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Biomedical subjects

J E Parrillo

Publications and source records attributed to J E Parrillo.

At least 19 recordsLinked to original sources
PubMed1992

Excimer laser ablation before autoperfusion balloon inflation: a novel therapeutic approach to high grade stenoses in vessels supplying substantial myocardium at risk.

The utility of a novel approach employing excimer laser ablation to form a channel for subsequent autoperfusion balloon angioplasty is presented. Two important advantages of this strategy are highlighted: (1) applicability to severe stenoses in vessels supplying substantial myocardium at risk and (2) ability to allow prolonged inflation time to minimize procedure related ischemia and optimize revascularization of the heart. We prospectively selected and studied five patients and performed excimer laser coronary angioplasty using either a 1.3 mm or 1.6 mm laser catheter followed by autoperfusion balloon dilatation. Procedural success was documented by a significant reduction in mean percent diameter stenosis from 89 +/- 4% (S.D.) to 53 +/- 4% after laser angioplasty (p < 0.0001) and subsequently to 20 +/- 4% after autoperfusion balloon angioplasty (p < 0.0001). Clinical success was attained and characterized by resolution of anginal symptoms for at least 4 weeks after hospital discharge. There were no major acute complications encountered; however, restenosis has occurred in 2 out of 5 patients. We therefore recommend this novel pre-dilation strategy with excimer laser followed by autoperfusion balloon angioplasty in selected patients with an extensive amount of myocardium at risk.

Adult↗
PubMed1992

Effect of septic serum on vascular smooth muscle: in vitro studies using rat aortic rings.

BACKGROUND AND METHODS: Septic shock in humans is characterized by hypotension, low systemic vascular resistance, and high cardiac output. We hypothesized that circulating vasodilatory substances are, in part, responsible for this low systemic vascular resistance. To investigate this possibility, we exposed isolated rat aortic rings to sera from patients with septic shock and to sera from dogs made septic by intraperitoneal implantation of infected clots. Isolated rings from rat thoracic aortas were mounted on hooks in chambers filled with modified Krebs' buffer and bubbled with 95% oxygen/5% CO2. After documentation of functional endothelium, the rings were precontracted with norepinephrine. Serum was then added and ring tension measured continuously over the next 20 mins. RESULTS: Sera from normal humans increased ring tension by 6% (60 +/- 39 [SEM] mg tension/mg ring). Sera from nine patients with septic shock decreased tension by 30% (350 +/- 42 mg tension/mg ring; p less than .001). In response to sera from control dogs, tension increased by 16% (122 +/- 37 mg tension/mg ring). In contrast, septic dog sera caused tension to decrease by 36% (278 +/- 38 mg tension/mg ring;p less than .001). Vasodilation was unaffected when the septic patient and dog sera were dialyzed to remove molecules less than 10,000 molecular weight. Chemical deendothelialization with sodium deoxycholate also did not affect the vasodilatory response to septic patient or dog sera. CONCLUSIONS: Septic sera can relax rat aortic smooth muscle. Dialyzing to exclude the effects of small molecules and removing the endothelium did not eliminate this vasodilatory response. These data suggest the presence in septic serum of circulating substances capable of relaxing vascular smooth muscle that may play an important role in the pathogenesis of the cardiovascular abnormalities in septic shock.

Animals↗
PubMed1992

Tumor necrosis factor challenges in canines: patterns of cardiovascular dysfunction.

Three groups of conscious canines were given different intravenous doses of human recombinant tumor necrosis factor (TNF) over 1 h, and the resulting cardiovascular abnormalities were examined for 10 days. As TNF dose increased [0 (controls), 30, 60, and 120 micrograms/kg body wt], the number of deaths increased (P less than 0.025; 0 of 6, 1 of 8, 4 of 8, number of deaths in each group, respectively). In all three groups receiving TNF, the mean left ventricular ejection fraction (LVEF) at 2 h after infusion decreased (P less than 0.003) compared with controls. The group receiving the highest dose of TNF (120 micrograms/kg body wt) had the greatest decrease (P less than 0.05) in LVEF from 0 to 2 h. At 8 h, all three groups receiving TNF had similar LVEF. In these three groups, other multiple measures of LV function at 8 h showed significant and similar decreases in cardiac contractility compared with controls. From 24 to 240 h, however, the time required for cardiac performance (LVEF) to return to normal was dose dependent (30 less than 60 less than 120 micrograms/kg body wt; P less than 0.05). Canines receiving the lowest dose of TNF had near normal cardiac function (LVEF) at 24 h, whereas canines receiving the highest dose had persistent cardiac abnormalities at 240 h. Thus, at 8 h, the severity of cardiac dysfunction is independent of TNF dose, but the rate of onset and the duration of cardiac abnormality are markedly dependent of dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Pulmonary and oxygen transport effects of intravenously administered endotoxin in normal humans.

