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C Kupatt

Publications and source records attributed to C Kupatt.

At least 19 recordsLinked to original sources
PubMed2002

Retroinfusion of NFkappaB decoy oligonucleotide extends cardioprotection achieved by CD18 inhibition in a preclinical study of myocardial ischemia and retroinfusion in pigs.

Myocardial reperfusion injury is partially mediated by postischemic inflammation. Beyond acute PMN recruitment, postischemic inflammation comprises subacute PMN adhesion, eg via NFkappaB activation. In a pig model of 60-min LAD occlusion by PTCA ballon inflation and 1 to 7 days of reperfusion, we investigated the impact of targeted NFkappaB decoy oligonucleotide (ODN) transfection in the area at risk (AAR) on infarct size and regional myocardial function. After 55 min of LAD occlusion, liposomes containing NFkappaB ODN were selectively retroinfused into the anterior interventricular vein for 5 min. Then, retroinfusion was stopped and reperfusion was initiated. Where indicated, CD18 antibody IB4 was infused systemically at 30 min of ischemia. Methylen blue and tetrazolium-red staining were used for quantification of the infarct size. Subendocardial segment shortening (SES) by sonomicrometric crystals in infarct area and AAR was assessed under pacing (expressed as % of control region). NFkappaB decoy ODN retroinfusion reduced infarct size (36 +/- 4% versus 49 +/- 5% in control hearts at day 7), whereas functional reserve of the AAR (SES 73 +/- 17% versus 46 +/- 18% at 180/min) tended to improve. Similar effects were observed after IB4 infusion (38 +/- 5% infarct size, 85 +/- 7% SES at 180/min). A combination of NFkappaB decoy ODN retroinfusion and IB4 infusion further decreased infarct size (26 +/- 2%) and improved functional reserve (SES 94 +/- 6% at 180/min). We conclude that NFkappaB decoy ODN transfection by retroinfusion is feasible in pig hearts and provides postischemic cardioprotection in addition to CD18 blockade.

Analysis of Variance↗
PubMed2002

[Differing aspects of human dignity in intensive medicine].

Human dignity often is used as an ethical category in medical judgement of current medical and intensive care decisions. The short history of the intensive care medicine, however, demonstrates a certain drift in the use of the term "human dignity". Parallel to the more pronounced patient autonomy, articulated in patient testaments, therapeutic decisions of current intensive care medicine individualize therapeutic approaches, instead of preferentially maximizing life span.

Critical Care↗
PubMed2001

Hyperoxia upregulates the NO pathway in alveolar macrophages in vitro: role of AP-1 and NF-kappaB.

The inducible nitric oxide (NO) synthase gene in alveolar macrophages (AMs) is a stress response gene that may contribute to tissue injury in the lung after respiration with high O(2) concentrations through extensive production of NO. In this study, we investigated the influence of hyperoxia on the NO pathway in rat AMs in vitro, its regulation by the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1, and the role of reactive oxygen species (ROS). AMs were treated with lipopolysaccharide (LPS) and/or interferon (IFN)-gamma and incubated under 21 or 85% O(2). Stimulation with LPS and IFN-gamma led to induction of the NO pathway that was further upregulated by hyperoxia. The binding activity of NF-kappaB, in contrast to that of AP-1, was activated on stimulation with LPS and IFN-gamma, and both were further increased under hyperoxia. The antioxidants pyrrolidine dithiocarbamate and N-acetyl-L-cysteine inhibited intracellular ROS production and the NO pathway under both normoxic and hyperoxic conditions but had diverse effects on the transcription factors. The results presented here indicate that hyperoxia can upregulate the NO pathway in stimulated AMs through increased production of intracellular ROS and activation of NF-kappaB and AP-1.

Acetylcysteine↗
PubMed2000

Involvement of CD95/Apo1/Fas in cell death after myocardial ischemia.

