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M Buerke

Publications and source records attributed to M Buerke.

50 records · Page 3Linked to original sources
PubMed1995

Aspirin therapy: optimized platelet inhibition with different loading and maintenance doses.

Inhibition of cyclooxygenase by aspirin has been shown to be beneficial in clinical situations such as acute myocardial infarction or unstable angina. The precise effect of various doses of aspirin on acute and long-term inhibition of platelet aggregation and thromboxane synthesis remains unclear. In this study we evaluated the effect of oral aspirin (0, 40, 100, 300, or 500 mg) as the initial loading dose in combination with different maintenance doses of aspirin (0, 40, or 100 mg/day) for 14 days on platelet function in healthy men. Bleeding time 2 or 24 hours after the first aspirin administration was significantly increased for 300 and 500 mg aspirin (p < 0.01). Two hours after the first administration of 100, 300, and 500 mg aspirin, a significant inhibition of collagen-induced platelet aggregation (ED50 collagen: from 3 +/- 1 to 17 +/- 2, 24 +/- 3, 22 +/- 3 micrograms/ml, respectively) was seen. At the same time serum thromboxane B2 synthesis was inhibited by more than 99% with 300 and 500 mg aspirin. At the end of the 14-day observation period, bleeding time was significantly prolonged for the different combinations of aspirin doses compared with initial values (p < 0.01). Collagen-induced platelet aggregation and serum thromboxane B2 synthesis were significantly inhibited for all aspirin combinations tested at 14 days (p < 0.05). The 40/40 mg aspirin combination was less effective, because it reached its maximal effect very late at day 7 of the observation period compared with the other combinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Myocardial and endothelial protection by TMS in ischemia-reperfusion injury.

N,N,N-trimethylsphingosine (TMS), a stable synthetic sphingosine derivative, was investigated in a feline model of myocardial ischemia (90 min) and reperfusion (270 min) injury. TMS (60 micrograms/kg), administered intravenously 10 min before reperfusion, significantly attenuated myocardial necrosis (15 +/- 3 vs. 31 +/- 4% necrosis of area at risk, P < 0.01) and cardiac myeloperoxidase activities, a marker of neutrophil accumulation, compared with vehicle-treated cats. Endothelium-dependent relaxation to acetylcholine in ischemic-reperfused coronary artery rings treated with TMS was also significantly preserved compared with vehicle (73 +/- 4 vs. 34 +/- 4% vasorelaxation, P < 0.01). Polymorphonuclear neutrophil (PMN) adherence to coronary endothelium 270 min after reperfusion was markedly attenuated in the TMS group compared with vehicle-treated cats (37 +/- 5 vs. 76 +/- 5 PMN/mm2, P < 0.01). TMS also attenuated upregulation of P-selectin on coronary venular endothelium by immunohistochemistry. This was consistent with in vitro findings that TMS attenuates PMN adherence to thrombin-stimulated coronary endothelium and P-selectin upregulation on thrombin-stimulated cat platelets. A sphingolipid derivative, TMS at physiological concentrations exerts cardioprotective actions and preserves coronary endothelial function following myocardial ischemia and reperfusion in vivo. The effects appear to be mediated by the inhibition of PMN-endothelial interaction and subsequent accumulation into the ischemic myocardium. Thus TMS may be a useful agent in attenuating myocardial reperfusion injury.

Animals↗
PubMed1994

Isolated cardiac myocytes are sensitized by hypoxia-reoxygenation to neutrophil-released mediators.

We exposed isolated rat cardiac myocytes to 20 min of hypoxia followed by 20 min of reoxygenation and observed the effect of supernatants of stimulated neutrophils [polymorphonuclear leukocytes (PMNs)] given at the beginning of reoxygenation. PMN supernatants induced cardiac myocyte injury, which was characterized by a significant (P < 0.01) reduction in cell viability to 53 +/- 3%, vs. 84 +/- 3% in rat myocytes subjected to hypoxia-reoxygenation (H/R) alone. The PMN supernatants also resulted in elevated creatine kinase (CK) activities in the myocyte medium. To examine specific PMN-released mediators that may contribute to this cell death, we studied the effects of hydrogen peroxide (H2O2), elastase, and platelet-activating factor on H/R cardiac myocytes. Incubation of myocytes after hypoxia with 10, 50, and 100 microM H2O2 decreased viability in a concentration-dependent manner (from 83 +/- 2 to 37 +/- 2%; P < 0.01). CK release of H/R myocytes was also significantly increased by 100 microM H2O2 (to 28 +/- 5 from 12 +/- 1% for H/R alone; P < 0.01). Similarly, elastase (5 micrograms/ml) given after hypoxia significantly reduced cardiac myocyte viability during reoxygenation (viability 58 +/- 1 vs. 85 +/- 1% H/R alone; P < 0.05) and increased CK release (to 29 +/- 3 from 11 +/- 1% for H/R alone; P < 0.01), an effect that was abolished by L-680,833, an elastase inhibitor. Unlike H2O2 and elastase, platelet-activating factor had no significant effect on myocyte viability or CK release after H/R.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Sialyl Lewisx-containing oligosaccharide exerts beneficial effects in murine traumatic shock.

