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R L Engler

Publications and source records attributed to R L Engler.

At least 37 records · Page 2Linked to original sources
PubMed1993

Complement C5a-mediated myocardial ischemia and neutrophil sequestration: two independent phenomena.

The intracoronary infusion of complement C5a causes a decrease in coronary blood flow and contractile dysfunction mediated by thromboxane (TxA2) and leukotrienes. Although these effects are accompanied by polymorphonuclear leukocyte (PMN) sequestration, the role of PMNs and the source of these eicosanoids remain unknown. To assess the contribution of PMNs to the C5a-induced myocardial ischemic response, the left anterior descending (LAD) coronary artery of pigs (n = 13) was cannulated and pump perfused at constant pressure with either normal arterial blood or neutropenic arterial blood (PMN count 0.02 x 10(3) cells/microliters) obtained from animals treated with cyclophosphamide (50 mg/kg iv, given 4 days before). The coronary vein draining the LAD region was cannulated for measurement of leukocyte count and TxB2 levels. Two groups of animals were studied: group 1 (n = 7) neutropenic animals were instrumented and normal animals served as blood donors and group 2 (n = 6) normal animals were instrumented and neutropenic animals served as blood donors. The myocardial response to intracoronary C5a (500 ng) was determined in each animal during coronary perfusion with normal arterial blood and also with neutropenic arterial blood. During perfusion with normal arterial blood, C5a decreased coronary flow to 52.3% and contractile function to 58.8% of preinfusion values. This was accompanied by a transient myocardial accumulation of PMNs (arterial-coronary venous gradient of 5.4 x 10(3) cells/microliters) and increased TxB2 levels in coronary venous blood (from 0.31 to 17.5 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Role of cardiac mast cells in complement C5a-induced myocardial ischemia.

Activated complement component C5a causes myocardial ischemia mediated by thromboxane (Tx) A2 and leukotrienes C4/D4. Blood cells are not involved in either the mediator release or the myocardial effects of C5a, suggesting that a C5a-sensitive, cardiac resident inflammatory cell is responsible. The goals of this study were to determine whether 1) cardiac mast cell activation accompanies the C5a response, 2) inhibition of mast cell degranulation inhibits the response, and 3) histamine release plays a role in the C5a-induced myocardial ischemia. The left anterior descending coronary artery (LAD) of open-chest pigs (n = 13) was perfused with arterial blood at constant pressure (95 mmHg). Coronary blood flow (CBF) was measured (in-line flowmeter) and regional function [percent segment shortening (%SS)] determined with sonomicrometry. A coronary vein was cannulated for measurement of plasma TxB2 and histamine (a marker of mast cell degranulation). Intracoronary C5a (500 ng) decreased coronary blood flow (45% of preinfusion levels) and LAD %SS (65% of preinfusion) and was accompanied by increases in coronary venous TxB2 (delta 63.3 ng/ml) and histamine (delta 200 nM). Mast cell inhibition with lodoxamide (2 mg/kg iv, n = 8) attenuated the C5a-induced fall in CBF (14 vs. 53% decrease, P < 0.01) and %SS (10 vs. 38% decrease, P < 0.01) and also reduced the C5a-induced increase in both coronary venous histamine (delta 26 vs. 278 nM, P < 0.05) and TxB2 (delta 0.34 vs. 63.3 ng/ml, P < 0.01). However, histamine H1 (pyrilamine) and H2 (ranitidine) receptor blockade had no effect on the C5a-induced fall in CBF or LAD %SS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effect of transient coronary occlusion on coronary blood flow autoregulation, vasodilator reserve and response to adenosine in the dog.

