W R Law

University of the Sciences in Philadelphia, Philadelphia, PA, United States

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Publications (78)260.59 Total impact

  • William R Law, Beth A Conlon, James D Ross
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    ABSTRACT: The total cardiac purine metabolome includes all of the adenine and guanine nucleoside and nucleosides and related molecules involved throughout the intracellular and extracellular compartments and various cell types in the heart. In considering purines as molecules involved in autocrine and paracrine communication, effective interstitial concentrations of the nucleoside adenosine, or purine metabolites, are of greatest interest. These molecules arise from the complex interactions between cardiac-specific cell types, including fibroblasts and myocytes, and noncardiac cells, such as tissue-resident macrophages and other immune cells that have vascular access. In the interstitial environment, adenosine can regulate vascular resistance, contractile function, and immunochemical interactions. The breakdown of purines can produce reactive oxygen species that also influence autocrine and paracrine interactions. A central enzyme in this paradigm, adenosine deaminase, is a pivotal molecule in regulating the balance between pro-inflammatory and anti-inflammatory signaling cascades. A new role for adenosine deaminase as an allosteric regulator of relevant membrane proteins has yet to be explored in the heart.
    Shock 10/2007; 28(3):259-64. · 2.61 Impact Factor
  • William R Law
    AJP Regulatory Integrative and Comparative Physiology 11/2006; 291(4):R957-8. · 3.28 Impact Factor
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    ABSTRACT: Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone. After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 microm bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4 degrees C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured. All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate-pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline. Adding bupivacaine to a depolarizing cardioplegia solution reduces cell damage and improves cardiac function after prolonged storage. Metabolic inhibition may contribute to this phenomenon, which is not entirely explained by sodium channel blockade.
    Anesthesiology 10/2006; 105(4):746-52. · 5.16 Impact Factor
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    ABSTRACT: Background: Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone.
    Anesthesiology 09/2006; 105(4):746-752. · 5.16 Impact Factor
  • William R Law
    Cardiovascular Research 08/2006; 71(1):8-9. · 5.81 Impact Factor
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    Beth A Conlon, James D Ross, William R Law
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    ABSTRACT: Adenosine is a ubiquitous molecule that influences every physiological system studied thus far. In this review, we consider the influence of this purine nucleoside on some of the physiological systems affected during sepsis and SIRS. In the control of perfusion and cardiac output distribution, endogenous adenosine appears to play an important role in regulating perfusion in various vascular beds. Some of this control is mediated by stimulation of adenylyl cyclase, while part occurs by stimulating the production of nitric oxide. In the heart, adenosine may act as an inhibitory modulator of TNF-alpha expression. With regard to innate immune responses the effects of adenosine vary considerably, and are complex. However, the dominant responses relevant to SIRS indicate attenuation of inflammatory responses. Many of the effects of adenosine may also involve modulating oxyradical-mediated response. This occurs via increased oxyradical production via adenosine degradation (xanthine oxidase pathway), or limiting inflammatory oxyradical generation. Attempts to exploit the beneficial responses to adenosine have met with some success, and are considered here.
    Frontiers in Bioscience 02/2005; 10:2548-65. · 3.29 Impact Factor
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    William R Law, James D Ross, Zivojin S Jonjev
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    ABSTRACT: Specific site proteolysis and loss of troponin I (TnI) during myocardial ischemic events can contribute to myocardial dysfunction. Adenosine supplementation of cardioplegic solutions results in improved functional preservation of the heart. We investigated the effect of adenosine on N-terminal and C-terminal proteolysis of TnI in the heart. Hearts from male Sprague-Dawley rats were isolated and perfused at a constant pressure. Cardioplegic arrest (St. Thomas #2 +/- 100 microm adenosine) was induced and hearts frozen at various times during the arrest. Antibodies directed against specific regions of TnI were used to visualize TnI in whole heart homogentates, as well as from cellular fractions, using western blot analysis. Cardioplegic arrest alone resulted in early N-terminal proteolysis of TnI, followed by later loss of sequences from the C-terminal end of the molecule. In addition, secondary protein bands that were immunoreactive to amino acid sequences centrally located on the TnI molecule were observed. There was also evidence of dissociation of TnI from the other myofibrillar proteins. The supplementation of cardioplegic solution with adenosine significantly attenuated the late C-terminal proteolytic degradation of TnI and its apparent dissociation from myofibrils proteins but had no effect on the early N-terminal proteolysis associated with cardioplegic arrest. These data may provide an explanation for partial protection against postarrest myocardial dysfunction provided by adenosine.
