm in diameter) were counted in situ within each region. In the subendocardium of HC pigs, the intramyocardial density of microvessels was significantly higher than in normal animals (1221.4+/-199.7 versus 758.3+/-90.8 vessels/cm(3), P:<0.05) because of an increase in the number of microvessels <200 microm in diameter (1214.4+/-199.7 versus 746. 6+/-101.5 vessels/cm(3), P:<0.05). The subepicardial vascular density was similar in both groups. CONCLUSIONS: -HC has differential effects on the spatial density of the subendocardial microvasculature that may play a role in regulation and/or spatial distribution of myocardial blood flow. This study also demonstrates the feasibility of studying myocardial microvascular architecture with micro-CT in pathophysiological states.

Endothelin in cardiovascular disease: from atherosclerosis to heart failure.

Since the discovery of endothelin (ET) as a potent vasoconstrictor, increasing evidence supports the role of ET in the pathogenesis of cardiovascular diseases including coronary artery disease and congestive heart failure. This peptide not only alters vascular tone and cardiac hemodynamics, but also has a substantial role in the regulation of cellular proliferation and apoptosis, activation of monocytes and cellular matrix production. Thus, ET may play a role in the pathogenesis of cardiovascular diseases through multiple mechanisms. The development of ET receptor antagonists has lead to a greater understanding of the role of the endogenous ET system in both physiologic and pathophysiologic states. Endothelin receptor antagonists are becoming new therapeutic tools for the treatment of cardiovascular disease and their study will lead to a greater understanding of the role of ET in disease progression.

Effects of ethanol on hippocampal place-cell and interneuron activity.

Mounting evidence suggests that ethanol exerts effects on learning and memory by altering cellular activity in the hippocampus and related structures. However, little is actually known regarding ethanol's effects on hippocampal function in awake, freely-behaving animals. The present study examines the effects of ethanol on hippocampal place-cell and interneuron activity in freely-behaving rats. Signals from individual hippocampal neurons were isolated while subjects traversed a symmetric Y-maze for food reward. Following 15 min of baseline recording, subjects were injected with one of four doses of ethanol (0.0, 0.5, 1.0 and 1.5 g/kg), and cellular activity was monitored for a 1-h time period. Following sufficient time for recovery (minimum of 3 h post injection), cellular activity was monitored for an additional 15-min period. Both 1.0 and 1.5 g/kg ethanol potently suppressed the firing of hippocampal place-cells without altering place-field locations. Ethanol did not significantly suppress out-of-field firing rates, leading to a decrease in spatial specificity (i.e. the ratio of in-field/out-of-field firing rates). Interneuron activity was not altered by 1.0 g/kg ethanol, but was occasionally suppressed by 1.5 g/kg ethanol. Results are interpreted in light of recent behavioral and electrophysiological studies examining the effects of ethanol on hippocampal function.

Hippocampectomized rats can use a constellation of landmarks to recognize a place.

The hippocampus, one of the most studied regions of the mammalian forebrain, plays some well-established roles in topographic navigation. For two decades, one widely accepted explanation for the observed impairment of hippocampectomized rats in spatial navigation has been an inability to form place representations. In this report, we present a direct experimental evidence that animals with hippocampal lesions can learn to recognize places using the constellation of distinct landmarks. The extrahippocampal implementation of all three basic constituents of topographic orientation - guidance, vector navigation, and place recognition - shows that the hippocampus, and its place cells, serve a much more specialized cognitive function than previously thought. We propose that this function includes multi-place and multi-vector topographic integration.

Latent attractors: a model for context-dependent place representations in the hippocampus.

Cells throughout the rodent hippocampal system show place-specific patterns of firing called place fields, creating a coarse-coded representation of location. The dependencies of this place code--or cognitive map--on sensory cues have been investigated extensively, and several computational models have been developed to explain them. However, place representations also exhibit strong dependence on spatial and behavioral context, and identical sensory environments can produce very different place codes in different situations. Several recent studies have proposed models for the computational basis of this phenomenon, but it is still not completely understood. In this article, we present a very simple connectionist model for producing context-dependent place representations in the hippocampus. We propose that context dependence arises in the dentate gyrus-hilus (DGH) system, which functions as a dynamic selector, disposing a small group of granule and pyramidal cells to fire in response to afferent stimulus while depressing the rest. It is hypothesized that the DGH system dynamics has "latent attractors," which are unmasked by the afferent input and channel system activity into subpopulations of cells in the DG, CA3, and other hippocampal regions as observed experimentally. The proposed model shows that a minimally structured hippocampus-like system can robustly produce context-dependent place codes with realistic attributes.