Myocardial ischemia of short duration (15 to 20 min) produces myocardial "stunning" during reperfusion. The vasoregulatory and contractile status of reperfused myocardium during normal and reduced perfusion pressures is of interest in the treatment of patients with unstable angina. In the present study the effects of 15 min of reversible ischemic injury on several aspects of coronary vasoregulation were assessed with use of pressure-flow curves in anesthetized open chest dogs. The left anterior descending coronary artery was cannulated and perfused with arterial blood with use of a servo-controlled roller pump. The autoregulatory gain and an adenosine dose-response curve for coronary flow before and after ischemia and reperfusion were obtained. The maximal autoregulatory gain values in the pressure range of 140 to 60 mm Hg were not significantly different before and after ischemia and reperfusion (0.41 +/- 0.08 vs. 0.5 +/- 0.06, p greater than 0.1). The adenosine dose-response curve was significantly shifted to the right after reperfusion; however, coronary blood flows during maximal adenosine vasodilation over a large range of perfusion pressures (140 to 60 mm Hg) were significantly greater after ischemia and reperfusion. The pressure-dependent decrease in segment shortening (sonomicrometry) over the coronary pressure range of 160 to 30 mm Hg was similar in myocardium before and after stunning. Contractile function in the stunned myocardium at normal (100 mm Hg) and low (40 mm Hg) coronary perfusion pressures was similarly and significantly enhanced by the administration of adenosine. It is concluded that 1) coronary autoregulation is unchanged after brief ischemia and reperfusion; 2) although maximal coronary vascular conductance assessed with adenosine is greater after ischemia, the coronary circulation shows a decreased coronary sensitivity to exogenous adenosine; 3) the relation of contractile function to coronary pressure before and after stunning is unchanged; and 4) enhancement of function in stunned myocardium by vasodilation with adenosine occurs at low and normal perfusion pressures.

Adenosine↗
PubMed1991

Intracoronary C5a induces myocardial ischemia by mechanisms independent of the neutrophil: leukocyte filters desensitize the myocardium to C5a.

Activation of the complement cascade with the generation of anaphylatoxins accompanies the inflammatory response elicited by acute myocardial ischemia and reperfusion. Although complement is activated in the interstitium during acute myocardial ischemia, we have studied mechanisms whereby complement might exacerbate ischemia by using a model employing intracoronary injection of C5a in nonischemic hearts. Intracoronary injection of complement component C5a induces transient myocardial ischemia, mediated through the production of the coronary vasoconstrictors thromboxane A2 and peptidoleukotrienes (LTC4, LTD4), and causes sequestration of polymorphonuclear leukocytes (PMN) in the coronary vascular bed. To further investigate the role of the PMN in the C5a-induced vasoconstriction, the left anterior descending coronary artery (LAD) in pigs was perfused at constant pressure and measurements of coronary blood flow, myocardial contractile function (sonomicrometry), arterial/coronary venous blood PMN count, and thromboxane B2 (TxB2) levels were performed. The myocardial response to intracoronary C5a (500 ng) was determined before, during, and after perfusion with blood depleted of PMNs using leukocyte filters (Sepacell R-500, Pall PL-100). In additional animals, the myocardial response to the PMN chemotactic agent, LTB4, and the effects of intracoronary C5a during constant flow perfusion were measured. Control intracoronary injection of C5a decreased flow (41% of baseline) and contractile function (39% of baseline), PMNs were trapped (5.1 x 10(3) cells/microliters), and TxB2 concentration increased in coronary venous blood. The response to C5a during coronary perfusion with arterial blood depleted of PMNs with Sepacell or Pall filters (less than 0.1 x 10(3) cells/microliters) was greatly blunted, with flow and contractile function falling by less than 14 and 8%, respectively, from baseline, and release of TxB2 was greatly attenuated. However, the myocardial ischemia and TxB2 release remained depressed in response to C5a after removal of the filters and perfusion with either arterial blood containing normal levels of PMNs or stored arterial blood never exposed to filters. In contrast, the repeat C5a challenge resulted in equivalent myocardial extraction of PMNs, thus indicating a dissociation of PMN sequestration from the acute ischemic response and release of TxB2. In separate experiments, the intracoronary injection of LTB4 also resulted in a pronounced myocardial extraction of PMNs (8.6 x 10(3) cells/microliters) greater than during C5a, but did not depress coronary flow or function. Perfusion at constant flow greatly diminished the ischemic response to C5a, indicating that vasoconstriction and resultant ischemia is the main cause of the contractile dysfunction. These data indicate that leukocyte filters inhibit the myocardial ischemia and release of TxB2 induced by C5a via mechanisms not related to PMN depletion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Thromboxane A2 and peptidoleukotrienes contribute to the myocardial ischemia and contractile dysfunction in response to intracoronary infusion of complement C5a in pigs.

