Search PubMed⌕ Search

Biomedical subjects

J E Parrillo

Publications and source records attributed to J E Parrillo.

At least 37 records · Page 2Linked to original sources
PubMed2000

Myocardial dysfunction in septic shock.

Over the last decade, it has become clear that myocardial depression, like vascular dysfunction, is typical of human septic shock. Human septic myocardial depression is characterized by reversible biventricular dilatation, decreased ejection fraction, and decreased response to fluid resuscitation and catecholamine stimulation (in the presence of overall hyperdynamic circulation). A circulating myocardial depressant substance, not myocardial hypoperfusion, is responsible for this phenomenon. This substance has been shown to represent low concentrations of TNF-alpha and IL-1 beta acting in synergy on the myocardium through mechanisms that include NO and cGMP generation. Despite major advances in our understanding of the hemodynamics and pathogenesis of cardiac dysfunction in sepsis, successful attempts to modulate these mechanisms to improve clinical outcomes in human trials have not been demonstrated to date. For the moment, the therapeutic approach to the patient with cardiac dysfunction in distributive or septic shock must be primarily aimed at reestablishing adequate organ perfusion and oxygen delivery by vigorous fluid resuscitation and vasopressor or inotropic support. In the long term, however, only continued research regarding the cellular mechanisms of organ dysfunction, including septic myocardial depression, will lead to successful therapeutic strategies. These strategies will likely involve direct manipulation of intracellular signaling processes that lead to organ dysfunction as manifested by septic myocardial dysfunction and septic shock.

Animals↗
PubMed2000

A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia.

BACKGROUND: Endotoxin (lipopolysaccharide [LPS]) has been associated with sepsis and the high mortality rate seen in septic shock. The administration of a small amount of LPS to healthy subjects produces a mild syndrome qualitatively similar to that seen in clinical sepsis. We used this model to test the efficacy of an endotoxin antagonist, E5531, in blocking this LPS-induced syndrome. METHODS: In a placebo-controlled, double-blind study, we randomly assigned 32 healthy volunteers to four sequential groups (100, 250, 500, or 1000 microg of E5531). Each group of eight subjects (six assigned to E5531, two assigned to placebo) received a 30-min intravenous infusion of study drug. LPS (4 ng/kg) was administered to all subjects as an intravenous bolus in the contralateral arm at the midpoint of the infusion. Symptoms, signs, laboratory values, and hemodynamics (by echocardiogram) were evaluated at prospectively defined times. RESULTS: In subjects receiving placebo, LPS caused headache, nausea, chills, and myalgias. E5531 led to a dose-dependent decrease in these symptoms that was statistically significant (p < .05) except for myalgias. The signs of endotoxemia (fever, tachycardia, and hypotension) were consistently inhibited at the three higher doses (250, 500, and 1000 microg, p < .05). Tumor necrosis factor-alpha and interleukin-6 blood levels were both lower in those who received E5531 (p < .0001). The C-reactive protein level and white blood cell count response were decreased at all doses (p < .0001). The hyperdynamic cardiovascular state (high cardiac index and low systemic vascular resistance) associated with endotoxin challenge was significantly inhibited at the higher doses of E5531. CONCLUSIONS: E5531 blocks the symptoms and signs and cytokine, white blood cell count, C-reactive protein, and cardiovascular response seen in experimental endotoxemia. This agent is a potent inhibitor of endotoxin challenge in humans and may be of benefit in the prevention or treatment of sepsis and septic shock.

Adolescent↗
PubMed2000

Nitric oxide synthase inhibition increases venular leukocyte rolling and adhesion in septic rats.