    Journal of Surgical Research 02/2005; 123(1):126-33. · 2.02 Impact Factor
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    B A Conlon, W R Law
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    ABSTRACT: Serum activity of the adenosine deaminase (ADA) isozyme, ADA2, has been reported to be elevated during various disease states. Macrophages have been suggested as the cellular source of extracellular ADA activity because they are one of the only cell types in which intracellular ADA2 activity has been measured, but extracellular secretion has never been demonstrated. Rat primary peritoneal macrophages (PPMs) and peripheral blood monocytes (PBMs) were harvested and incubated for 18 h in RPMI supplemented with horse serum. PPM and PBM lysates were assayed for intracellular ADA activity (ammonia production). In vitro and in vivo extracellular ADA activities were measured in media and rat serum, respectively. Activity of ADA1 was confirmed by selective inhibition with erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA). ADA2 activity was inhibited by 2'-deoxycoformcin only, and was increased at a low pH (6.5). Activity of both ADA isozymes was found in PPMs and PBMs, and their media. In a separate group of rats, peritonitis was induced by ip insertion of 400 mg/kg caecal slurry. PPMs were harvested 24 h later and incubated for 18 h. In PPMs from rats with peritonitis both isozymes were elevated by a similar proportion. In contrast, media from these PPMs had a lower ADA1 and a higher ADA2 activity compared to PPMs from nonseptic rats. This resulted in a greater proportion of ADA2 in media. The isozyme proportions in serum from septic rats more closely resembled that of the PPM media. The response of PBM was small relative to that of PPM. These results suggest that macrophages are a significant source of extracellular ADA isozymes, the activity of which increases during an inflammatory response. Because extracellular isozymes profiles differ from cellular concentrations, the data also suggest differential release of each isozyme from PPMs.
    Clinical & Experimental Immunology 11/2004; 138(1):14-20. · 3.41 Impact Factor
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    ABSTRACT: On the basis of the hypothesis that cardioplegia-associated myocardial depression was due to activation of protein kinase C, we examined whether specific protein kinase C isozymes would translocate to a cellular fraction containing myofilaments. Isolated rat hearts were perfused with Krebs-Ringer bicarbonate buffer for 30 minutes and arrested with 4 degrees C St Thomas No. 2 cardioplegic solution for 0 to 120 minutes (n = 5 per group). The 3 fractions of the left ventricle tissue represented the myofibrillar/nuclear fraction (P1), membranes (P2), and cytosol (supernatant). The distributions of protein kinase C isozymes alpha, delta, epsilon, and eta were examined after separation by electrophoresis, immunoblotting/chemiluminescence, and densitometry. A significant increase in protein kinase C-delta in the P1 fraction was detected after 5 minutes of cardioplegic arrest and remained increased for 60 minutes. Increases in P1 protein kinase C-alpha and -epsilon were seen transiently at 5 minutes, and protein kinase C-epsilon demonstrated a secondary increase in P1 at 30 to 60 minutes. There was also a significant relative increase in protein kinase C-alpha and protein kinase C-delta in the P2 fraction after 60 minutes of cardioplegia. These data are consistent with our hypothesis that activation of protein kinase C isozymes is associated with altered myofilament function after cardioplegic arrest.