Intracoronary infusions of activated complement C5a result in myocardial ischemia, contractile dysfunction, and leukocyte accumulation. The hypothesis was tested that the generation of the coronary vasoconstrictors, thromboxane A2 and the 5-lipoxygenase leukotrienes (LTC4 and LTD4), contributes to the C5a-induced decrease in coronary blood flow and contractile function. The left anterior descending coronary artery in anesthetized swine was cannulated and servo pump-perfused with arterial blood at constant pressure and measured flow. Regional subendocardial contractile function was assessed with sonomicrometry. The interventricular vein was cannulated for sampling of coronary venous blood for leukocyte count. The responses in left anterior descending coronary artery blood flow and percent segment shortening to intracoronary infusions of LTC4 (1 microgram), LTD4 (1 microgram), thromboxane agonist U46619 (7.5 micrograms), and C5a (500 ng) were assessed before and after 1) LTD4/LTE4 receptor blockade with leukotriene receptor blocker LY171883 (10 mg/kg i.v.) (n = 5), 2) thromboxane A2/prostaglandin H2 receptor blockade with thromboxane receptor blocker BM13505 (2 mg/kg i.v.) (n = 5), and 3) combined thromboxane and leukotriene receptor blockade (n = 5). In the absence of receptor blockade, intracoronary C5a decreased coronary flow (50-60%) and regional segment function (60-70%) compared with the preinfusion levels. This was accompanied by a fall in coronary venous blood leukocyte levels by 5-6 x 10(6) cells/ml in the absence of alterations in arterial blood leukocyte count. Intracoronary injections of LTD4, LTC4, or U46619 also resulted in prompt decreases in coronary blood flow (50-60%) and segment function (70-80%) from preinfusion levels. Leukotriene receptor blockade with LY171883 abolished these responses to LTD4 and LTC4. Administration of LY171883 also attenuated (p less than 0.05) the myocardial response to C5a; coronary flow and segment function decreased by approximately 28% from preinfusion levels. Thromboxane receptor blockade with BM13505 eliminated the response in coronary flow and segment function to intracoronary U46619. Similar to LY171883, administration of BM13505 blunted (p less than 0.05) the C5a-induced decreases in coronary flow and contractile function, which fell by approximately 20-25% from the preinfusion level. After the combined LTD4/LTE4 receptor and thromboxane A2/prostaglandin H2 receptor blockade, intracoronary C5a resulted in little change in both coronary blood flow and segment shortening. In contrast to the flow and function effects, the C5a-induced myocardial leukocyte extraction was not decreased by leukotriene and/or thromboxane receptor blockade.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Perspectives of leukocyte activation in the microcirculation.

Recent evidence for a role of granulocytes in ischemic organ injury and in hemorrhagic shock is provided. Compared to red cell, granulocytes are large cells and have a stiff cytoplasm, making them prone to entrapment in the microcirculation. After activation, granulocytes become adhesive, they can elaborate superoxide radicals and release proteolytic enzymes. In the circulation a subgroup of granulocytes are in a spontaneously activated state. If during shock such cells become trapped in the microcirculation they impose a risk for organ injury. In a short term shock protocol, the group of surviving and non-surviving animals can be sharply distinguished by the number of activated granulocytes before shock. Experimental forms of granulocyte activation in the coronary circulation cause temporary trapping of cells, an increase in vascular resistance, and a transient reduction of muscle contraction even in the presence of a normal perfusion pressure. Detection of spontaneous granulocyte activation requires the development of new tests which can be carried out on fresh unseparated blood samples. We provide here also a critical evaluation of experimental neutropenia as a test for granulocyte related hypotheses.

Animals↗
PubMed1990

Effects of leukocyte activation on myocardial vascular resistance.