Ethanol, memory, and hippocampal function: a review of recent findings.

For well over a century, ethanol was believed to exert its effects on cognition and behavior by producing a ubiquitous depression of central nervous system activity. A general disruption in brain function was consistent with the belief that ethanol's effects on cognition and behavior were also quite general. Substantial evidence now indicates that ethanol produces a host of selective effects on neural activity, resulting in regional differences in ethanol's effects in the brain. Consistent with such evidence, recent research suggests that ethanol's effects on cognition and behavior are not as global as previously assumed. The present paper discusses evidence that many of ethanol's effects on learning and memory stem from altered cellular activity in the hippocampus and related structures. Potential mechanisms for ethanol's disruption of hippocampal function are reviewed. Evidence suggests that ethanol disrupts activity in the hippocampus by interacting directly with hippocampal neurons and by interacting with critical hippocampal afferents.

Coronary endothelial function is preserved with chronic endothelin receptor antagonism in experimental hypercholesterolemia in vitro.

Hypercholesterolemia is associated with increased circulating and tissue endothelin-1 immunoreactivity, decreased nitric oxide (NO) activity, and altered endothelial function. We tested the hypothesis that chronic endothelin receptor antagonism preserves endothelial function and increases NO in experimental porcine hypercholesterolemia. Pigs were randomized to 3 groups: Group 1, a 2% high-cholesterol (HC) diet alone (n=7); group 2, RO-48-5695, a combined endothelin receptor antagonist, and an HC diet (n=8); and group 3, ABT-627, a selective endothelin-A receptor antagonist, and an HC diet (n=8). Coronary epicardial and arteriolar endothelial function was determined by a dose-response relaxation to bradykinin (10(-11) to 10(-6) mol/L), in all groups and in pigs maintained on a normal diet. Plasma total oxidized products of NO (NO(x)) were determined by chemiluminescence at baseline and after 12 weeks. Bradykinin-stimulated coronary epicardial and arteriolar relaxation in group 1 was attenuated compared with normal-diet controls. This relaxation was normalized with endothelin receptor antagonism. Plasma NO(x) decreased after 12 weeks in group 1 (-74.8+/-5.5%). This decrease was attenuated in the endothelin receptor antagonist groups (group 2, -28.2+/-15.0%; group 3, -38.9+/-20.6%). Chronic endothelin receptor antagonism preserves coronary endothelial function and increases NO in hypercholesterolemia. This study supports a role of endothelin-1 in the regulation of NO activity and suggests a possible therapeutic role for endothelin receptor antagonists in hypercholesterolemia.

In vivo renal vascular and tubular function in experimental hypercholesterolemia.

Hypercholesterolemia (HC) is often associated with impaired peripheral and coronary vascular responses to endothelium-dependent vasodilators, which are probably due to low bioavailability of nitric oxide. To examine the effect of HC on renal vascular and tubular function, 22 domestic pigs were studied after being fed a 12-week normal (n=11) or HC (n=11) diet. Renal regional perfusion and intratubular contrast media concentration in each nephron segment (representing fluid reabsorption) were quantified in vivo with electron-beam computed tomography before and after a suprarenal infusion of either acetylcholine (6 pigs of each diet) or sodium nitroprusside (SNP; 5 pigs of each diet). An increase in cortical perfusion, observed in normal pigs with acetylcholine (+35+/-6%, P=0. 002) and SNP (+12+/-4%, P=0.005), was blunted in the HC group (+8. 8+/-4.0, P=0.01, and -4.6+/-4.0%, P=0.1, respectively, P=0.003 and P=0.005 compared with normal) as was an increase in medullary perfusion (+58+/-21 in normal versus +24+/-11% in HC, P=0.04). A decrease in the intratubular contrast media concentration in the distal tubule and collecting duct of normal pigs was observed in all tubular segments (and was significantly enhanced in the proximal tubule and Henle's loop) in the HC group, which was associated with increased sodium excretion. The tubular and renal excretory responses to SNP were similar between the groups. In conclusion, early experimental HC in the pig attenuates renal perfusion response to both endothelium-dependent and -independent vasodilators possibly because of decreased bioavailability or decreased vascular responsiveness to nitric oxide. This vascular impairment may play a role in maladjusted renovascular responses and contribute to renal damage in later stages of atherosclerosis.