    Journal of Thoracic and Cardiovascular Surgery 01/2004; 126(6):1880-5. · 3.53 Impact Factor
  • William R Law, Victor E Valli, Beth A Conlon
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    ABSTRACT: We sought to determine the potential usefulness of 2'-deoxycoformycin (pentostatin), an inhibitor of adenosine deaminase, as a postinsult, or prophylactic treatment for systemic inflammatory response syndrome resulting from fecal peritonitis. Prospective, randomized, controlled experiment. Small animal basic science laboratory. Male Spague-Dawley rats, weighing 300 to 350 g. Rats with fecal peritonitis (intraperitoneal cecal slurry) were treated with 1 mg/kg pentostatin intraperitoneally 24 hrs before, or intravenously when signs of illness presented (2 hrs after induction of peritonitis). Signs of illness included tachycardia, tachypnea, and leukopenia. All rats received 50 mL/kg 0.9% saline resuscitative fluid at 2 hrs. Survival to day 6 was 100% in nonseptic sham rats, but 33% in untreated septic rats. In rats given pentostatin either 2 hrs after the insult, or 24 hrs before the insult, 6-day survival improved to 81% and 78%, respectively. Histology revealed diffuse peritonitis, and evidence of systemic inflammatory response syndrome, including local and distant site vascular damage and leukocyte activation. These responses to the septic challenge were abrogated by pentostatin treatment. Return of significant amount of tissue adenosine deaminase activity by 24 hrs and later recovery of white blood cell counts argue against any potential for inappropriate immunosuppression by pentostatin. These data indicate that the novel use of pentostatin to prevent systemic inflammatory response syndrome secondary to fecal peritonitis shows uncommon promise as a therapeutic tool. All indices of systemic inflammatory response syndrome were abrogated and survival improved when pentostatin was not given until after signs of the illness became manifest. Because protection was afforded with treatment 24 hrs in advance of the inciting insult, pentostatin also has the unique potential for use as a true prophylactic agent.
    Critical Care Medicine 06/2003; 31(5):1475-81. · 6.12 Impact Factor
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    ABSTRACT: The ability of increased endogenous adenosine to mitigate microvascular derangements in sepsis was studied. Pentostatin (2'-deoxycoformycin), an inhibitor of adenosine deaminase, was administered to mice immediately after induction of sepsis by cecal ligation and puncture. Intravital video microscopy of cremasteric postcapillary venules was performed. Leukocyte rolling and adhesion were significantly increased in septic mice compared with control mice. Treatment of septic mice with pentostatin significantly decreased leukocyte rolling and adhesion (6.02 +/- 0.09 versus 1.72 +/- 0.12 rolling cells/min, 2.07 +/- 0.04 versus 0.62 +/- 0.05 adherent cells/100 microm per minute; p < 0.001). Albumin leakage (ratio) was significantly attenuated in septic animals treated with pentostatin (0.42 +/- 0.05 versus 0.21 +/- 0.04; p < 0.01). Circulating levels of interleukin-6, tumor necrosis factor-alpha, and soluble tumor necrosis factor type II receptor were decreased in septic mice treated with pentostatin. Survival was significantly improved at 48 hours in mice treated with pentostatin. These results suggest an important role for adenosine in modulating both leukocyte-dependent and -independent mechanisms of endothelial injury in sepsis. Exploiting the advantageous action of endogenous adenosine represents a potentially useful and novel therapeutic approach for the treatment of sepsis.