BACKGROUND: The death of cardiac cells during ischemia and reperfusion is partially mediated by apoptosis, as seen, eg, in autopsy material of patients after acute myocardial infarction. METHODS AND RESULTS: To study the role of CD95/Fas/Apo1 for induction of postischemic cell death, we used an ischemia/reperfusion model of isolated rat and mouse hearts in Langendorff perfusion. In this model, caspase-dependent apoptosis occurred during postischemic reperfusion. Moreover, soluble CD95 ligand/Fas ligand was released by the postischemic hearts early after the onset of reperfusion. In addition, this ligand was synthesized de novo under these circumstances. Similar findings were observed for other "death-inducing" ligands, such as tumor necrosis factor (TNF)-alpha and TNF-related apoptosis-inducing ligand. In primary adult rat myocyte culture, hypoxia and reoxygenation caused a marked increase in sensitivity to the apoptotic effects of CD95 ligand. Isolated hearts from mice lacking functional CD95 (lpr) display marked reduction in cell death after ischemia and reperfusion compared with wild-type controls. CONCLUSIONS: These data suggest that CD95/Apo1/Fas is directly involved in cell death after myocardial ischemia. The CD95 system might thus represent a novel target for therapeutic prevention of postischemic cell death in the heart.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Endothelial function and hemostasis.

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.

Arteriosclerosis↗
PubMed2000

Endothelial activation--a strategic event during postischemic myocardial inflammation.

Reperfusion after limited ischemia increases leukocyte adhesion, which may contribute to postischemic myocardial and endothelial stunning. Leukocyte adhesion is enhanced immediately after the onset of reperfusion, indicating rapid regulatory mechanisms. In addition, de novo synthesis of, e.g., adhesion molecules induced by reperfusion has been described, providing a prolonged postischemic inflammatory reaction. Enhanced transcription of adhesion molecules involves NF kappa B activation which appears as an essential transcription factor for reperfusion-induced subacute endothelial activation. Both, acute and subacute endothelial activation seem to contribute to the final extent of leukocyte-dependent reperfusion injury and successive treatment of both appears to be a promising therapeutic strategy for postischemic myocardial inflammation and its detrimental effects.

Animals↗
PubMed2000

Selective pressure-regulated retroinfusion of coronary veins as an alternative access of ischemic myocardium: implications for myocardial protection, myocardial gene transfer and angiogenesis.

There is renewed interest in the coronary venous system as an alternative access to ischemic myocardium. Selective pressure-regulated retroinfusion is a catheter-based approach which has been shown to increase the efficacy of retrograde oxygen delivery and drugs in experimental and clinical studies. Selective pressure-regulated retroinfusion may also target retrograde delivery of angiogenic growth factors and gene vectors to ischemic myocardium.

Angiogenesis Inducing Agents↗
PubMed2000

Reactive oxygen species and nitric oxide in myocardial ischemia and reperfusion.

Oxygen radicals and reactive oxygen species (ROS) are known to be generated in large amounts under inflammatory conditions and in the first few minutes of postischemic organ reperfusion. Due to the interaction of ROS with nitric oxide (NO), formed constitutively by endothelial cells, two alternatives are feasible. On the one hand, reaction with superoxide radicals may induce toxification (formation of peroxynitrite), and, on the other hand, by reacting with superoxide and hydroxyl radicals, NO can serve as a radical scavenger (formation of the innocuous anions, nitrate and nitrite, respectively). However, NO is considered to play a pivotal role in numerous physiological and pathophysiological processes, with effects arising from both lack and surfeit of this easily diffusible and chemically very reactive molecule. Physiologic contributions to vascular dilatation and inhibition of platelet and leukocyte activation, e.g., are infringed by enhanced inactivation of NO. Such inactivation occurs readily due to spontaneous reaction of NO with the superoxide radical, formed, e.g., by stressed endothelial cells and activated leukocytes. Conversely, overproduction of NO by induced NO synthase (iNOS) may lead to circulatory shock, cell apoptosis or even cell necrosis. Caution would, thus, seem to be warranted when attempting to interfere with homeostasis of NO. We have investigated the ability of NO to act as a radical scavenger during myocardial reperfusion in experimental and clinical settings. In the former, inhibition of angiotensin converting enzyme was employed to generate more endogenous NO (via bradykinin), in the latter, low-dose sodium nitroprusside was used as the donor of exogenous NO in patients undergoing coronary bypass grafting. Inhibition of leukocyte adhesion, attenuation of platelet activation and mitigation of redox-stress and inflammation were observed in both instances. Accordingly, modest enhancement of NO levels should afford cardioprotection during reperfusion.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Effects of endothelium/leukocytes/platelet interaction on myocardial ischemia--reperfusion injury.