We investigated the effects of a soluble sialyl Lewisx-containing oligosaccharide (SLex-OS) in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, a survival time of 85 +/- 15 min, significant increases in ileal myeloperoxidase (P < 0.01), and plasma free amino-nitrogen activities (P < 0.01). Treatment with SLex-OS (10 mg/kg) 10 min posttrauma prolonged survival time to 198 +/- 29 min (P < 0.01), significantly attenuated ileal myeloperoxidase activity (P < 0.01), and diminished the accumulation of plasma free amino-nitrogen (P < 0.01), drug vs. vehicle, respectively. Furthermore, endothelium-dependent relaxation to acetylcholine in superior mesenteric artery rings isolated from SLex-OS-treated shock rats was significantly preserved (70 +/- 6 vs. 40 +/- 5% relaxation). No beneficial effects were observed using a nonfucosylated control oligosaccharide. Moreover, addition of SLex-OS significantly inhibited unstimulated human polymorphonuclear neutrophil (PMN) adherence in vitro to trauma-activated superior mesenteric artery endothelium ex vivo (P < 0.001). Our results indicate that SLex-OS exerts beneficial effects in traumatic shock states by blocking selectin-mediated leukocyte-endothelium interaction, thus improving survival, attenuating intestinal PMN accumulation, and diminishing shock-induced tissue injury.

Animals↗
PubMed1994

Polymorphonuclear leukocyte-induced vasocontraction and endothelial dysfunction. Role of selectins.

The roles of selectin adhesion molecules (P- and L-selectin) and their counterreceptor sialyl Lewisx were investigated in polymorphonuclear leukocyte (PMN)-induced cat coronary vasocontraction and endothelial dysfunction. Unstimulated autologous PMNs (10(6) cells/mL) were added to organ chambers containing cat coronary artery rings stimulated with either thrombin (2 U/mL) or hydrogen peroxide (100 mumol/L). PMNs elicited a significant vasocontraction in thrombin- (119 +/- 14 mg) and hydrogen peroxide- (132 +/- 15 mg) stimulated coronary rings. This PMN-induced vasocontraction was significantly attenuated by pretreatment with either an anti-P-selectin, an anti-L-selectin monoclonal antibody (ie, MAb PB 1.3 and MAb DREG-200), or a sialyl Lewis(x)-containing oligosaccharide (SLe(x)-OS). Endothelial function as assessed by endothelium-dependent vasorelaxation to acetylcholine was also significantly attenuated after PMN-induced vasocontraction in stimulated coronary rings. This endothelial dysfunction was significantly prevented by either PB 1.3, DREG-200, or SLe(x)-OS. In contrast, endothelium-independent relaxation to acidified sodium nitrite was not altered by PMN incubation, indicating that vascular smooth muscle function was unaffected. Adherence of PMNs to coronary endothelium also significantly increased following stimulation of endothelium with either thrombin or hydrogen peroxide, but this was significantly attenuated by PB 1.3, DREG-200, or SLe(x)-OS. Thus, PMN-endothelial interaction mediated by either selectin adhesion molecules (ie, P-selectin and L-selectin) or sialyl Lewis(x) may play an important role in PMN-induced vasocontraction and endothelial dysfunction. This mechanism may be important in the early endothelial dysfunction observed following reperfusion of an ischemic coronary vasculature.

Animals↗
PubMed1994

Physiological concentrations of nitric oxide do not elicit an acute negative inotropic effect in unstimulated cardiac muscle.