    American Journal of Respiratory and Critical Care Medicine 07/2002; 166(1):16-20. · 11.04 Impact Factor
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    ABSTRACT: By pharmacological manipulation of endogenous adenosine, using chemically distinct methods, we tested the hypothesis that endogenous adenosine tempers proinflammatory cytokine responses and oxyradical-mediated tissue damage during endotoxemia and sepsis. Rats were pretreated with varying doses of pentostatin (PNT; adenosine deaminase inhibitor) or 8-sulfophenyltheophylline (8-SPT; adenosine receptor antagonist) and then received either E. coli endotoxin (lipopolysaccharide; 0.01 or 2.0 mg/kg) or a slurry of cecal matter in 5% dextrose in water (200 mg/kg). Resultant levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 were measured in serum and in liver and spleen. Untreated, 2 mg/kg lipopolysaccharide elevated serum TNF-alpha, IL-1beta, and IL-10. PNT dose dependently attenuated, without ablating, the elevation in serum TNF-alpha and IL-1beta and raised liver and spleen IL-10. PNT also attenuated elevation of TNF-alpha in serum, liver, and spleen at 4 and 24 h after sepsis induction, and 8-SPT resulted in higher proinflammatory cytokines. Modulating endogenous adenosine was also effective in exacerbated (8-SPT) or diminished (PNT) tissue peroxidation. Survival from sepsis was also improved when PNT was used as a posttreatment. These data indicate that endogenous adenosine is an important modulatory component of systemic inflammatory response syndromes. These data also indicate that inhibition of adenosine deaminase may be a novel and viable therapeutic approach to managing the systemic inflammatory response syndrome without ablating important physiological functions.
    AJP Regulatory Integrative and Comparative Physiology 06/2002; 282(5):R1324-32. · 3.28 Impact Factor
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    Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2002; 39:277-277.
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    ABSTRACT: We tested the hypothesis that some of the maintenance of resting, regional hepato-splanchnic perfusion that is mediated by endogenous adenosine (ADO) during sepsis is interdependent with nitric oxide (NO). Twenty-four hours after sepsis/sham induction, rats were divided into two groups. Group 1 received a 10-min infusion of the ADO antagonist 8-sulfophenyltheophylline (8-SPT; 0.9 mg/kg x min), followed by 10 min of 8-SPT plus L-NAME (0.5 mg/kg x min). Group 2 received L-NAME first followed by 8-SPT in the presence of L-NAME (all groups: n = 6-10). Hemodynamic and regional hepato-splanchnic blood flow measurements were made prior to infusions, 10 min after initiation of each single agent infusion, and again after double agent infusion. Twenty-four hours after sepsis hepato-splanchnic blood flow was significantly elevated, compared to nonseptic rats. Both ADO receptor blockade alone and NOS inhibition alone decreased total hepato-splanchnic blood flow to nonseptic values. Decreases in small intestinal and cecal blood flow accounted for the majority of this decrease, but decreased hepatic arterial perfusion contributed as well. No further alterations were seen when 8-SPT was infused in the presence of L-NAME, nor when L-NAME was infused in the presence of 8-SPT. These data indicate that there is significant interdependence of endogenous NO and ADO in maintaining resting small bowel, cecal, and hepatic arterial perfusion during sepsis. The lack of responses in other regions of the hepato-splanchnic circulation demonstrate regional specificity of this ADO-NO interdependence.
