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Biomedical subjects

R W Samsel

Publications and source records attributed to R W Samsel.

At least 19 recordsLinked to original sources
PubMed1996

Cytokine production at the site of disease in chronic eosinophilic pneumonitis.

Chronic eosinophilic pneumonitis (CEP) is characterized by longstanding respiratory symptoms accompanied by a massive pulmonary eosinophil infiltration. We hypothesized that cytokine(s) produced in the disease sites are implicated in the pathophysiology of CEP. We studied peripheral blood and bronchoalveolar lavage fluids (BALF) obtained from two lung segments of a patient with CEP. Seventy times more eosinophils were found in the BALF from an involved lung segment (showing patchy opacification on a chest roentgenogram) than from an uninvolved segment. The eosinophil-active cytokines interleukin-5 (IL-5), IL-6, and IL-10 were strikingly elevated in the BALF from the involved lung segment, whereas no or minimal levels of these cytokines were detectable in the BALF from the uninvolved segment or serum, respectively. Leukocytes in the involved lung segment, but not those in peripheral blood, expressed messenger ribonucleic acid (mRNA) for IL-5, IL-6, and IL-10. In contrast, IL-2, IL-3, IL-4, interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha) were not detected in any sample. These findings suggest that increased production of several cytokines, such as IL-5, IL-6, and IL-10, in the involved lung segment, but not in the uninvolved lung segment or peripheral blood, is a critical pathophysiologic feature of CEP.

Adult↗
PubMed1995

Systemic and gut O2 extraction during endotoxemia. Role of nitric oxide synthesis.

Endotoxin administration decreases intrinsic responsiveness of arteries to contractile agonists, both in vivo and in vitro. Endotoxin also impairs systemic and intestinal ability to increase microvascular O2 extraction in response to decreases in O2 delivery. During endotoxemia, contractile responsiveness can be increased by stereospecific inhibitors of nitric oxide (NO) synthase, suggesting that the hypotension and loss of microvascular function caused by endotoxin may result from increased nitric oxide biosynthesis. This study tested whether inhibition of NO synthesis could reverse the systemic and intestinal oxygen extraction defects seen after endotoxin challenge in the dog. Oxygen extraction and hemodynamic responses to progressive decreases in O2 delivery (stagnant hypoxia) were measured systemically and in isolated autoperfused intestine segments in anesthetized dogs. Systemic and intestinal O2 extractions at the onset of O2 supply dependency were significantly impaired in endotoxin-challenged (n = 6) compared with control (n = 7) animals. Inhibition of NO synthase activity with N omega-nitro-L-arginine methyl ester (L-NAME), 50 mg/kg + 100 mg/kg/h, completely inhibited endothelium-dependent vasodilation responses evaluated in vitro, and significantly but incompletely reversed the systemic hypotension in animals previously given endotoxin (n = 9). Despite this improvement, critical O2 extraction ratios remained significantly reduced. Administration of L-NAME in the absence of endotoxin (n = 8) significantly increased systemic vascular resistance and decreased cardiac output and O2 delivery, but it did not impair critical O2 extraction ratios in whole body or isolated intestine. We conclude that inhibition of NO synthesis in this model of endotoxemia can improve arterial pressure without improving those microvascular functions that may influence tissue O2 extraction efficacy.

Acetylcholine↗
PubMed1995

Bronchoalveolar lavage fluid from immature rats with hyperoxia-induced airway remodeling is mitogenic for airway smooth muscle.

We previously demonstrated that hyperoxia-exposed immature rats develop airway smooth muscle layer thickening; this remodeling appears partially attributable to smooth muscle hyperplasia. In this study, we tested the hypothesis that excess mitogenic activity for airway smooth muscle cells is present within the lungs of hyperoxia-exposed immature rats. We assessed the proliferative effect of bronchoalveolar lavage (BAL) fluid from air- and O2-exposed animals on cultured rat tracheal smooth muscle cells. BAL fluids from air- or O2-exposed immature rats increased DNA synthesis ([3H]-thymidine incorporation at 24 h of incubation) and cell number (compared with DMEM-treated control cells, at 2 days of incubation), but BAL fluid from O2-exposed animals had significantly greater mitogenic effects. This excess mitogenic activity was lipid inextractable and was ablated by trypsin digestion, indicating that at least one polypeptide growth factor was responsible; molecular sieve fractionation demonstrated a molecular weight of > 10 kD. Because platelet-derived growth factor (PDGF) has been identified in other models of hyperoxia exposure, we tested the further hypothesis that PDGF contributes to the observed excess mitogenic activity. Addition of neutralizing anti-PDGF antibodies to BAL-stimulated smooth muscle cultures did not reduce BAL fluid-induced mitogenesis. These data indicate that the lungs of O2-exposed rats contain excess mitogenic activity for airway smooth muscle, attributable to non-PDGF polypeptide growth factors. It is conceivable that this abnormal mitogenic activity contributes to O2-induced airway smooth muscle remodeling observed in immature rats in vivo.