We examined the effect of several nitric oxide (NO) donors, authentic NO gas, and L-arginine in isolated cat and rat papillary muscles. We did not observe significant inotropic effects in response to any NO donor (ie, SPM-5185, C87-3754, and S-nitroso-N-acetylpenicillamine [SNAP]) from 1 nmol/L to 100 mumol/L. Similarly, authentic NO, at concentrations far in excess of those that maximally dilate the coronary vasculature (ie, 500 nmol/L), also failed to exert a detectable inotropic effect in these preparations. However, in the presence of 5 mumol/L norepinephrine, 500 nmol/L NO exerted a 12 +/- 3% decrease in isolated rat papillary muscle contractility (P < .05). Addition of L-arginine up to 25 mmol/L exerted no inotropic effects in isolated rat papillary muscles. However, at 50 mmol/L, L-arginine decreased contractile force by 21 +/- 4% (P < .01). On further examination, the negative inotropic effect of 50 mmol/L L-arginine appeared to be nonspecific, since the inactive stereoisomer, D-arginine, at 50 mmol/L exerted the same effect. Further studies in isolated adult rat cardiac myocytes elicited similar results, in that 50 mmol/L of L- and D-arginine equally decreased contraction amplitude and the underlying cytosolic calcium transient. Moreover, 500 nmol/L of the NO donor SPM-5185 only modestly decreased contraction amplitude or intracellular calcium in isolated rat cardiac myocytes. These results indicate that administration of physiological concentrations of exogenous NO does not acutely depress the inotropic state of the rat or cat heart to a physiologically significant extent.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Sialyl Lewisx-containing oligosaccharide attenuates myocardial reperfusion injury in cats.

Neutrophil (PMN) adhesion to the vascular endothelium is an important mechanism of myocardial reperfusion injury. The adhesion process is initially mediated by selectins (e.g., P- and L-selectin), and monoclonal antibodies directed against these adhesion molecules exert cardioprotective activity in ischemia/reperfusion models. The counterreceptors for these selectins are thought to be carbohydrate-containing moieties. In this connection, we studied the effect of a soluble sialyl Lewisx-containing oligosaccharide (SLex-OS) on PMN-endothelial interactions in a feline model of myocardial ischemia/reperfusion (MI/R). SLex-OS (10 mg/kg), administered 10 min before R, significantly reduced myocardial necrosis compared with its vehicle 270 min after reperfusion (6 +/- 1% vs. 35 +/- 4% of area at risk, P < 0.01). The cardioprotection was confirmed by significantly lower plasma creatine kinase activities in SLex-OS vs. vehicle-treated cats (P < 0.01). Cardiac contractility (dP/dt max) of cats receiving SLex-OS was significantly preserved after 270 min of R (97 +/- 2% vs. 78 +/- 5% of initial, P < 0.01). Furthermore, endothelium-dependent relaxation to acetylcholine in coronary artery rings isolated from MI/R cats treated with SLex-OS was significantly preserved (73 +/- 7% vs. 22 +/- 6% vasorelaxation, P < 0.01). In vitro PMN adherence to coronary vascular endothelium after 270 min of R was significantly attenuated in the SLex-OS-treated group compared with the vehicle group (14 +/- 5 vs. 91 +/- 12 PMN/mm2, P < 0.01). Our results indicate that a SLex-OS is cardioprotective and preserves coronary endothelial function after MI/R, indicating an important role of sialyl Lewisx in PMN accumulation, endothelial dysfunction, and myocardial injury in myocardial ischemia/reperfusion.

Animals↗
PubMed1994

Humanized monoclonal antibody DREG-200 directed against I-selectin protects in feline myocardial reperfusion injury.

Polymorphonuclear leukocytes (i.e. neutrophils) significantly mediate damage in myocardial ischemia followed by reperfusion. In the present study, the cardioprotective effects of a humanized form of a monoclonal antibody directed against L-selectin designated monoclonal antibody (mAb) HuDREG-200 were examined in a feline model of 90-min myocardial ischemia followed by 270 min of reperfusion. In preliminary studies, flow cytometric analysis indicated that HuDREG-200 binds to feline neutrophils. In vitro administration of mAb HuDREG-200 significantly inhibited (P < .01) adherence of unstimulated neutrophils to ischemic-reperfused coronary endothelium in a concentration-dependent manner. Humanized DREG-200 (2 mg/kg) administered 10 min before reperfusion significantly attenuated myocardial necrosis compared to an isotype-matched humanized control mAb (HuABL364) which does not bind to L-selectin (14 +/- 3 vs. 29 +/- 3% necrosis/area-at-risk, P < .01), representing a 52% reduction in myocardial necrosis. This myocardial preservation also was related to reduced creatine kinase release and improved recovery of cardiac contractility (i.e. left ventricular dP/dtmax). Moreover, endothelial function, as assessed by relaxation to acetylcholine, also was significantly preserved in ischemic-reperfused coronary arteries isolated from cats treated with mAb HuDREG-200 compared to mAb HuABL364 (68 +/- 6 vs. 18 +/- 5, P < .01). Thus, a humanized anti-L-selectin mAb appears to be an effective means of preserving the ischemic myocardium from reperfusion injury and of preserving myocardial contractile function, at least during the early reperfusion period.