    Journal of Surgical Research 12/2000; 94(1):61-7. · 2.02 Impact Factor
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    ABSTRACT: Opioid receptor antagonists can act centrally and peripherally. It is unclear if these 2 pathways differentially mediate the perfusion-associated effects of opioid antagonism during endotoxemia. Male, Sprague-Dawley rats (340-390 g) were surgically prepared with left ventricular, tail artery, and jugular vein catheters 24 h before experiments were begun. Conscious, unrestrained rats were challenged with Escherichia coli lipopolysaccharide (LPS; 2 mg/kg/hr over 30 min) infusion. Measurements of regional blood flows were made using radioactive microspheres prior to (baseline), and at 60 and 120 min after LPS infusion. Saline (1 mL/kg bolus + 0.5 mL/kg/h infusion), naloxone (Nlx; 4 mg/kg bolus + 2 mg/kg/h infusion), or naloxone methyl bromide (Nlx-mb; 4.64 mg/kg, bolus + 2.32 mg/kg/h infusion) were administered 40 min after LPS infusion was begun. Nlx-mb does not cross the blood-brain barrier, and was thus used to differentiate central from peripherally mediated responses. At the end of each experiment, blood samples were collected for determination of ET-1 and nitric oxide metabolites (NOx = NO3 + NO2) using enzyme-linked immunosorbent assay (ELISA) and Griess reaction methods, respectively. Endotoxemia produced a significant decrease in cardiac output and an increase in systemic vascular resistance. Treatment with Nlx or Nlx-mb significantly attenuated the endotoxin-induced elevation in systemic vascular resistance and the decrease in cardiac output at 60 min after induction of endotoxemia compared with their respective baseline values. Nlx and Nlx-mb also attenuated the endotoxin-induced increases in hepatic portal and skeletal vascular resistances. These observations suggested that the ameliorative effect of Nlx on endotoxemia-induced regional vascular resistance alterations was mediated via peripheral opioid receptor mechanisms. However, although Nlx attenuated the endotoxin-induced decreases in the blood flow to the stomach and pancreas, Nlx-mb attenuated the endotoxin-induced decreases in the blood flow to the small intestine and cecum, in addition to the pancreas and, to some extent, the stomach. As such, separate central and peripherally mediated actions of opioid receptor antagonism were indicated. Nlx also resulted in an increase in the plasma levels of ET-1 only, whereas Nlx-mb increased the plasma levels of ET-1 and NOx. These observations suggest that separate central and peripheral effects of opioids during endotoxemia play a role in the associated circulatory alterations, and may differentially affect the release and/or synthesis of vasoactive mediators that might be related to their varied hepatosplanchnic vascular response during endotoxemia.
    Shock 11/2000; 14(4):441-6. · 2.61 Impact Factor
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    ABSTRACT: Adenosine receptor blockade increases regional resting vascular resistance during sepsis. In healthy subjects, part of adenosine's actions are mediated via stimulation of nitric oxide synthase. Because nitric oxide synthase activity is thought to be a major contributor to altered vascular tone in sepsis, we tested the hypothesis that some of the nitric oxide-mediated resting regional resistance during sepsis is secondary to endogenous adenosine stimulation of nitric oxide synthase. Prospective, randomized, controlled experiment. Shock-trauma and basic science laboratory. Male Sprague-Dawley rats. Twenty-four hours after sepsis or sham induction, rats were separated into two groups (n = 6 to 10 in each group). Group 1 received a 10-min infusion of the adenosine antagonist 8-sulfophenyltheophylline (0.9 mg/kg x min) followed by a 10-min infusion of L-nitro-arginine-methyl ester (0.5 mg/kg x min). Group 2 similarly received L-nitro-arginine-methyl ester followed by 8-sulfophenyltheophylline in the presence of L-nitro-arginine-methyl ester. Hemodynamic and blood flow measurements (microspheres) were made before infusions, 10 mins after the administration of each single-agent infusion, and 10 mins after combined-agent infusions were administered. No significant resistance alterations were observed in nonseptic rats. In septic rats, adenosine receptor blockade alone increased hepatosplanchnic and skeletal muscle vascular resistance, but no further increases were seen when L-nitro-arginine-methyl ester was added. Nitric oxide synthase inhibition alone increased hepatosplanchnic and skeletal muscle vascular resistances. When 8-sulfophenyltheophylline was added to the infusion, skeletal muscle vascular resistance increased significantly more than with L-nitro-arginine-methyl ester alone, but there were no further increases in hepatosplanchnic resistance. Renal and adipose vascular resistances increased with L-nitro-arginine-methyl ester infusions, and 8-sulfophenyltheophylline produced no effect. During sepsis, nitric oxide caused resting vasodilation independent of adenosine in the renal and adipose vasculature. In the hepatosplanchnic circulation, there is reciprocal adenosine-nitric oxide interaction in maintaining resting regional resistance. Skeletal muscle displayed a dual adenosine-mediated (nitric oxide-independent) and nitric oxide-mediated (adenosine receptors required) interaction to regulate resting resistance during sepsis. These data indicate that in the hepatosplanchnic and skeletal muscle vasculature, all of the resting nitric oxide-mediated vasodilation is secondary to endogenous adenosine action, but in adipose and renal vasculature, resting nitric oxide mediated vasodilation is independent of adenosine. Endogenous adenosine also appears to play a significant role in determining resting skeletal muscle resistance that is independent of nitric oxide synthase during sepsis.