OBJECTIVE: Excess production of nitric oxide (NO) has been implicated in hypotension and blood flow abnormalities in sepsis, but NO is also an important inhibitor of leukocyte rolling and adhesion. Leukocyte adhesion is increased in sepsis despite elevated NO production. We hypothesized that inhibition of NO synthase (NOS) could increase leukocyte adhesion in sepsis. DESIGN: Prospective animal study. SETTING: Experimental animal laboratory. SUBJECTS: Twenty-five male rats, anesthetized with ketamine and acepromazine. INTERVENTIONS: Topical superfusion of the nonselective NOS inhibitor N(G)-monomethyl-L-arginine (NMA) on skeletal muscle postcapillary venules. MEASUREMENTS AND MAIN RESULTS: Rats made septic by cecal ligation and puncture were compared with controls that underwent sham ligation. Leukocyte rolling and adhesion were measured in cremasteric postcapillary venules of septic and control rats using in vivo videomicroscopy. The effects of NOS inhibition on leukocyte rolling and adhesion were also measured. After a stable baseline was reached, 1 microM of the nonselective NOS inhibitor NMA was suffused topically followed by physiologic buffer. The effects of L-arginine on leukocyte rolling and adhesion were also measured, both before and after suffusion of NMA. Leukocyte rolling and adhesion was increased in septic rats as compared with controls (control 5.5+/-0.9 rolling cells/min, 1.0+/-0.3 adherent cells/min; septic 13.7+/-2.0 rolling cells/min, 3.1+/-0.6 adherent cells/min; p < .001), and NOS inhibition further increased leukocyte rolling and adhesion in both septic and control rats (control 14.0+/-1.7 rolling cells/min, 2.8+/-0.5 adherent cells/min; septic 25+/-2.1 rolling cells/min, 5.4+/-0.5 adherent cells/min; both p < .001 vs. baseline). Prior suffusion of excess L-arginine prevented the increase in leukocyte adhesion with NMA in septic rats (2.6+/-0.4 adherent cells/min vs. 3.0+/-0.6 adherent cells/min; n = 3; p > .05). When administered after NMA, excess L-arginine partially reversed leukocyte adhesion in septic rats (5.4+/-0.7 adherent cells/min, with NMA vs. 4.3+/-0.7 adherent cells/min, after L-arginine; n = 5; p < .05). Venular shear did not differ between septic and control rats (600+/-109 (sec(-1)) vs. 620+/-37 (sec(-1)); p > .05). CONCLUSIONS: Although NOS inhibition may ameliorate hypotension in sepsis, such therapy may be deleterious by increasing leukocyte adhesion.

Animals↗
PubMed2000

Direct current cardioversion: indications, techniques, and recent advances.

Direct current cardioversion/defibrillation is an important part of the intensivist's armamentarium. Emergent application may be lifesaving. Elective cardioversion should be used cautiously, with attention to patient selection and proper techniques. Repetitive, futile attempts at direct current cardioversion should be avoided. Reducing or eliminating arrhythmia precipitants may be safer and more effective than this more dramatic intervention.

Anticoagulants↗
PubMed2000

NADH/NAD redox state of cytoplasmic glycolytic compartments in vascular smooth muscle.

The cytoplasmic NADH/NAD redox potential affects energy metabolism and contractile reactivity of vascular smooth muscle. NADH/NAD redox state in the cytosol is predominately determined by glycolysis, which in smooth muscle is separated into two functionally independent cytoplasmic compartments, one of which fuels the activity of Na(+)-K(+)-ATPase. We examined the effect of varying the glycolytic compartments on cystosolic NADH/NAD redox state. Inhibition of Na(+)-K(+)-ATPase by 10 microM ouabain resulted in decreased glycolysis and lactate production. Despite this, intracellular concentrations of the glycolytic metabolite redox couples of lactate/pyruvate and glycerol-3-phosphate/dihydroxyacetone phosphate (thus NADH/NAD) and the cytoplasmic redox state were unchanged. The constant concentration of the metabolite redox couples and redox potential was attributed to 1) decreased efflux of lactate and pyruvate due to decreased activity of monocarboxylate B-H(+) transporter secondary to decreased availability of H(+) for cotransport and 2) increased uptake of lactate (and perhaps pyruvate) from the extracellular space, probably mediated by the monocarboxylate-H(+) transporter, which was specifically linked to reduced activity of Na(+)-K(+)-ATPase. We concluded that redox potentials of the two glycolytic compartments of the cytosol maintain equilibrium and that the cytoplasmic NADH/NAD redox potential remains constant in the steady state despite varying glycolytic flux in the cytosolic compartment for Na(+)-K(+)-ATPase.

Animals↗
PubMed2000

The relative influence of lesion length and other stenosis morphologies on procedural success of coronary intervention.