Animals↗
PubMed1994

The effect of adrenergic agonists on the systemic response to hemorrhage.

PURPOSE: Systemic blood loss elicits a variety of reflex cardiovascular responses, which preserve cardiac output as possible and preserve arterial blood pressure when cardiac output decreases. When compensatory venoconstriction is exhausted, hemorrhage reduces oxygen delivery (QO2), and systemic vasoconstriction competes with local metabolic vasodilation to preserve tissue oxygen uptake (VO2). Through their effects on vascular tone and blood flow distribution, adrenergic agents might interfere with the physiological responses to reduced O2 delivery. This study was designed to determine the effects of dobutamine and norepinephrine on oxygen extraction and systemic vascular resistance during progressive hemorrhage. METHODS: We infused dobutamine or norepinephrine into anesthetized, ventilated dogs and measured the systemic vascular resistance, oxygen consumption, and oxygen extraction ratio as oxygen delivery (blood flow) was reduced by blood withdrawal. Four groups were compared: control (saline), dobutamine (10 micrograms/kg/min), high-dose norepinephrine (1.0 microgram/kg/min), and low-dose norepinephrine (0.1 microgram/kg/min). RESULTS: High-dose norepinephrine increased oxygen demand but did not alter extraction significantly at the critical point. Neither low-dose norepinephrine nor dobutamine affected oxygen extraction during hemorrhage. Dobutamine and norepinephrine both ablated the increase in systemic vascular resistance that accompanies hemorrhage. Low-dose norepinephrine was not different from control. CONCLUSIONS: Norepinephrine and dobutamine appear to block reflex vasoconstriction, and mechanistic explanations for this finding remain speculative. Despite inhibition of reflex vasoconstriction, neither dobutamine nor norepinephrine significantly impaired oxygen extraction during hemorrhage.

Animals↗
PubMed1994

Cardiovascular physiology teaching: computer simulations vs. animal demonstrations.

The roots of physiology lie in laboratory observation, and physiology courses continue to rely on laboratory observation to provide students with practical information to correlate with their developing base of conceptual knowledge. To this end, animal laboratories provide a functioning example of interactions among organ systems and a source of data for student analysis. However, there are continuing objections to using animals for teaching, and animal labs are costly in time and effort. As an alternative laboratory tool, computer software can simulate the operation of multiple organ systems: responses to interventions illustrate intrinsic organ behavior and integrated systems physiology. Advantages of software over animal studies include alteration of variables that are not easily changed in vivo, repeated interventions, and cost-effective hands-on student access. Nevertheless, simulations miss intangible aspects of experimental physiology, and results depend critically on the assumptions of the model. We used both computer and animal demonstrations in teaching cardiovascular physiology to first-year medical students. The students rated both highly, but the computer-based session received a higher rating. We believe that both forms of teaching have educational merit. At the introductory level, the computer appears to provide an effective alternative.

Animals↗
PubMed1994

Airway reopening pressure in isolated rat lungs.

In a previous modeling study, we predicted that the yield pressure for airway reopening (Pyield) should depend on airway fluid surface tension (gamma) and airway radius (R), according to the relationship Pyield = 8.3 gamma/R. To test this prediction, we studied tantalum bronchograms of isolated perfused rat lungs from three rats by using microfocal X-ray imaging. Thirty-two airways with diameters ranging from 300 to 2,400 microns were recorded as the airways were collapsed and reinflated. Airway pressure was reduced transiently to -40 cmH2O to produce airway closure. Airway pressure was then slowly increased from 0 to 25 cmH2O. In each airway, the observed diameter remained constant until a Pyield was reached; at this pressure, airways were seen to "pop" open, allowing clear identification of airway reopening pressure. When Pyield was plotted against diameter at maximum inflation, the experimental data were in approximate agreement with predictions of Pyield made assuming a gamma of 35 dyn/cm. The close correspondence of the measured values with these predictions suggests that surfactant is present in these airways and facilitates airway reopening.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Adrenergic vasoconstriction augments tissue O2 extraction during reductions in O2 delivery.