Little data are available describing the initial changes in pulmonary function and oxygen transport during human endotoxemia. We studied 26 normal humans after intravenously administered endotoxin (4 ng/kg). To evaluate alterations in gas exchange, hemodynamic monitoring was performed in nine subjects given endotoxin and six subjects given saline only. Compared with the control subjects, no changes in gas exchange occurred at 3 h, but after volume loading (mean, 2.2 L saline infused from 3 to 5 h) the PaO2 fell (86.1 +/- 2.3 mm Hg, p = 0.042), and the AaPO2 widened (18.5 +/- 1.7 mm Hg, p = 0.005). Oxygen consumption and delivery both increased significantly at 3 h (219 +/- 17 and 1,030 +/- 43 ml/min.min2) and 5 h (203 +/- 7 and 949 +/- 48 ml/min.min2) (p less than or equal to 0.035), whereas oxygen extraction fell at 3 h (p = 0.041). Seventeen subjects underwent bronchoalveolar lavage 14 +/- 4 days before and at 1.5 to 3 h (n = 8) or 5 h after (n = 9) the administration of endotoxin. No increase in the total number of cells or percent or absolute number of neutrophils was found at either time point. The rate of clearance of inhaled 99mTc-diethylenetriamine pentacetate aerosol, a measure of alveolar epithelial permeability, increased in subjects scanned before 3 h (n = 8; p less than 0.05), whereas no significant changes occurred in subjects scanned 5 h after endotoxin (n = 5) or in control subjects (n = 6). Early inflammatory responses after intravenous administration of endotoxin to normal humans results in alterations in gas exchange and lung permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Differential effects of fatty acids on glycolysis and glycogen metabolism in vascular smooth muscle.

The effects of fatty acids of different chain lengths on aerobic glycolysis, lactic acid production, glycogen metabolism and contractile function of vascular smooth muscle were investigated. Porcine carotid artery segments were treated with 50 microM iodoacetate and perchloric acid tissue extracts were then analyzed by 31P-NMR spectroscopy to observe the accumulation of phosphorylated glycolytic intermediates so that the activity of the Embden-Myerhof pathway could be tracked under various experimental paradigms. Aerobic glycolysis and lactate production in resting arteries were almost completely inhibited with 0.5 mM octanoate, partially inhibited with 0.5 mM acetate and unaffected by 0.5 mM palmitate. Inhibition of glycolysis by octanoate was not attributable to inhibition of glucose uptake or glucose phosphorylation. Basal glycogen synthesis was unchanged with palmitate and acetate, but was inhibited by 52% with octanoate incubation. The characteristic glycogenolysis which occurs upon isometric contraction with 80 mM KCl in the absence of fatty acid in the medium was not demonstrable in the presence of any of the fatty acids tested. Glycogen sparing was also demonstrable in norepinephrine contractions with octanoate and acetate, but not with palmitate. Additionally, norepinephrine-stimulated isometric contraction was associated with enhanced synthesis of glycogen amounting to 6-times the basal rate in medium containing octanoate. Contractile responses to norepinephrine were attenuated by 20% in media containing fatty acids. Thus, fatty acids significantly alter metabolism and contractility of vascular smooth muscle. Fatty acids of different chain lengths affect smooth muscle differentially; the pattern of substrate utilization during contraction depends on the contractile agonist and the fatty acid present in the medium.

Animals↗
PubMed1991

Factors that determine the hemodynamic response to inhalation anesthetics.

The hemodynamic response to inhalation anesthesia is influenced by three factors: 1) the specific drug, 2) the dose, and 3) individual characteristics of the subject. To investigate the importance of these factors on the cardiovascular response, we administered five doses [0, 0.5, 1.0, 1.5, and 2.0 minimum alveolar concentration (MAC)] of enflurane, halothane, and isoflurane to each of six dogs. Twelve hemodynamic variables were measured. For all variables, a change in the dose of each drug produced a consistent effect in each dog. Increases in dose resulted in significant decreases in seven variables [left ventricular ejection fraction, cardiac index (CI), stroke volume index (SVI), mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), left ventricular stroke work index (LVSWI), and heart rate (HR)] and a significant increase in one variable [central venous pressure (CVP)]. In contrast, the response of individual dogs to different drugs was not consistent. For seven variables [MAP, MPAP, LVSWI, CVP, pulmonary capillary wedge pressure (PCWP), end-diastolic volume index (EDVI), and end-systolic volume index (ESVI)], a significant difference in the responses of a dog to two drugs was greater than zero, whereas a significant difference in the response of at least one other dog to the same two drugs was less than zero (discordant dog-drug interactions). Thus, in contrast to the consistency of the cardiovascular response to changes in dose, the hemodynamic response to different drugs was inconsistent among dogs. We also studied the effect of fluid challenge on hemodynamic response at 1.5 or 2.0 MAC of the three drugs given to each dog.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1991

The effect of tumor necrosis factor on vascular smooth muscle. In vitro studies using rat aortic rings.