Acute ethanol administration impairs spatial performance while facilitating nonspatial performance in rats.

Acute ethanol administration produces learning and memory impairments similar to those found following lesions to the hippocampal system in rats. For example, both ethanol and hippocampal lesions impair performance on spatial learning and memory tasks while sparing performance on many nonspatial learning and memory tasks. Lesions to the hippocampal system can also alter the nature of the information that the animal uses to guide its behavior, from using spatial information to using individual cues. In the present experiment, rats were trained, while sober, to navigate on an eight-arm radial arm maze to a specific arm for food reward. During training, the rewarded arm was always in the same specific location and contained well-defined cues. After the rat learned the task, a memory test was conducted under different doses of ethanol (0.0 g/kg [saline control], 1.0, 1.5, or 2.0 g/kg, intraperitoneal). On the test day the maze was rotated so that the cued arm was 90 degrees to the right of its original position. During testing, intact rats showed a significant bias to approach the place where they had been previously rewarded, even though the cue was no longer located there. Acute ethanol administration dose dependently reduced approaches to the rewarded place. However, ethanol administration did not result in increases in random choices; rather, it resulted in a dose-dependent increase in approaches to the cued arm, now in a new location. These results extend previous research showing that acute ethanol administration and lesions to the hippocampal system produce similar effects on learning and memory in rats.

Placing hippocampal single-unit studies in a historical context.

A profound increase in the study of the role of the hippocampus in behavior and cognitive processing resulted from the startling discovery by O'Keefe and Dostrovsky in 1971 that hippocampal neurons fire selectively in different regions or "place fields" of an environment. That discovery spawned a comprehensive theory of hippocampal function that was elucidated in the publication, The Hippocampus as a Cognitive Map by O'Keefe and Nadel in 1978. According to the theory, the hippocampus serves as the neural substrate for maps of allocentric space. The goal of this paper is to revisit the historical background for the development of the cognitive map theory and to examine the context in which the theory and the phenomenon of place field activity began to gain acceptance by the scientific community. While subsequent research has led some to question if the theory can adequately account for all consequences of hippocampal lesions and all the correlates of hippocampal cellular activity, it is clear the theory has stood the test of time and has been successful in generating an enormous amount of fruitful research.

Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia.

BACKGROUND: Endothelin-1 (ET-1) is an endothelium-derived peptide that constricts coronary vessels through stimulation of the ET-A and ET-B receptors. Experimental porcine hypercholesterolemia is associated with impaired coronary endothelial function and elevated ET-1 concentrations. This study was designed to test the hypothesis that chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. METHODS AND RESULTS: Acetylcholine (10(-6) to 10(-4) mol/L) was serially infused into the left anterior descending coronary artery in pigs at baseline and after 12 weeks of a high-cholesterol diet. In the interim, the animals were randomized to 3 groups: Group 1 received no therapy, group 2 received 3 mg/kg per day RO 48-5695, a combined ET-A/ET-B receptor antagonist, and group 3 received 4 mg/kg per day ABT-627, a selective ET-A receptor antagonist. Percent change in coronary artery diameter, coronary blood flow, and coronary vascular resistance were calculated on the basis of quantitative coronary angiography and intracoronary Doppler. At 12 weeks, total cholesterol was significantly and similarly increased in all groups. Chronic endothelin receptor antagonism significantly increased coronary blood flow in response to acetylcholine at 12 weeks (group 1: -41.6%+/-10.7%, group 2: -4.7%+/-11.9%, group 3: 11.4%+/-7.4%). CONCLUSIONS: Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. This study supports the role for ET-1 in the pathogenesis of endothelial function. Moreover, endothelin receptor antagonists may have a therapeutic role by maintaining coronary endothelial function in pathophysiological states.

The potential usage of dual chamber pacing in patients with implantable cardioverter defibrillators.