The contribution of the leukocyte, particularly the granulocyte, to the tissue injury resulting from the inflammatory response accompanying organ ischemia is a subject of intense, current interest. Leukocytes are large and viscous cells which adhere to vascular endothelium, and are a source of a variety of toxic and vasoactive substances. There are several lines of evidence indicating their involvement in the development of abnormal and heterogeneous tissue perfusion in a wide variety of pathologic states. They have been implicated in the capillary stasis and no-reflow following hemorrhagic shock, and in ischemia and reperfusion of skeletal muscle, brain, and heart. The mechanisms responsible for the detrimental influence of the granulocyte on tissue perfusion include their inherent rheologic properties, their role in the generation of vascular smooth muscle-constricting substances, and their potential for damaging vascular endothelium. One contributing aspect of the inflammatory response is leukocyte activation by products of the complement cascade. In our in vivo model system, stimulation of the granulocyte with activated complement C5a (intracoronary) is associated with myocardial ischemia and a transient myocardial accumulation of granulocytes. The enhanced generation of thromboxane A2 and leukotrienes appears to be primarily responsible for this increase in coronary vascular resistance.

Animals↗
PubMed1989

Free radical and granulocyte-mediated injury during myocardial ischemia and reperfusion.

The success of thrombolytic/reperfusion therapy in limiting the extent of myocardial infarction may be limited by reperfusion injury. Damage from acute ischemia is not due solely to the interruption of blood flow; rather, ischemia initiates a cascade of reactions involving partially reduced oxygen, inflammatory mediators, mechanical capillary obstruction by granulocytes and other events that lead to irreversible injury. A surprising consequence is that reperfusion by delivering oxygen and granulocytes may counteract some of the benefits of restoring flow. Mechanisms of neutrophil and free radical injury include superoxide radical formation and lipid peroxidation, progressive leukocyte capillary plugging and capillary no-reflow, and edema. The interaction of various specific mechanisms of injury in the heart (i.e., xanthine oxidase, mitochondrial superoxide leak, neutrophil superoxide, degranulation and capillary plugging, and neutrophil-derived vasoconstrictors) deserves further study.

Animals↗
PubMed1989

Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes, and injury.

Morbidity and mortality from acute coronary artery occlusion may be reduced if local myocardial adenosine concentration is augmented because 1) coronary collateral blood flow during ischemia increases with adenosine infusion, and 2) granulocytes that accumulate in the microcirculation during ischemia are, to a large extent, inhibited by adenosine from generating superoxide anion free radicals, from adhering to vascular endothelium, and from damaging endothelial cells in culture. Using a cultured lymphoblast model system, we found that 5-amino-4-imidazole carboxamide (AICA) riboside enhanced adenosine accumulation during ATP catabolism. Therefore, AICA riboside pretreatment was used in canine myocardium to selectively increase adenosine concentration in the ischemic area during 1 hour of ischemia. At 5 minutes of ischemia, endocardial flow to ischemic myocardium in saline-treated and AICA riboside-treated dogs was 0.06 +/- 0.03 and 0.34 +/- 0.11 ml/min/g, respectively (p less than 0.01); flow to nonischemic myocardium was not affected. Ventricular tachycardia and premature ventricular depolarizations were significantly attenuated in the AICA riboside-treated dogs. Blood pressure and heart rate were not affected by AICA riboside. In venous blood from ischemic tissue, adenosine increased from undetectable levels (less than 0.01 microM) to 0.22 +/- 0.08 microM in saline and 1.79 +/- 0.06 microM in AICA riboside-treated dogs, respectively (p less than 0.001). Coronary vein inosine concentrations were greater in saline than in AICA riboside-treated dogs. In separate in vitro studies, AICA riboside did not alter the removal rate of adenosine from canine blood. Indium-labeled granulocyte accumulation was significantly less in ischemic myocardium in AICA riboside-treated compared with saline-treated dogs. In addition, adenosine, but not AICA riboside, inhibited in vitro canine granulocyte superoxide production. We conclude that AICA riboside given before myocardial ischemia augments adenosine concentration, decreases arrhythmias, decreases granulocyte accumulation, and improves collateral flow to ischemic myocardium. One of the beneficial mechanisms could be an increased production of adenosine rather than inosine from ATP catabolism that causes vasodilation and inhibition of granulocytes. We propose a new hypothesis regarding regulation of the inflammatory reaction to ischemia in the microcirculation. Adenosine, in addition to its vasodilator action, is an anti-injury autacoid that links ATP catabolism to inhibition of granulocyte adherence, microvascular obstruction, and superoxide anion formation.