When systemic O2 delivery is reduced, increases in systemic O2 extraction are facilitated by sympathetically mediated increases in vascular resistance that limit blood flow to regions with low metabolic demand. Local metabolic vasodilation competes with this vasoconstriction, thereby effecting a balance between tissue O2 supply and demand. This study examined the role of sympathetically mediated vasoconstriction on the critical level of O2 extraction in hindlimb and whole body during progressive reductions in O2 delivery. In anesthetized dogs, the left hindlimb was vascularly isolated and its O2 delivery was decreased in stages by reducing the speed of an occlusive pump. In a normovolemic group (n = 6), blood volume was maintained to minimize sympathetic tone while flow to the hindlimb was reduced. In a hypovolemic group (n = 6), blood volume was removed in stages to augment sympathetic tone progressively while flow to the limb was reduced simultaneously. A phenoxybenzamine group (n = 6) was identical to the hypovolemic group, except that alpha-adrenergic effects were inhibited with phenoxybenzamine (3 mg/kg). The systemic critical O2 extraction ratio in the phenoxybenzamine group (0.60 +/- 0.06) was less than for the hypovolemic group (0.71 +/- 0.04; P = 0.004). In the hindlimb, critical O2 extractions were significantly less in the normovolemic (0.46 +/- 0.17) and phenoxybenzamine (0.49 +/- 0.10) groups compared with the hypovolemic group (0.72 +/- 0.10; P < or = 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗
PubMed1994

Systemic hemorrhage augments local O2 extraction in canine intestine.

When O2 delivery (QO2) to a tissue is reduced, microvascular adjustments facilitate increases in O2 extraction, thereby delaying the onset of O2 supply-limited metabolism until a critically low QO2 is reached. The present study investigated the contribution of the autonomic nervous system to these adjustments by measuring O2 extraction in isolated intestine. In anesthetized dogs, a 30- to 50-g segment of intestine was vascularly isolated and its QO2 was decreased in stages by reducing the speed of an occlusive pump. In a normovolemic group (n = 11), blood volume was maintained to minimize sympathetic tone while flow to the intestine was reduced. In a hypovolemic group (n = 7), blood volume was removed in stages to augment sympathetic tone as flow to the intestinal segment was simultaneously reduced. A hypovolemic alpha-adrenergic-blocked (alpha-blocked) group (n = 6) was identical to the corresponding alpha-adrenergic intact (alpha-intact) group except that alpha-adrenergic effects were inhibited with phenoxybenzamine (3 mg/kg). The systemic critical O2 extraction ratio in the alpha-blocked group (69 +/- 6%) was less than that in the alpha-intact group (77 +/- 7%; P = 0.05). In the intestine, the critical O2 extraction ratio was significantly poorer in the normovolemic (45 +/- 11%) group than in either hypovolemic group (alpha-intact: 69 +/- 3%, P < 0.00005; alpha-blocked: 62 +/- 9%, P < 0.005). These findings demonstrate that systemic hemorrhage significantly augments critical O2 extraction in intestine during progressive local stagnant hypoxia and suggest that nonadrenergic vasoconstrictor mechanisms may play an important role.

Adrenergic alpha-Antagonists↗
PubMed1993

Absence of supply dependence of oxygen consumption in patients with septic shock.

We tested whether oxygen consumption (VO2) was dependent on oxygen delivery (QO2) in 10 patients with septic shock when QO2 was changed by the use of the inotropic agent, dobutamine. The mean acute physiology and chronic health evaluation (APACHE) II score of the patients was 27.3 +/- 8.1 with a mean blood pressure on entry of 66.8 +/- 12.4 mm Hg, and all had been volume resuscitated to a pulmonary artery occlusion pressure of greater than 10 mm Hg. We measured VO2 by analysis of respiratory gases (VO2G) while calculating VO2 by the Fick equation (VO2F) at three different O2 deliveries. When the dobutamine infusion rate was increased from 2.5 +/- 4.0 to 12.3 +/- 6.0 micrograms/kg/min, thermodilution cardiac output increased from 7.7 +/- 2.6 to 10.1 +/- 2.7 L/min (P < .01). Accordingly, dobutamine increased QO2 from 13.5 +/- 3.8 to 18.2 +/- 4.3 mL/min per kg (increase of 36.4% +/- 19.7%; P < .01), but VO2G did not increase (3.2 +/- 0.5 to 3.2 +/- 0.6 mL/min per kg). During these same interventions, the VO2F tended to increase (2.9 +/- 0.7 to 3.4 +/- 0.8 mL/min per kg, P < .06), presumably a spurious correlation because of measurement errors shared by the calculation of VO2F and QO2. Neither lactic acidosis nor acute respiratory distress syndrome (ARDS) conferred supply dependence of VO2G, but the presence of ARDS was predictive of death in this cohort. It is concluded that VO2 is independent of QO2 in patients with septic shock and lactic acidosis. These data confirm that maximizing QO2 beyond values achieved by initial fluid and vasoactive drug resuscitation of septic shock does not improve tissue oxygenation as determined by respiratory gas measurement of VO2.