Platelet fibrinogen receptor (GPIIb/IIIa) antagonists clinically improve the effectiveness of thrombolysis or PTCA in treatment of acute myocardial infarction. 7E3Fab, the chimeric Fab fragment of a monoclonal GPIIb/IIIa antibody, reduces the incidence of death, reinfarction or restenosis in patients and may improve blood flow and regional wall motion in reperfused myocardium. Besides inhibition of platelet aggregation, 7E3Fab may block fibrinogen bridging between the polymorphonuclear neutrophil (PMN) adhesion molecule MAC-1 and platelet GP IIb/IIIa, thus attenuating interaction of platelets with PMN. Experimentally, the interaction of platelets with PMN exacerbated postischemic myocardial stunning. In our own studies in isolated guinea pig hearts, human PMN, platelets and fibrinogen where simultaneously infused during the initial reperfusion period after 15 min of global ischemia. FACS analysis of cells in the coronary effluant revealed that 7E3Fab reduced platelet GP IIb/IIIa expression to 10% of baseline. PMN-platelet aggregate formation in the coronary effluate was markedly reduced by 7E3Fab, parallel to a decrease of PMN-platelet aggregates found by in situ double fluorescence microscopy in the postischemic coronary vasculature. The inhibition of PMN-platelet aggregate formation by 7E3Fab treatment coincided with a significant improvement of external heart work, which suffered a 50% reduction after ischemia, reperfusion, and exposure to PMN, platelets and fibrinogen. Obviously, application of 7E3Fab inhibits formation and coronary retention of PMN-platelet aggregates in the postischemic, reperfused myocardium. This effect may contribute to the clinically observed beneficial effects of this adjuvant treatment after myocardial ischemia.

Abciximab↗
PubMed2000

Myocardial gene transfer by selective pressure-regulated retroinfusion of coronary veins.

Catheter-based percutaneous transluminal gene delivery (PTGD) into the coronary artery still falls behind the expectations of an efficient myocardial gene delivery system. In this study gene delivery was applied by selective pressure-regulated retroinfusion through the coronary veins to prolong adhesion of replication defective adenovirus within the targeted myocardium. Adenoviral vectors consisted either of luciferase (Ad.rsv-Luc) or beta-galactosidase (Ad.rsv-betaGal) reporter gene under control of an unspecific promotor derived from the Rous sarcoma virus (RSV). In this pig model, selective retrograde gene delivery into the anterior cardiac vein during a brief period of ischemia substantially increased reporter gene expression in the targeted myocardium (LAD region) compared with antegrade delivery as a control. Repeated retrograde delivery during two periods of brief ischemia resulted in a more homogeneous transmural expression predominantly observed in cardiomyocytes (X-gal-staining). In the nontargeted myocardium (CX region) there was no evidence for adenoviral transfection. From our data we infer that selective pressure-regulated retroinfusion is a promising approach for efficient percutaneous transluminal gene delivery to the myocardium. Gene Therapy (2000) 7, 232-240.

Adenoviridae↗
PubMed2000

Endothelial preconditioning by transient oxidative stress reduces inflammatory responses of cultured endothelial cells to TNF-alpha.

Brief episodes of ischemia can render an organ resistant to subsequent severe ischemia. This 'ischemic preconditioning' is ascribed to various mechanisms, including oxidative stress. We investigated whether preconditioning exists on an endothelial level. Human umbilical vein endothelial cells (HUVECs) were transiently confronted with oxidative stress (1 mM H(2)O(2), 5 min). Adhesion molecules ICAM-1 and E-selectin and release of cytokines IL-6 and IL-8 to subsequent stimulation with TNF-alpha (2.5 ng/ml, 4 h) were measured (flow cytometry and immunoassay), as were nuclear translocation of the transcription factor NFkappaB (Western blotting, confocal microscopy) and redox status of HUVECs (quantification of glutathione by HPLC). TNF-alpha elevated IL-6 in the cell supernatant from 8.8 +/- 1 to 41 +/- 3 pg/ml and IL-8 from 0.5 +/- 0. 03 to 3 +/- 0.2 ng/ml. ICAM-1 was increased threefold and E-selectin rose eightfold. Oxidative stress (decrease of glutathione by 50%) reduced post-TNF-alpha levels of IL-6 to 14 +/- 3 and IL-8 to 1 +/- 0.2; the rise of ICAM-1 was completely blocked and E-selectin was only doubled. The anti-inflammatory effects of preconditioning via oxidative stress were paralleled by reduction of the translocation of NFkappaB on stimulation with TNF-alpha, and antagonized by the intracellular radical scavenger N-acetylcysteine. 'Anti-inflammatory preconditioning' of endothelial cells by oxidative stress may account for the inhibitory effects of preconditioning on leukocyte adhesion in vivo.