Animals↗
PubMed1994

Effects of taprostene on neutrophil-endothelial interactions in isolated coronary arteries.

We examined the effects of taprostene (2.5 x 10(-8) M to 1 x 10(-7) M), a stable prostacyclin analog, on PMN-endothelial interaction (i.e., adherence) and subsequent vasocontraction and endothelial dysfunction. Taprostene effectively inhibited the adherence of leukotriene B4-stimulated autologous cat polymorphonuclear (PMN) leukocytes to isolated cat coronary artery endothelium. Taprostene also inhibited coronary artery vasocontraction to leukotriene B4-stimulated PMNs (p < 0.01). In isolated coronary artery rings stimulated with either 2 U/ml of thrombin or 100 microM hydrogen peroxide (H2O2), adherence of unstimulated PMNs to coronary endothelium was significantly increased, resulting in vasocontraction and subsequent endothelial dysfunction. However, taprostene (1 x 10(-7) M) significantly attenuated unstimulated PMN adherence to stimulated coronary endothelium. This antiadherence action effectively attenuated PMN-induced coronary artery vasocontraction (p < 0.01) and significantly blunted the subsequent PMN-induced endothelial dysfunction (p < 0.01) characterized by a loss of endothelium-derived nitric oxide (NO). Thus, taprostene exerts a profound inhibitory effect on PMN-endothelium interaction and subsequent PMN-mediated coronary endothelial dysfunction, which may be beneficial in ischemia-reperfusion and other inflammatory states.

Analysis of Variance↗
PubMed1993

Monoclonal antibody to L-selectin attenuates neutrophil accumulation and protects ischemic reperfused cat myocardium.

BACKGROUND: Interaction of CD11/CD18 located on neutrophil membranes with its endothelial counter-receptor, intercellular adhesion molecule-1, plays a major role in polymorphonuclear leukocyte (PMN)-mediated endothelial dysfunction and myocardial injury associated with ischemia and reperfusion. However, PMN-derived L-selectin, which is thought to play an early role in PMN rolling along the vascular endothelium, has not been studied in a setting of myocardial ischemia and reperfusion. METHODS AND RESULTS: In this study, we evaluated the effects of a monoclonal antibody against L-selectin, DREG-200, in a feline model of myocardial ischemia (1.5 hours) and reperfusion (4.5 hours). DREG-200 (1 mg/kg) or an isotype-matched IgG1 antibody, MAb R3.1, which does not cross-react in cats, was administered as a bolus 10 minutes before reperfusion. In MAb R3.1-treated cats, myocardial ischemia followed by reperfusion resulted in significant coronary vascular endothelial dysfunction, elevated cardiac myeloperoxidase activity indicative of neutrophil accumulation in the ischemic myocardium, and severe myocardial injury. In contrast, administration of DREG-200 at 1 mg/kg significantly attenuated myocardial necrosis (14 +/- 4 versus 32 +/- 3 expressed as percentage of area at risk, P < .001) and attenuated coronary endothelial dysfunction (P < .01) associated with ischemia/reperfusion. Moreover, myeloperoxidase activity in the ischemic myocardium was significantly lower than MAb R3.1-treated cats (0.4 +/- 0.1 versus 0.9 +/- 0.2 U/100 mg tissue, P < .05). CONCLUSIONS: These results demonstrate that blocking L-selectin with DREG-200 exerts a significant cardioprotective effect in a feline model of myocardial ischemia and reperfusion, indicating that L-selectin plays a significant role in mediating PMN accumulation and PMN-induced endothelial and myocardial injury after ischemia and reperfusion.

Animals↗
PubMed1992

Stimulation of PAF-synthesis in pulmonary artery endothelial cells by Staphylococcus aureus alpha-toxin.