Adult↗
PubMed1993

Effects of endotoxin in vivo on endothelial and smooth-muscle function in rabbit and rat aorta.

In order to determine whether endotoxemia induced generalized defects in vascular contraction and endothelium-dependent relaxation, we studied the effect of in vivo endotoxin administration in Sprague-Dawley rats and New Zealand White rabbits on endothelial and arterial smooth-muscle responses of isolated thoracic aorta in vitro. Endotoxin treatment significantly decreased contractile responses to phenylephrine (PE), angiotensin II (AII), serotonin (5-HT), and potassium chloride. This effect was not altered by indomethacin or endothelial denudation. Treatment of vessels with NG-nitro-L-arginine (NNLA), an inhibitor of arginine-dependent nitric oxide biosynthesis, or with methylene blue, an inhibitor of soluble guanylate cyclase, resulted in significant improvement of the contractile defect in endotoxin-treated vessels. The restorative effect of NNLA on contractile responses in endotoxin-treated aortic rings was similar in the presence or absence of an intact endothelium. Endothelium-dependent relaxation in response to acetylcholine, substance P, or the calcium ionophore A23187 was markedly impaired in vessels from endotoxin-treated rabbits, while endothelium-independent relaxation in response to nitroprusside was similar in both groups. These results suggest that endotoxemia both induces basal, nonendothelial nitric oxide synthesis and impairs the agonist-stimulated release of endothelium-derived relaxing factor (EDRF). These findings may have mechanistic importance in the hemodynamic derangements of endotoxemia.

Angiotensin II↗
PubMed1993

Extracellular calcium and intrinsic tone in the human umbilical artery.

Previous in vitro studies of the human umbilical artery (HUA) have suggested that this vessel exhibits significant intrinsic tone, even in the absence of contractile agonists. Other investigators have found that these vessels are unresponsive to nitrovasodilators, suggesting that the guanylate cyclase-mediated relaxation mechanism may not be operative. To clarify these observations, human umbilical cords were obtained at the time of delivery and HUA rings were studied in organ baths. In contrast to other systemic arteries, HUA rings exhibited unstable initial tone in the absence of pharmacologic agonists. This intrinsic tone was augmented when the extracellular ionized calcium concentration was increased and abolished when extracellular calcium was removed. Rings maintained in the presence of extracellular calcium for 1 hr became less responsive to changes in extracellular calcium than did rings maintained in calcium-free buffer. Serotonin produced oscillatory, quantal contractions in the presence of calcium; in the absence of extracellular calcium, it elicited only concentration-dependent graded contractions. In the presence of nifedipine or in the absence of extracellular calcium, nitroglycerin fully relaxed contractions elicited by serotonin. Thus, in HUA, extracellular calcium produces intrinsic tone that diminishes spontaneously with time.

Calcium↗
PubMed1992

L-canavanine selectively augments contraction in aortas from endotoxemic rats.

Contractile responses to KCl or phenylephrine were inhibited in endothelium-denuded aorta from endotoxin-treated rats. L-Canavanine, a selective inhibitor of inducible nitric oxide synthase, augmented contractile responses in vessels from endotoxin, but not saline-pretreated animals. In contrast to nitroarginine, L-canavanine did not inhibit endothelium-dependent relaxation induced by acetylcholine. Selective inhibitors of inducible nitric oxide synthase may be useful probes of vascular dysfunction in sepsis.

Animals↗
PubMed1992

Regulation of perfused capillary density in canine intestinal mucosa during endotoxemia.