Apoptosis↗
PubMed2000

c7E3Fab reduces postischemic leukocyte-thrombocyte interaction mediated by fibrinogen. Implications for myocardial reperfusion injury.

Reperfusion injury after coronary occlusion is in part mediated by leukocyte activation and adhesion. Platelets may interact with polymorphonuclear granulocytes (PMNs), causing aggravated reperfusion injury. We studied whether c7E3Fab, a chimeric Fab fragment blocking platelet glycoprotein (GP) IIb/IIIa, decreases PMN-platelet-dependent myocardial dysfunction after ischemia. Isolated guinea pig hearts (n=5 per group) perfused at a constant flow of 5 mL/min were subjected to ischemia (15 minutes, 37 degrees C) and reperfusion. Human PMNs (10x10(6) cells, 3 mL), platelets (400x10(6), 3 mL), and fibrinogen (1 mg/mL) were infused for 3 minutes after 2 minutes of reperfusion, with or without c7E3Fab. Flow cytometry detected GPIIb/IIIa (platelets) and MAC-1 (aMbeta2, PMNs) as well as coaggregates of both in the effluent, whereas double-fluorescence microscopy visualized intracoronary PMN-platelet coaggregates. Postischemic recovery of pressure-volume work (12-cm H(2)O preload and 60-mm Hg afterload) was defined as the ratio of postischemic to preischemic external heart work (mean+/-SEM). c7E3Fab reduced platelet GPIIb/IIIa detection to 10% of controls, blocked a transcoronary MAC-1 increase (+25% without versus -23% with c7E3Fab), and inhibited PMN-platelet coaggregation in the effluent (49+/-12% without versus 17+/-2% with c7E3Fab) as well as in the hearts themselves (5.0+/-0.7/cm(2) without versus 1.2+/-0.3/cm(2) surface area with c7E3Fab). Postischemic recovery of external heart work (83+/-5% in cell-free hearts) declined to 46+/-4% after postischemic PMN-platelet infusion, but not in the presence of c7E3Fab (74+/-11%) or LPM19c (71+/-6%). We conclude that c7E3Fab inhibits formation of PMN-platelet aggregates during myocardial reperfusion, an effect that protects against PMN-platelet-dependent stunning.

Abciximab↗
PubMed1999

ACE-inhibition attenuates cardiac cell damage and preserves release of NO in the postischemic heart.

Cardioprotective effects of angiotensin-converting enzyme (ACE) inhibition have been demonstrated in postischemic reperfusion. This occurred via bradykinin and indirect evidence suggested mediation by nitric oxide (NO), which probably acts as a radical scavenger. To test this hypothesis, we measured release of lactate dehydrogenase (LDH) from isolated guinea pig hearts (constant flow perfusion, 37 degrees C) as a marker of cellular damage, before and after global ischemia (15 min), and we investigated the release of NO during reperfusion, both, without and with ACE inhibition. The main catabolites of NO, nitrate and nitrite, were also quantified. Coronary perfusion pressure (CPP) indicated coronary resistance changes. Cilazaprilat (CIL, 10 microM) was used for inhibition of ACE. Marked and protracted cellular damage occurred during reperfusion in the control group, myocardial LDH release rising nearly 10-fold from 1.5 mU/ml (basal level) to 14 mU/ml during acute reperfusion, then declining to 7 mU/ml after 5 min. ACE inhibition mitigated the acute rise of LDH (9 mU/ml), and reduced its release to preischemic values already after 3 min of reperfusion. Postischemic NO release in the 2nd min of reperfusion was about 40% of the preischemic value (approx. 200 nM) in untreated hearts, while there was 70% recovery after ACE inhibition. After 25 min, NO had recovered to 69% in controls vs. 100% with CIL. Coronary venous nitrate + nitrite was not infringed during early reperfusion (2nd min). After 25 min, nitrate + nitrite had decreased in controls (about 75% of preischemic values), but increased to 110% with CIL. In control hearts, CPP rose continuously from the 10th to the 25th min of reperfusion (from 39 to 55 mmHg), indicating progressive vasoconstriction. CIL significantly attenuated this effect. The results suggest that NO might be consumed during early reperfusion in the act of detoxifying radicals. In control hearts, "endothelial stunning" takes place. Concerning NO production and vasodilatory tone, ACE-inhibition augments postischemic NO release and mitigates disturbances caused by ischemia and reperfusion.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Tumor necrosis factor-alpha contributes to ischemia- and reperfusion-induced endothelial activation in isolated hearts.