As coronary interventional technology improves, the influence of lesion length (LL) on procedural success and device selection may vary. Thus, the authors prospectively analyzed 957 consecutive coronary interventions (CI) in 1,404 stenoses to ascertain the influence of lesion length on CI outcome. Stenosis morphology was prospectively classified by the AHA/ACC criteria. LL was analyzed both as dichotomous (S: < 10 mm, L: > 10 mm) variables and by the three-tiered AHA/ACC criteria (I: < 10 mm, II: 10-20 mm, III: > 20 mm). There was a significant univariate relationship between CI success and S stenosis (S: 95.8% vs L: 91.8%, p = 0.002 and I: 96.0%, II: 91.7%, III: 89.3%). Numerous interrelationships involving the morphologic characteristics were noted: lesion morphologies associated with S lesions were concentric (p = 0.0001) and had smooth contour (p = 0.0001), ostial location (p = 0.05) and little calcification (p = 0.0007), while irregular contour (p=0.0001), calcification (p=0.0076), eccentric (p=0.0001), thrombus (p = 0.0001), recent (p = 0.0001) or chronic (p = 0.001) total occlusion were associated with L lesions. When these relationships were taken into account by multiple logistic regression analysis, lesion length was not predictive of procedural outcome (p = 0.099). One morphologic type was associated with increased CI success: irregular contour (p = 0.022); recent (p < 0.0001) or chronic (< 0.0001) occlusions were associated with decreased CI success. Another factor considered was device selection: S lesions were associated with greater balloon angioplasty usage (p = 0.002), whereas more coronary stents (p = 0.024) and rotoblator (p = 0.018) devices were used in L lesions. More balloon angioplasty was performed in concentric (p < 0.0001) lesions; interventional devices were employed more often in eccentric (p < 0.0001) and irregular lesions (p < 0.0001). More complications were noted in lesions with thrombus (p = 0.0002), but lesion length was not predictive (p = NS). Lesion length is not a significant predictor of procedural success when adjusted for other lesion morphologies in the modern interventional era. The availability of new devices has improved the results in longer lesions since the AHA/ACC criteria were originally proposed.

Aged↗
PubMed1999

Transcriptional regulation of Fas gene expression by GA-binding protein and AP-1 in T cell antigen receptor.CD3 complex-stimulated T cells.

Fas (CD95 or APO-1), a transmembrane cell surface receptor of the tumor necrosis factor receptor family, is up-regulated in activated T lymphocytes. Our present study identified an upstream enhancer element (between nucleotide positions -862 and -682) containing a GA-binding protein (GABP) site and a low affinity activating protein-1 (AP-1)-binding site. T cell activation increased the DNA binding of GABP and AP-1 to this enhancer site. The specificity of GABP and AP-1 binding was demonstrated by competition electrophoretic mobility shift assay and supershift electrophoretic mobility shift assay with antibodies against GABP and AP-1, respectively. Mutational analysis of Fas promoter revealed that both GABP- and AP-1-binding sites were required for initiating Fas gene transcription. We further show that anti-CD3 mAb, phorbol 12-myristate 13-acetate, and phorbol 12-myristate 13-acetate/ionomycin strongly activated promoters carrying multiple copies of the Fas enhancer, and mutation of either the GABP or AP-1 binding site severely reduced transcriptional activity. Taken together, these results suggest that the transcription factors GABP and AP-1 play a critical role in the induction of Fas gene expression in T cell antigen receptor.CD3-stimulated Jurkat cells.

Base Sequence↗
PubMed1999

Clinical practice guidelines in unstable angina improve clinical outcomes by assuring early intensive medical treatment.