When O2 delivery (blood flow X arterial O2 content) is reduced, many tissues respond by increasing perfused capillary density. This facilitates the increase in O2 extraction required to maintain tissue O2 consumption in the face of limited O2 supply. In a previous study of isolated canine small intestine (J. Appl. Physiol. 64: 2410-2419, 1988), endotoxin administration was associated with an impaired ability to increase O2 extraction in response to progressive reductions in O2 delivery. The aim of the present study was to determine whether reductions in perfused capillary density occur after endotoxin administration. Fourteen male dogs were anesthetized with chloralose (150 mg/kg iv) and urethan (750 mg/kg iv), and a segment of small intestine was exteriorized through a midline laparotomy. The segment was isolated vascularly, autoperfused, and maintained at body temperature. Escherichia coli endotoxin (5 mg/kg) or sham challenge was administered, and the animals were allowed to stabilize. Blood flow and arterial and gut venous blood O2 contents were measured after 3 h. Perfused vessels were then labeled by injecting colloidal carbon (less than 0.8 microns) through the arterial cannula and clamping the artery and vein as the bolus passed through the tissue. In some of the experiments a second gut segment was successfully obtained within 1 h of the first, yielding a total of 14 gut segments in nine endotoxin animals and nine segments in five control animals. Morphological analysis of capillary surface density in mucosal villi and crypts showed a significantly higher perfused capillary density in control tissue blocks (77.8 +/- 9.2%) than in blocks from endotoxin-treated animals (68.8 +/- 8.0%, P less than 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Hepatic oxygen and lactate extraction during stagnant hypoxia.

As O2 delivery falls, tissues must extract increasing amounts of O2 from blood to maintain a normal O2 consumption. Below a critical delivery threshold, increases in O2 extraction cannot compensate for the falling delivery, and O2 uptake falls in a supply-dependent fashion. Numerous studies have identified a critical delivery in whole animals, but the regional contributions to the critical O2 delivery are less fully understood. In the present study, we explored the limits of O2 extraction in the isolated liver, seeking to determine 1) the normal relationship between O2 consumption and delivery in the liver and 2) the relationship of hepatic lactate extraction to the drop in hepatic O2 consumption at low O2 deliveries. To answer these questions, using support dogs as a source for oxygenated metabolically stable blood, we studied eight pump-perfused canine livers. By lowering the blood flow in a model of stagnant hypoxia, we explored the relationship between O2 consumption and delivery over the entire physiological range of O2 delivery. The critical O2 delivery was 28 +/- 5 (SD) ml.kg-1.min-1; the livers extracted 68 +/- 9% of the delivered O2 before reaching supply dependence. This suggests that the liver has an O2 extraction capacity quite similar to the body as a whole and not different from other tissues that have been isolated. At high blood flows, the livers extracted approximately 10% of the lactate delivered by the blood, but the arteriovenous lactate differences were small. At low blood flows, however, the livers changed from lactate consumption to production. The O2 delivery coinciding with the dropoff in lactate extraction did not differ significantly from the critical O2 delivery. We conclude that reductions in lactate uptake by the liver do not precede the transition to O2 supply dependence.

Animals↗
PubMed1991

Oxygen delivery to tissues.

For health, well perfused tissues, oxygen uptake is determined primarily by metabolic need rather than by oxygen supply. Tissue hypoxia supervenes when tissue oxygen tension (PO2) falls below a critical point, and the point where this occurs can be predicted from the systemic oxygen delivery or extraction ratio. A growing body of evidence suggest that tissue oxygen extraction may be impaired in adult respiratory distress syndrome (ARDS) and sepsis. In these syndromes the minimum oxygen delivery needed to maintain a normal oxygen uptake appears to be increased, as tissues become hypoxic despite high levels of delivery. However, controversy surrounds every phase of this observation, from its experimental basis, to potential causes, to its implications for patient care. In this review, we discuss the physiology of oxygen transport, the determinants of tissue oxygenation in normal and pathological states, and the therapeutic implications of oxygen transport.

Animals↗
PubMed1990

Effects of surface tension and viscosity on airway reopening.

We studied airway opening in a benchtop model intended to mimic bronchial walls held in apposition by airway lining fluid. We measured the relationship between the airway opening velocity (U) and the applied airway opening pressure in thin-walled polyethylene tubes of different radii (R) using lining fluids of different surface tensions (gamma) and viscosities (mu). Axial wall tension (T) was applied to modify the apparent wall compliance characteristics, and the lining film thickness (H) was varied. Increasing mu or gamma or decreasing R or T led to an increase in the airway opening pressures. The effect of H depended on T: when T was small, opening pressures increased slightly as H was decreased; when T was large, opening pressure was independent of H. Using dimensional analysis, we found that the relative importance of viscous and surface tension forces depends on the capillary number (Ca = microU/gamma). When Ca is small, the opening pressure is approximately 8 gamma/R and acts as an apparent "yield pressure" that must be exceeded before airway opening can begin. When Ca is large (Ca greater than 0.5), viscous forces add appreciably to the overall opening pressures. Based on these results, predictions of airway opening times suggest that airway closure can persist through a considerable portion of inspiration when lining fluid viscosity or surface tension are elevated.

Airway Obstruction↗