-During myocardial reperfusion, polymorphonuclear neutrophil (PMN) adhesion involving the intercellular adhesion molecule-1 (ICAM-1) may lead to aggravation and prolongation of reperfusion injury. We studied the role of early tumor necrosis factor-alpha (TNF-alpha) cleavage and nuclear factor-kappaB (NF-kappaB) activation on ICAM-1 expression and venular adhesion of PMN in isolated hearts after ischemia (15 minutes) and reperfusion (30 to 480 minutes). NF-kappaB activation (electromobility shift assay) was found after 30 minutes of reperfusion and up to 240 minutes. ICAM-1 mRNA, assessed by Northern blot, increased during the same interval. Functional effect of newly synthesized adhesion molecules was found by quantification (in situ fluorescence microscopy) of PMN, given as bolus after ischemia, which became adherent to small coronary venules (10 to 50 microm in diameter). After 480 minutes of reperfusion, ICAM-1-dependent PMN adhesion increased 2.5-fold compared with PMN adhesion obtained during acute reperfusion. To study the influence of NF-kappaB on PMN adhesion, we inhibited NF-kappaB activation by transfection of NF-kappaB decoy oligonucleotides into isolated hearts using HJV-liposomes. Decoy NF-kappaB but not control oligonucleotides blocked ICAM-1 upregulation and inhibited the subacute increase in PMN adhesion. Similar effects were obtained using BB 1101 (10 microg), an inhibitor of TNF-alpha cleavage enzyme. These data suggest that ischemia and reperfusion in isolated hearts cause liberation of TNF-alpha, activation of NF-kappaB, and upregulation of ICAM-1, an adhesion molecule involved in inflammatory response after ischemia and reperfusion.

Animals↗
PubMed1999

Selectins and beta 2-integrins mediate post-ischaemic venular adhesion of polymorphonuclear leukocytes, but not capillary plugging, in isolated hearts.

Leukocytes adhering to venular endothelium and emigrating into the tissue contribute to myocardial reperfusion injury. The aim of the present study was to characterize the contribution of two different families of adhesion molecules, selectins and integrins, to post-ischaemic capillary plugging and venular adhesion of leukocytes in an isolated heart model. Guinea-pig hearts were perfused using the Langendorff technique. After 20 min stabilization global ischaemia was induced for 15 min at 37 degrees C. With the onset of reperfusion 10(7) isolated polymorphonuclear leukocytes (PMN), prelabelled with rhodamine 6G, were infused within 1 min. Perfusion was continued for 2 min to wash out all cells not firmly adhering to the vascular endothelium. Hearts were then arrested, mounted on a microscope stage and perfused with a cardioplegic solution containing 0.01% fluorescein isothiocyanate (FITC)-dextran (MW 150,000). In situ videofluorescence microscopy was used to quantify PMN plugging and adherent PMN. Four groups were studied: control (no treatment or ischaemia, n = 6); ischaemia (no treatment and 15 min ischaemia, n = 5); fucoidin (pretreatment of hearts and PMN with 0.3 mg/ml selectin inhibitor fucoidin and 15 min ischaemia, n = 5) and CD18 (pretreatment of PMN with 0.1 mg monoclonal antibody against CD18 and 15 min ischaemia, n = 5). Capillary plugging by PMN was 25 +/- 5 PMN/mm2 epicardial surface area and increased moderately to 55 +/- 6 PMN/mm2 in reperfused hearts. This increase was not affected by fucoidin or CD18 antibody. In contrast, post-ischaemic adhesion of PMN in small venules increased ninefold from 21 +/- 5 to 196 +/- 23 PMN/mm2 endothelial surface area. The increase in PMN adhesion to venular endothelium was blocked completely by pretreatment with fucoidin (19 +/- 5 PMN/mm-2) or CD18 antibody (7 +/- 2 PMN/mm-2). We conclude that selectin interaction alone is not sufficient to account for post-ischaemic PMN adhesion in the small venules of the coronary vasculature, because blocking the integrin subunit CD18 also inhibited PMN adhesion completely. On the other hand, neither integrins nor selectins seem to be involved in post-ischaemic capillary plugging by PMN in our perfused heart model.