    Critical Care Medicine 07/2000; 28(6):1931-9. · 6.12 Impact Factor
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    ABSTRACT: Adenosine-supplemented cardioplegia improves myocardial function after cardioplegic arrest. However, the underlying cellular mechanism(s) responsible for adenosine's protective actions remains unclear. We tested the hypothesis that protection by adenosine-supplemented cardioplegia would be associated with selective activation of protein kinase C (PKC) isozymes delta and epsilon. Isolated rat hearts were perfused (37 degrees C, Krebs-Ringer bicarbonate buffer) for 30 min, after which baseline functional measurements were made. This was followed by 120 min of cold cardioplegic arrest at 4 degrees C with either St. Thomas No. 2 (ST#2), ST#2 + adenosine (100 microM, ADO) or ST#2 + ADO + 8-sulfophenyltheophylline (50 microM, SPT). Hearts were reperfused for 60 min and functional measurements made. Distribution of PKC isoforms was determined (immunoblotting) after 30 min of warm perfusion (No-CDPL) or after 30 min of perfusion followed by 15 min of cardioplegic arrest. ADO prevented myocardial dysfunction after cardioplegic arrest. PKC-delta did not differ in the cytosolic fraction among groups. However, ADO prevented increases in particulate fraction PKC-delta, but elicited a significant increase in the particulate fraction PKC-epsilon, while ST#2 or SPT significantly decreased the cytosolic fraction PKC-epsilon. Both functional and cellular changes associated with ADO were receptor mediated. This novel, dual action of adenosine-supplemented cardioplegia on PKC isoforms may be responsible for the associated functional improvements.
    Journal of Surgical Research 05/2000; 89(2):163-8. · 2.02 Impact Factor
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    ABSTRACT: Adenosine supplementation of cardioplegic solutions in cardiac operations improves postarrest myocardial recovery after cardioplegic arrest and reperfusion; however, the mechanism of the action of adenosine remains unknown. We tested the hypotheses that adenosine-supplemented cardioplegic solution improves myofibrillar protein cooperative interaction and increases myocardial anaerobic glycolysis. The hearts of male Sprague-Dawley rats were randomized to undergo 120 minutes of cardioplegic arrest with 1 of 3 cardioplegic solutions: (1) St Thomas' Hospital No. 2 cardioplegic solution (St Thomas group), (2) St Thomas' Hospital No. 2 cardioplegic solution plus adenosine (100 micromol/L) (adenosine group), and (3) St Thomas' Hospital No. 2 cardioplegic solution plus adenosine (100 micromol/L) plus the nonspecific adenosine receptor antagonist 8-p -sulfophenyltheophylline (50 micromol/L) (sulfophenyltheophylline group). A fourth group of hearts underwent no cardioplegic arrest. Systolic and diastolic functional recovery was improved in the adenosine group compared with that in the other two groups, independent of coronary flow. Adenosine supplementation of cardioplegic solution prevented the decrease in myofibrillar protein cooperative interaction seen after cardioplegic arrest and reperfusion (St Thomas and sulfophenyltheophylline groups). Adenosine-supplemented cardioplegic solution also caused significantly increased anaerobic glycolysis during cardioplegic arrest. These responses were blocked in the sulfophenyltheophylline group. The changes in myocardial glycolytic activity and myofilament cooperativity coincided with functional recovery in the three cardioplegia groups and may represent mechanisms underlying protection with adenosine-supplemented cardioplegic solution.