OBJECTIVES: To determine the influence of clinical practice guidelines on treatment patterns and clinical outcomes in unstable angina and the effectiveness of guideline reminders on implementing practice guidelines, two groups of medium and high risk patients with unstable angina were compared. BACKGROUND: New guidelines have been published by the Agency for Health Care Policy and Research (AHCPR) for evaluating and managing patients with unstable angina. The impact of these guidelines to improve the quality of care has never been tested. METHODS: Group 1 included 338 consecutive medium or high risk patients admitted before publication of the AHCPR guidelines, and group 2 consisted of 181 consecutive similar risk patients admitted after institution of the AHCPR guideline reminders at this institution. Dissemination of clinical practice guidelines was ensured by a grand rounds lecture and by posting guideline reminders on all group 2 patients' charts within 24 h of admission. RESULTS: The two groups were similar in terms of most baseline characteristics, including hypercholesterolemia, diabetes, hypertension, smoking history, baseline ST segment depression and previous coronary artery bypass graft surgery. Group 1 patients were older (68+/-13 vs. 63+/-16 years, p = 0.001) and more frequently had a previous myocardial infarction (39% vs. 22%, p = 0.001). Group 2 patients more frequently required intravenous nitroglycerin to control the index episode of chest pain (43% vs. 34%, p = 0.003). Group 2 patients more frequently received aspirin (96% vs. 88%, p = 0.009) during admission and underwent coronary angiography (71% vs. 58%, p = 0.006). More importantly, group 2 patients received oral beta-blockers (p = 0.008), aspirin and coronary angiography (p = 0.001) earlier than group 1 patients and experienced recurrent angina (29% vs. 54%) and myocardial infarction or death less frequently (3% vs. 9%, p = 0.028). CONCLUSIONS: In unstable angina, clinical practice guidelines were associated with greater use of aspirin and coronary angiography and greater use and earlier administration of beta-blockers. Variation in drug use over time was also reduced. Objective improvement in clinical outcome was also noted. Thus, practice guidelines improve the quality of care of patients with unstable angina.

Adrenergic beta-Antagonists↗
PubMed1999

Cardiogenic shock.

PURPOSE: To review the cause, epidemiology, pathophysiology, and treatment of cardiogenic shock. DATA SOURCES: A MEDLINE search of the English-language reports published between 1976 and 1998 and a manual search of bibliographies of relevant papers. STUDY SELECTION: Experimental, clinical, and basic research studies related to cardiogenic shock. DATA EXTRACTION: Data in selected articles were reviewed, and relevant clinical information was extracted. DATA SYNTHESIS: Cardiogenic shock is a state of inadequate tissue perfusion due to cardiac dysfunction, most commonly caused by acute myocardial infarction. Mortality rates for patients with cardiogenic shock remain frustratingly high, ranging from 50% to 80%. The pathophysiology of cardiogenic shock involves a downward spiral: Ischemia causes myocardial dysfunction, which, in turn, worsens ischemia. Areas of nonfunctional but viable (stunned or hibernating) myocardium can also contribute to the development of cardiogenic shock. The key to achieving a good outcome is an organized approach that includes rapid diagnosis and prompt initiation of therapy to maintain blood pressure and cardiac output. Expeditious coronary revascularization is crucial. When available, emergency cardiac catheterization and angioplasty seem to improve survival. More recent developments, such as placement of coronary stents and use of glycoprotein IIb/IIIa antagonists, are promising but have not yet been well studied in patients with cardiogenic shock. In hospitals without direct angioplasty capability, stabilization with intra-aortic balloon counterpulsation and thrombolysis followed by transfer to a tertiary care facility may be the best option. CONCLUSIONS: Improved understanding of the pathophysiology of shock and myocardial infarction has led to improved treatment. If cardiogenic shock is managed with rapid evaluation and prompt initiation of supportive measures and definitive therapy, outcomes can be improved.

Angioplasty, Balloon, Coronary↗
PubMed1999

Simultaneous intracoronary ultrasound and Doppler flow studies distinguish flow-mediated from receptor-mediated endothelial responses.

Abnormalities in vascular endothelial function, which occur early in atherosclerosis, may play an etiologic role in the development of the disease or represent a marker for the extent of atherosclerosis. Endothelial dysfunction, usually characterized by demonstration of decreased endothelium-dependent vasorelaxation, may be a sensitive and specific method to detect vascular disease in its earliest stages. In this context, separation of abnormalities in receptor-mediated and flow-mediated endothelium-dependent vasodilatory responses may allow for the most accurate characterization of endothelial dysfunction. In 35 patients undergoing routine annual cardiac catheterization after heart transplantation, changes in epicardial lumen area and coronary blood flow in response to intracoronary administration of adenosine, acetylcholine, and nitroglycerin were measured simultaneously using an intravascular ultrasound (IVUS) catheter positioned over a Doppler flow wire in the left anterior descending coronary artery. The combination of these techniques allowed for distinction between receptor-mediated and flow-mediated endothelium-dependent vascular responses. Peak flow with the endothelium-independent resistance vessel dilator adenosine occurred at 18+/-2 sec; the maximal lumen area response occurred later, at 43+/-11 sec (P < 0.001). Acetylcholine, an endothelium-dependent small- and large-vessel vasodilator, caused an immediate increase in both flow and lumen area, but a second peak of dilation was observed, and maximal area occurred 46 sec after maximal flow (54+/-14 vs. 100+/-26 sec, P < 0.001). Simultaneous IVUS and Doppler flow measurements after infusion of vasoactive agents allows for distinction between and evaluation of the relative contribution of agonist-mediated and flow-mediated responses, which may offer important and unique insights into coronary endothelial function.