UNLABELLED: Bradycardia support by ICDs has been limited to fixed rate, ventricular pacing. Concomitant placement of a pacemaker and an ICD exposes a patient to potentially life-threatening device interactions. ICDs capable of dual chamber pacing have recently become available. The number of ICD recipients who stand to benefit from the addition of dual chamber pacing is debated, but no data have addressed this question. This retrospective study analyzed all patients who received nonthoractomy ICD system placement at the Mayo Clinic in Rochester, MN between March 1991 and October 1996 in order to determine the proportion of patients in whom a dual chamber pacing ICD may be indicated. DEFINITIONS: (1) Definitely indicated = pacemaker present at ICD implant or NASPE Class I pacing indication; (2) Probably indicated = NASPE Class II pacing indication, NYHA Functional Class III or IV, or history of systolic congestive heart failure; (3) Possibly indicated = history of paroxysmal atrial fibrillation or an ejection fraction < or = 20%. The results were that nonthoracotomy ICDs were placed in 253 patients. A dual chamber ICD would have been definitely indicated in 11% of the study group, probably indicated in 28%, and possibly indicated in 14%. Chronic atrial fibrillation was present at ICD implant in 6.7% of patients and developed in 0.9%/yr during follow-up. The addition of dual chamber pacing to ICDs stands to potentially benefit approximately half (53%) of ICD recipients. These data do not address all patients who may benefit from dual chamber sensing.

Apoptosis. Basic concepts and implications in coronary artery disease.

Apoptosis is an active form of cell death that is intricately regulated and distinct from necrosis. Data suggest that apoptosis may play a role in the pathophysiology of coronary atherosclerotic disease. Anatomic evidence of apoptosis has been observed in coronary atherosclerosis, restenosis, and transplant arteriopathy, accompanied by an increase in biochemical and genetic markers of apoptosis. Vasoactive substances such as nitric oxide and angiotensin II also regulate vascular smooth muscle cell apoptosis; vasodilating factors may induce apoptosis, whereas vasoconstricting factors may inhibit apoptosis. The aim of this article is to review key points regarding the detection of apoptosis, its regulation, and its possible role in the pathogenesis of coronary artery disease.

Enhanced coronary vasoconstriction to oxidative stress product, 8-epi-prostaglandinF2 alpha, in experimental hypercholesterolemia.

OBJECTIVES: The F2-isoprostanes are a family of novel prostaglandin isomers and a stable product of in vivo oxidative stress. 8-epi-prostaglandinF2 alpha, a member of this isoprostane family, is a vasoconstrictor and its local release may contribute to the abnormal vasomotor tone associated with hypercholesterolemia. We therefore aimed to outline the role of 8-epi-prostaglandinF2 alpha as a coronary vasoconstrictor in experimental hypercholesterolemia. METHODS AND RESULTS: Pigs were randomized to two experimental groups (each n = 9): normal (N) and high cholesterol (HC) diet. To determine the vasoconstrictive effects of 8-epi-prostaglandinF2 alpha in vitro, doses from 10(-9) to 10(-5) M were used to constrict coronary epicardial rings. Plasma total and LDL cholesterol levels were significantly higher in the HC group compared with the N group (P < 0.005) as were plasma 8-epi-prostaglandinF2 alpha levels (P < 0.001). 8-epi-prostaglandinF2 alpha immunoreactivity was present in the vessel wall in both groups. Normal vessels with intact endothelium (n = 8 rings) contracted to 8-epi-prostaglandinF2 alpha (maximal contraction 15.5 +/- 8.74%). In the HC group, rings with intact endothelium had a greater contractile response to 8-epi-prostaglandinF2 alpha compared to normals (72.3 +/- 7.9%; n = 8; P < 0.0001). This was reversed by preincubation with NOR-3, a NO donor (maximal contraction 6.7 +/- 1.56%; n = 5; P < 0.0001). Enhanced contraction in normal vessels occurred with endothelial denudation (98.4 +/- 3.56%; n = 6; P < 0.0001) and with preincubation of the endothelium-intact rings with L-NMMA (N-monomethyl-L-arginine), an NO synthase inhibitor (85.5 +/- 10.3%, n = 6, P < 0.001). The enhanced contraction seen with hypercholesterolemia did not occur with other prostanoid vasoconstrictors. CONCLUSION: Experimental hypercholesterolemia leads to a significant increase in 8-epi-prostaglandinF2 alpha levels in addition to enhanced 8-epi-prostaglandinF2 alpha-induced coronary vasoconstriction, in vitro. These findings support a role for the F2-isoprostanes in the regulation of coronary vasomotor tone in pathophysiologic states.