Staphylococcus aureus alpha-toxin is a pore-forming exotoxin that probably represents a significant virulence factor in staphylococcal infections. Previous studies demonstrated that this agent stimulated arachidonate metabolism with subsequent formation of prostacyclin in endothelial cells and leukotriene B4 in granulocytes. We now examined the effect of alpha-toxin on the synthesis of platelet-activating factor (PAF) in cultured porcine pulmonary artery endothelial cells. PAF was labeled by bioincorporation of tritiated acetate and separated/quantitated using thin-layer chromatography, straight-phase-HPLC, or post-HPLC-bioassay. Alpha-toxin induced synthesis of small amounts of PAF in a time- and dose-dependent manner. The maximal amount of PAF elicited by alpha-toxin was approximately 7% of that observed after application of the ionophore A23187. Staphylococcal alpha-toxin but not the ionophore induced a rapid fall in cellular ATP-content. On kinetic grounds, the decrease in ATP-levels did not explain the differences in stimulated PAF-synthesis. Low amounts of PAF induced by the action of alpha-toxin on endothelial cells may contribute to the development of inflammatory lesions in infectious disease.

Adenosine Triphosphate↗
PubMed1992

Synergistic platelet inhibitory effect of the phosphodiesterase inhibitor piroximone and iloprost.

Platelet activity is regulated through synthesis and degradation of the intracellular second messengers cAMP or cGMP. The antiplatelet effect of the phosphodiesterase (PDE) III inhibitor Piroximone (PIR) was studied in vitro in platelet rich plasma. ADP induced aggregation was inhibited by PIR with an IC50 of 67 +/- 43 microM. The inhibitory effect was time and dose dependent. The antiaggregatory effects in vivo were studied in anaesthetised rats. Reduction of platelet count following injection of 100 micrograms/kg bw collagen was measured after bolus injection of PIR and vehicle. Piroximone bolus 2 mg/kg bw resulted in a 50% inhibition of platelet aggregation in rats. Cyclic AMP levels in washed platelets rose time and dose dependently after PIR. Coincubation of PDE III inhibitor PIR and adenylate cyclase activator Iloprost (ILO) resulted in a significant synergistic enhancement of the antiaggregatory effect. The PDE III inhibitor PIR exerted an effective inhibition of platelet aggregation in vivo and in vitro. The inhibitory effects in vitro were synergistically augmented by the prostacyclin analog Iloprost. These platelet inhibitory effects might be of clinical importance.

Adenosine Diphosphate↗
PubMedDate not supplied

Staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility in perfused rat hearts: role of thromboxane generation.

BACKGROUND: Cardiac performance is severely depressed in septic shock. Endotoxin has been implicated as the causative agent in Gram-negative sepsis, but similar abnormalities are encountered in Gram-positive sepsis. We investigated the influence of the major exotoxin of Staphylococcus aureus, staphylococcal alpha-toxin, in isolated perfused rat hearts. METHODS AND RESULTS: Alpha-toxin 0.25 to 1 microg/mL caused a dose-dependent increase in coronary perfusion pressure that more than doubled. In parallel, we noted a decrease in left ventricular developed pressure and the maximum rate of left ventricular pressure rise (dP/dt(max)), dropping to a minimum of <60% of control. These changes were accompanied by a liberation of thromboxane A(2) and prostacyclin into the coronary effluent. The release of creatine kinase, lactate dehydrogenase, potassium, and lactate did not surpass control heart values, and leukotrienes were also not detected. Indomethacin, acetylsalicylic acid, and the thromboxane receptor antagonist daltroban fully blocked the alpha-toxin-induced coronary vasoconstrictor response and the decrease in left ventricular developed pressure and dP/dt(max), whereas the lipoxygenase inhibitor nordihydroguaiaretic acid, the platelet activating factor antagonist WEB 2086, and the alpha-adrenergic antagonist phentolamine were entirely ineffective. Inhibition of nitric oxide synthase even enhanced the alpha-toxin-induced increase in coronary perfusion pressure and the loss in myocardial performance. CONCLUSIONS: Purified staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility. The responses appear to be largely attributable to the generation of thromboxane and are even enhanced when the endogenous nitric oxide synthesis is blocked. Bacterial exotoxins, such as staphylococcal alpha-toxin, may thus be implicated in the loss of cardiac performance encountered in Gram-positive septic shock.

Animals↗