    Journal of Thoracic and Cardiovascular Surgery 04/2000; 119(3):601-9. · 3.53 Impact Factor
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    ABSTRACT: After coronary artery bypass grafting procedures, a higher incidence of morbidity and mortality has been reported in diabetic patients. We tested whether coronary artery bypass grafting in diabetics affects the endothelin-1 and nitric oxide coronary effluent profile during reperfusion. Twenty-one consecutive patients (9 with type II diabetes mellitus, 12 non-diabetics) underwent coronary artery bypass grafting by one surgeon. The two groups did not differ in preoperative ejection fraction, Parsonnet score, number of vessels bypassed, or cross-clamp time. Each patient was treated in the same intraoperative manner with single atrial, aortic, and antegrade and retrograde cardioplegia (CPL) cannulas. Cold CPL arrest was by antegrade and retrograde infusion of modified Buckberg CPL solution. Warm CPL solution was infused before reperfusion. Coronary sinus blood samples were obtained for estimation of endothelin-1 and nitrite plus nitrate before CPL arrest and at 1 and 15 minutes after each of 2 reperfusion periods. In diabetics, endothelin-1 was significantly increased at all reperfusion times as compared with non-diabetics. Nitrite plus nitrate levels were significantly higher in patients with diabetes than in those without, but did not change with time in either of the groups. Reperfusion after CPL during coronary artery bypass grafting procedure can trigger the release of endothelin-1 in patients with diabetes mellitus. This may favor increased vascular tone or positive inotropic responses after coronary artery bypass grafting and may contribute to significant cardiovascular consequences in diabetic patients.
    The Annals of Thoracic Surgery 07/1999; 67(6):1659-63. · 3.45 Impact Factor
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    ABSTRACT: Endothelin-1 (ET-1) has been shown to be a potent agonist for monocyte production of the neutrophil chemotactic cytokine interleukin-8 (IL-8). We have shown that diabetic patients demonstrate elevated coronary ET-1 after coronary artery bypass grafting (CABG). We hypothesized that these same diabetic patients would manifest elevated coronary IL-8 and conjugated diene concentrations (an index of reperfusion injury). Sixteen patients [9 nondiabetics and 7 type II diabetics] underwent nonemergent CABG. The two groups did not differ significantly in preoperative ejection fraction, number of vessels bypassed, or cross-clamp time. Coronary sinus samples were obtained prior to cardioplegic arrest (baseline) and at 1 and 15 min after reperfusion periods A and B (A, reperfusion of native coronaries + LIMA; B, reperfusion of saphenous vein grafts in addition to native coronary system + LIMA). Plasma samples were analyzed for IL-8 (ELISA) and conjugated dienes (spectrophotometry). Initially after reperfusion, IL-8 in both groups was significantly lower than precardioplegia values. In reperfusion B, only the diabetic group demonstrated a significant increase in IL-8 concentrations at 1 and 15 min compared to nondiabetics. Conjugated diene levels were significantly higher in diabetics at each time point than nondiabetics. This study demonstrates an early decrease in IL-8 in both groups, most likely related to depressed production secondary to hypothermia. The subsequent elevation in IL-8 only in the diabetic group was seen without concomitant conjugated diene elevation. While no evidence of reperfusion injury was demonstrated in this time frame, the elevation of IL-8 in diabetics after CABG may contribute to later infiltration and associated oxidative damage.
    Journal of Surgical Research 07/1999; 84(1):46-50. · 2.02 Impact Factor

Publication Stats

727 Citations
260.59 Total Impact Points

Institutions

  • 2007
    • University of the Sciences in Philadelphia
      • Department of Biological Sciences
      Philadelphia, PA, United States
  • 1986–2005
    • University of Illinois at Chicago
      • • Department of Physiology and Biophysics (Chicago)
      • • Department of Surgery (Chicago)
      • • Department of Medicine (Chicago)
      Chicago, IL, United States
  • 1990–1991
    • Loyola University Medical Center
      • Department of Surgery
      Maywood, IL, United States
  • 1988–1991
    • Loyola University
      New Orleans, Louisiana, United States