Adenosine↗
PubMed1989

Thromboxane is produced in response to intracoronary infusions of complement C5a in pigs. Cyclooxygenase blockade does not reduce the myocardial ischemia and leukocyte accumulation.

Activated polymorphonuclear leukocytes (PMNs) contribute to myocardial injury during ischemia and reperfusion. There is evidence that activation of the complement pathway may be one of the mechanisms of PMN activation during ischemia. Intracoronary infusion of complement C5a during normal perfusion pressure is associated with decreased coronary flow, contractile dysfunction, and PMN accumulation. The mechanisms responsible for these changes have not been identified. Thromboxane A2 (TXA2) is a potential mediator of this myocardial ischemic response. Activated PMNs produce TXA2, a known coronary vasoconstrictor, and TXA2 was shown to be a mediator of the pulmonary hypertensive response to activated complement. The goal of the present study was to determine if an enhanced TXA2 production is associated with the myocardial response to C5a and whether cyclooxygenase blockade would reduce the myocardial ischemia. In open-chest pigs, intracoronary C5a (500 ng) caused reversible reductions in blood flow (50.0% of control), regional contractile function (25.8% of control), leukocyte trapping (1.0 x 10(6) cells/g myocardium or a peak artery-coronary venous difference of 5.3 x 10(3) cells/microliters blood), and increased coronary venous TXB2 (the TXA2 breakdown product) from 1.6 pmol/ml to a peak of 6.9 pmol/ml. Cyclooxygenase blockade with aspirin or indomethacin, which prevented TXB2 production, did not alter the response in flow, function, or PMN trapping. Ibuprofen, a known direct inhibitor of PMNs in addition to its cyclooxygenase blockade effect, reduced the response slightly. The pig coronary vascular bed was responsive to the TXA2 agonist U46619, which reduced flow and function without PMN trapping. Mechanical reductions in coronary flow to levels equivalent to those during the C5a infusions did not increase coronary venous TXB2 nor cause PMN trapping but did cause equivalent contractile dysfunction. Incubation of whole blood with C5a at concentrations equivalent to those achieved in vivo did not cause TXB2 production. We conclude that 1) TXA2 is produced in response to intracoronary C5a and 2) cyclooxygenase blockade does not prevent the C5a-induced myocardial ischemia, contractile dysfunction, and PMN trapping. The TXA2 production likely involves a vascular site or a blood cell-vascular interaction. This model system indicates the potential for persistently activated PMNs to cause continued ischemia during myocardial reperfusion.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

Granulocytes and no-reflow phenomenon in irreversible hemorrhagic shock.

Recent evidence shows that circulating granulocytes play an important role in capillary stasis and tissue injury. We investigated two aspects of the problem in a Wiggers hemorrhagic shock model of the rat: the survival rate and the microvascular no-reflow phenomenon. A conventional group of rats with normal blood cells and a neutropenic group of rats pretreated with intraperitoneal antigranulocyte antibody were used to evaluate the effects of granulocytes. Two hemorrhagic shock protocols (HSP) were carried out. In HSP-1, the rats were subjected to 40 mm Hg mean arterial pressure for 3 hours. The conventional group (n = 11) showed a 36% survival rate compared with 100% in the neutropenic group (n = 6). In HSP-2, the hypotension was more severe, 30 mm Hg mean arterial pressure for 7 hours. There were no survivors in the conventional group (n = 8), compared with a 100% survival rate in the neutropenic group (n = 6). The extent, location, and mechanism of the no-reflow phenomenon was investigated by examining histological sections from several organs after infusion of a contrast medium to mark vessels with flow in a control group without shock and in the HSP-2 model 2 hours after blood replacement. The arterioles and venules uniformly contained contrast medium in all three groups; only capillaries showed no-reflow. A significantly higher percentage of no-reflow was observed in the capillaries of the conventional shock group than in the neutropenic shock group. We concluded that the obstruction of capillaries was largely due to trapped granulocytes, suggesting that these leukocytes play a key role in the capillary no-reflow phenomenon and survival from hemorrhagic shock.