Acetylcholine↗
PubMed1999

Unstable angina and non-Q wave myocardial infarction: does the clinical diagnosis have therapeutic implications?

OBJECTIVES: The goal of this review is to reevaluate the unstable coronary syndromes in the setting of new therapies and biochemical markers. BACKGROUND: Patients with acute coronary syndromes comprise a large subset of many cardiology practices. Patients with unstable angina (UA) and non-Q wave myocardial infarction (NQMI) may sustain a small amount of myocardial loss but have significant amounts of viable, yet ischemic, myocardium, placing them at high risk for future cardiac events. In the past, enzyme differentiation of NQMI from UA was considered important to assess prognosis and direct therapy. METHODS: Manuscripts published in peer-reviewed journals over the past three decades were reviewed and selected for this review. Recent abstracts were also considered and cited where appropriate. RESULTS: In the late 1990's, although UA and NQMI remain parts of a spectrum, it is apparent that the distinction between these two entities is no longer sufficient to identify high risk patients; rather, specific electrocardiographic changes, aspects of the clinical history, newer biochemical markers, and angiographic findings help to better distinguish higher risk individuals from a large patient population with unstable coronary syndromes and these factors usually determine therapy. CONCLUSIONS: Based on these results, it is likely that newer therapies such as glycoprotein IIb/IIIa receptor antagonists, low molecular weight heparins, and coronary stents will be directed toward these high risk patients.

Angina, Unstable↗
PubMed1999

Relation of NADH/NAD to contraction in vascular smooth muscle.

The relationship of NADH/NAD to O2 consumption with respect to the different phases of contraction in vascular smooth muscle in response to a maximal depolarizing concentration of KCl was investigated. The NADH bound to cellular proteins could be distinguished from free NADH in whole tissue homogenates. Evidence suggested that the NADH was bound to pyruvate dehydrogenase and perhaps to other dehydrogenases since binding paralleled the changes in the activity of pyruvate dehydrogenase with contraction. The measured changes in NADH were attributed to that within the mitochondrial compartment since the contribution of reducing equivalents within the cytoplasmic compartment was negligible. During the phase of contraction in which force was initially being generated and at which O2 consumption was the highest, there was a net increase in NADH/NAD. After stable isometric force was maintained, at which time O2 consumption had returned to slightly above the basal pre-contraction level, there was a net decrease in NADH/NAD. Previous evidence indicates the phosphorylation potential (ATP/ADP) may decrease during this phase of contraction. It is concluded that contraction of vascular smooth muscle is accompanied by a changing pool of reducing equivalents. Factors which govern O2 consumption may change during the different phases of muscle contraction.

Animals↗
PubMed1999

How well does radionuclide dipyridamole stress testing detect three-vessel coronary artery disease and ischemia in the region supplied by the most stenotic vessel?

PURPOSE: This study was done to evaluate the accuracy of radionuclide dipyridamole stress imaging to detect multivessel disease and ischemia in segments of myocardium supplied by the most stenotic vessel. METHODS: A retrospective analysis of consecutive patients with known triple-vessel disease of at least 50% stenosis in each of the three major epicardial coronary arteries who had exercise (n=44) or dipyridamole (n=86) stress testing, or both, within 6 months of coronary angiography. RESULTS: The accuracy of dipyridamole stress testing to detect three-vessel disease was 52% and ischemia was detected in the region supplied by the most stenotic vessel in 67% of patients. The sensitivity and specificity rates of radionuclide imaging to detect ischemia in the region supplied by the vessel of tightest stenosis were 69% and 74% for the left anterior descending coronary artery (LAD), 61% and 78% for the right coronary artery (RCA), and 61% and 57% for the left circumflex coronary artery (LCX). Based on these values, in 39% of patients in whom the RCA or LCX was the most stenotic vessel and in 31% of patients in whom the LAD was the most stenotic vessel, perfusion defects were not present on their nuclear scans. CONCLUSIONS: These results have important implications for interventional cardiologists who perform angioplasty on the most stenotic vessel, because the regions supplied by these vessels may not be the most ischemic. Furthermore, dipyridamole stress imaging may significantly underestimate the number of patients with substantial three-vessel coronary artery disease when qualitative imaging is done.