Animals↗
PubMed1998

Inhibition of nuclear factor kappaB activation attenuates apoptosis resistance in lymphoid cells.

Death-inducing ligands (DILs) such as tumor necrosis factor alpha (TNFalpha) or the cytotoxic drug doxorubicin have been shown to activate a nuclear factor kappaB (NFkappaB)-dependent program that may rescue cells from apoptosis induction. We demonstrate here that TRAIL (TNF-related apoptosis-inducing ligand), a recently identified DIL, also activates NFkappaB in lymphoid cell lines in a kinetic similar to TNFalpha. NFkappaB activity is independent from FADD, caspases, and apoptosis induction. To study the influence of NFkappaB activity on apoptosis mediated by TRAIL, CD95, TNFalpha, or doxorubicin, NFkappaB activation was inhibited using the proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal or transient overexpression of mutant IkappaBalpha. Sensitivity for induction of apoptosis was markedly increased by these treatments in apoptosis sensitive cell lines. Moreover, both in cell lines and in primary leukemia cells that are resistant towards induction of apoptosis by DILs and doxorubicin, antagonization of NFkappaB activity partially restored apoptosis sensitivity. These data suggest that inhibition of NFkappaB activation may provide a molecular approach to increase apoptosis sensitivity in anticancer treatment.

Antibiotics, Antineoplastic↗
PubMed1998

Adenosine endogenously released during early reperfusion mitigates postischemic myocardial dysfunction by inhibiting platelet adhesion.

The purpose of this study was to investigate platelet effects on postischemic heart function in conjunction with adenosine effects on intracoronary platelet adhesion. Homologous platelets were infused into the coronaries of isolated guinea pig hearts, either during low-flow ischemia or during reperfusion, and external heart work (EHW) and intracoronary platelet adhesion were determined. In most experiments, thrombin was added to the perfusate. The influence of endogenous adenosine was studied by use of the uptake blocker dipyridamole and the unspecific adenosine-receptor blocker theophylline, the A1-receptor blocker 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and the A2-receptor blocker 3,7-dimethyl-1-propargylxanthine (DMPX). The importance of nitric oxide and prostaglandin I2 (PGI2) was tested by using nitro-L-arginine (NOLAG) and indomethacin, respectively. When platelets were applied with thrombin during low-flow ischemia, EHW recovered to only 63 +/- 4% of the preischemic value, as compared with 89 +/- 3% without platelets (p < 0.05). Despite thrombin, platelets incurred no significant functional loss when applied in the first minute of reperfusion (but again in the fifth minute); however, when theophylline was also present, recovery of EHW amounted to only 42 +/- 12%. Intracoronary adhesion of platelets was negligible without thrombin, and highest during low-flow ischemia with thrombin (35 +/- 3% of the applied number). No adhesion occurred during the first minute of reperfusion, whereas in the fifth minute, adhesion was again 20.8 +/- 4%. Dipyridamole increased adenosine release and attenuated adhesion at this time. Theophylline increased adhesion in the first minute of reperfusion (33 +/- 6.4%), whereas NOLAG and indomethacin proved to be ineffective. DPCPX and DMPX each increased platelet retention during the first minute of reperfusion, their effects being additive. Intracoronary adhesion of platelets induced by thrombin in isolated hearts can reduce postischemic recovery of heart function. During reperfusion, but not during low-flow, endogenous adenosine can prevent platelet adhesion and loss of myocardial function, an action mediated both by A1- and A2-receptor-dependent mechanisms.

Adenosine↗