Animals↗
PubMed1988

C5a decreases regional coronary blood flow and myocardial function in pigs: implications for a granulocyte mechanism.

Granulocytes cause some of the pathophysiological effects associated with the capillary no-reflow phenomenon during ischemia and in ischemia-reperfusion injury. However, no study has examined the consequences of in vivo granulocyte activation during normal perfusion pressures. In this study, we examined the effects of intracoronary administration of the complement component C5a, which is known to be a potent granulocyte activating factor. Nine open-chest, anesthetized pigs were instrumented to monitor regional coronary blood flow and segment shortening, left ventricular dP/dt, heart rate, and pulmonary artery and aortic blood pressures and to sample arterial and regional coronary venous blood for oxygen content and complete blood counts. Intracoronary infusion of human or porcine C5a in doses ranging from 10 to 500 ng produced a significant reduction in regional coronary blood flow and myocardial function. Although perfusion pressure and heart rate remained constant, venous oxygen content fell, indicating an imbalance between myocardial oxygen supply and demand. In addition, the arteriovenous difference of white blood cells was increased significantly after anaphylatoxin infusion, indicating intravascular trapping in the myocardium. Granulocytes accounted entirely for the differences in leukocyte counts because no significant changes in platelet, lymphocyte, or hematocrit levels were observed. Injection of vehicle alone did not alter any of the monitored variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Misrepresentation and responsibility in medical research.

Early in 1985, after being questioned about duplicate data in two of his papers, Robert A. Slutsky, M.D., resigned his appointments as a radiology resident (trainee) and nonsalaried associate clinical professor in the Department of Radiology at the University of California, San Diego. During the following year, faculty committees investigated Slutsky's entire bibliography of 137 articles published in seven years; 77 (including reviews) were classified as valid, 48 were judged questionable, and 12 were deemed fraudulent. The majority of these papers were published while Slutsky was a research or clinical trainee in cardiology, nuclear medicine, and then radiology. Our analysis of this case leads us to conclude that research fraud, although probably rare, in view of the size of the research establishment, may evade detection, and that there are scientists prepared to run the appreciable risk of submitting inaccurate statements for publication. Sophisticated dishonesty can escape detection by peer review and replication. The emphasis on competition and the pressure to produce, while intended to advance the discovery of truth, may foster a conflict between personal career goals and the intellectual motivation of scientists to seek the truth. The scientific community needs to address the issues raised by recent reports of fraud. Each institution and granting agency must have procedures for investigating suspected fraud or unethical practices, procedures that protect both the person who reports such practices and the accused person from premature disclosure. As we heighten awareness, we must avoid a "witch hunt." Deterrence of research fraud is clearly needed, but institution of practices that might stifle originality or discourage cooperative research would be counterproductive.

Authorship↗
PubMed1987

Effects of AQA-39 on granulocytes in the microcirculation of rat mesentery.

Recent evidence suggests that granulocytes play a key role in perfusion of the microcirculation. In this regard two phenomena are of specific importance: pseudopod formation and adhesion to the endothelium. Thus we studied the influence of AQA-39 on leukocyte adhesion to the endothelium in rat mesentery venules and on pseudopod formation in human granulocytes. Direct intravital estimates of granulocyte fracture stress were obtained by measurement of the ratio of leukocyte and midstream velocity. The marginating and circulating cell flux and the areal density of stationary granulocytes on the intraluminal side of the endothelium were measured simultaneously in the same venular segments. During administration of 10 mg kg-1 AQA-39 the fracture stress is significantly reduced resulting in decreased areal density of marginating cells and also washout of strongly adhering stationary leukocytes found frequently on the endothelium of such vessels. Furthermore it was observed on single granulocytes that AQA-39 leads to transient obliteration of pseudopod formation. These results suggest that the effect of AQA-39 on flow may be mediated in part by reduction in granulocyte adhesion to the endothelium and suppression of pseudopod formation.

Animals↗