The mechanisms of vasodilation in septic shock have not been well elucidated. We used isolated rat aortic rings as an in vitro model of vascular reactivity to assess the acute, direct effects on vascular smooth muscle relaxation of four cytokines: interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), and tumor necrosis factor (TNF). The rings were precontracted with catecholamines and then test cytokines were added. The changes in tension with IL-1 at 1,000 U/ml, IL-2 at 1,000 U/ml, and IL-6 at 500 U/ml differed from controls by -67 +/- 59, -5 +/- 42, and 8 +/- 56 mg/mg of tissue, respectively (for each, n = 10, p = NS). The change in tension with TNF at 1,000 U/ml differed from controls by -176 +/- 42 mg/mg of tissue (n = 20), p less than 0.001). Chemical removal of the endothelium with deoxycholate diminished TNF-induced vasodilation to -62 +/- 14 mg/mg of tissue (p less than 0.05). The relaxation with TNF occurred in a concentration-dependent fashion and was unaffected by indomethacin. This study demonstrates that TNF has an acute, concentration-dependent, cyclooxygenase-independent, vasodilatory effect on vascular smooth muscle. The effect of TNF was partially, but not fully, dependent on the presence of an intact endothelium, implying that TNF acts on both the endothelium and the smooth muscle. These findings suggest that TNF may play an important role in the vasodilation characteristic of septic shock.

Animals↗
PubMed1991

Ocular permeability after systemic administration of endotoxin in humans.

Acute anterior uveitis in response to the administration of systemic gram-negative endotoxin was studied in humans. The blood-aqueous barrier was evaluated in eight normal human subjects at 8 or 24 hours after systemic administration of purified gram-negative endotoxin. No significant changes in the blood-aqueous barrier were found, as evaluated by permeability to fluorescein, number of aqueous cells, flare, or intraocular pressure, despite profound endotoxin-induced cardiac, pulmonary, and circulatory effects. Gram-negative endotoxin does not appear to affect the human blood-aqueous barrier in doses that can safely be given to humans.

Adult↗
PubMed1990

Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy.

Septic shock is the commonest cause of death in intensive care units. Although sepsis usually produces a low systemic vascular resistance and elevated cardiac output, strong evidence (decreased ejection fraction and reduced response to fluid administration) suggests that the ventricular myocardium is depressed and the ventricle dilated. In survivors, these abnormalities are reversible. Failure to develop ventricular dilatation in nonsurvivors suggests that dilatation is a compensatory mechanism needed to maintain adequate cardiac output. With a canine model of septic shock that is very similar to human sepsis, myocardial depression was confirmed using load-independent measures of ventricular performance. Endotoxin administration to humans simulates the qualitative, cardiovascular abnormalities of sepsis. The pathogenesis of septic shock is extraordinarily complex. Diverse microorganisms can generate toxins, stimulating release of potent mediators that act on vasculature and myocardium. A circulating myocardial depressant substance has been closely associated with the myocardial depression of human septic shock. Therapy has emphasized early use of antibiotics, critical care monitoring, aggressive volume resuscitation, and, if shock continues, use of inotropic agents and vasopressors. Pharmacologic or immunologic antagonism of endotoxin or other mediators may prove to enhance survival in this highly lethal syndrome.

Animals↗
PubMed1990

Serum neopterin levels following intravenous endotoxin administration to normal humans.

Endotoxin was administered intravenously to five normal subjects. Measurement of serum neopterin levels demonstrated no significant change from baseline during the first 6 h after endotoxin administration, but were elevated two to four-fold at 24 h. In the three subjects in whom it was measured, a two-fold rise of the mean serum neopterin levels persisted at 48 h. The acute inflammatory events initiated by endotoxin administration to normal humans result in a delayed, but sustained, rise in serum neopterin levels which persists well after the acute phase response has subsided.

Acute-Phase Reaction↗
PubMed1990

Antiendotoxin activity of lipid A analogues: requirements of the chemical structure.

Lipid X, a monosaccharide precursor of lipid A, has been found to prevent death in animals given a lethal dose of endotoxin, but the mechanism of this protective effect is unknown. We previously reported that lipid X blocks endotoxin-induced priming of human neutrophils in a manner consistent with competitive inhibition. To determine the molecular requirements for this antiendotoxin activity, we studied several derivatives of lipid X using the neutrophil priming assay. Neutrophil priming was quantitated by measuring stimulated superoxide (O2-) release. The removal of either acyl group from lipid X or even the simple change of the amide to an ester linkage at C2 of the glucosamide ring resulted in a marked loss of antagonism. Monosaccharide analogues, structurally related to native lipid A by the presence of acyloxyacyl side chains, demonstrated marked inhibition of endotoxin-induced priming at low concentrations but an endotoxin-like, priming effect at high concentrations. The addition of a phosphate group at position 4 of the sugar moiety was the only modification studied so far that produced a pure antagonist with increased antiendotoxin activity. Demonstration of these structural requirements for the antiendotoxin activity of lipid A analogues supports the hypothesis that this effect may be mediated via specific cellular binding sites. Lipid X derivatives may be useful for studying the interaction of endotoxin with cells and their antiendotoxin activity may prove beneficial in the treatment of septicemia.

Bacterial Infections↗