Aged↗
PubMed1999

Effects of epinephrine and amrinone on contractility and cyclic adenosine monophosphate generation of tumor necrosis factor alpha-exposed cardiac myocytes.

OBJECTIVE: This study utilized an in vitro neonatal rat cardiac myocyte assay to evaluate potential differences in the response of TNF-alpha-exposed myocytes to stimulation with the adrenergic agent, epinephrine, and the phosphodiesterase III inhibitor, amrinone. DESIGN: Contractility was assessed by measuring the maximum extent of the contraction of electrically paced neonatal rat cardiac myocytes in tissue culture using a closed-loop video tracking system. Myocytes were incubated in control or media containing TNF-alpha (50 ng/mL) for 20 mins and were then stimulated with increasing concentrations of either epinephrine (0.1 to 100 ng/mL) for 15 mins or amrinone lactate (0.25 to 10 microg/mL) for 20 mins. MEASUREMENTS AND MAIN RESULTS: Compared with control myocytes, TNF-alpha-exposed myocytes stimulated with increasing concentrations of epinephrine demonstrated a decreased peak augmentation of contractility (p<.0001 analysis of variance). This decrease was paralleled by a decrease in epinephrine-stimulated generation of cyclic AMP, as measured by enzyme-linked immunoassay (p = .05 polynomial regression). In contrast, increasing concentrations of amrinone produced increased peak augmentation of contractility (p = .003 analysis of variance) in TNF-alpha-exposed cardiac myocytes (relative to controls). However, this increase was not reflected by increased amrinone-stimulated generation of cyclic AMP relative to control myocytes not exposed to TNF-alpha (p = NS polynomial regression). CONCLUSIONS: Our data suggest that TNF-alpha induces a defect in beta-adrenergic signal transduction and catecholamine-stimulated contractility in neonatal rat cardiac myocytes. In addition, TNF-alpha augments the inotropic response of myocardial tissue to phosphodiesterase inhibitors through a mechanism independent of cyclic AMP generation. Phosphodiesterase inhibitors such as amrinone may be found to exert significant inotropic effects in catecholamine-refractory septic shock with myocardial depression and other conditions of inflammatory myocardial dysfunction.

Amrinone↗
PubMed1999

Effects of nitric oxide synthase inhibition on microvascular reactivity in septic mice.

Persistent vasodilation refractory to vasopressor agents is characteristic of septic shock. Induction of nitric oxide synthase (NOS) by sepsis-induced cytokines within the vasculature is one of the primary mediators of this refractory vasodilation. To evaluate the mechanism of vasodilation in sepsis, we used in vivo videomicroscopy to measure microvascular vasoconstrictive responses to topical suffusion of norepinephrine in mice made septic by cecal ligation and puncture, and contrasted the effects of topical superfusion of the nonselective NOS inhibitor N(G)-methyl-L-arginine (L-NMMA) and the selective inducible NOS (iNOS) inhibitor S-methyl-isothiourea (SMT). Mice with sepsis were less sensitive to the vasoconstrictive effects of norepinephrine than controls (EC50, the concentration that produces half-maximal response 2.0+/-0.6 x 10(-6) M vs. 7.9+/-2.2 x 10(-8) M, P=0.01). Selective inhibition of inducible iNOS with topical SMT (100 microM) markedly increased catecholamine reactivity in mice with sepsis but did not affect reactivity in controls (P=0.0007 for sepsis, P=0.24 for controls). Nonselective NOS inhibition with topical L-NMMA produced a similar increase in catecholamine reactivity in mice with sepsis but not controls (P=0.001 for sepsis, P=0.56 for controls). When excess (1 mM) L-arginine, the substrate for NOS, was added to the superfusion buffer along with both SMT and L-NMMA, arteriolar responsiveness to norepinephrine was decreased to the original values. These experiments demonstrate that iNOS inhibition is as effective as nonselective NOS inhibition in reversing decreased catecholamine reactivity in sepsis. This suggests a crucial role for microvascular activation of iNOS in the pathophysiology of hypotension and decreased vasopressor responsiveness in sepsis.

Animals↗