Protection from myocardial ischemic injury in cats and pigs by defibrotide--different mode of action?
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
T Hohlfeld
Publications and source records attributed to T Hohlfeld.
Endothelial protection by defibrotide--a new strategy for treatment of myocardial infarction?
Myocardial ischemia is associated with endothelial injury and an apparently insufficient generation of endothelium-derived vasodilating and platelet and white cell inhibitory mediators, such as prostacyclin (PGI2) and EDRF. This paper reviews some recent findings of our laboratory on cardioprotective effects of defibrotide, a PGI2 stimulating agent, in experimental myocardial ischemia and its possible sites of action in several in vitro assay systems. Defibrotide (32 mg/kg x h) reduced the infarct size by 50% in pigs, subjected to 1 h of coronary artery ligation followed by 3 h of reperfusion. This was associated with significant inhibition of neutrophil activation during the reperfusion period and a two-to threefold increase in cardiocoronary PGI2 generation. In vitro studies on PAF- and calcium ionophore-stimulated human granulocytes confirmed a dose-dependent (10-1000 micrograms/ml) antineutrophil effect of defibrotide (inhibition of lysosomal enzyme release) which was independent of the type of stimulus. Defibrotide (0.1 mg/ml) also inhibited superoxide anion generation from PAF stimulated neutrophils in Langendorff-perfused guinea pig hearts and was equipotent to a specific PAF antagonist (BN 52021). Defibrotide (0.1 mg/ml) did not stimulate PGI2 release from cultured porcine aortic endothelial cells but enhanced PGI2 release four- to fivefold above control if endothelial cells were coincubated with platelets. These data demonstrate a considerable cardioprotective potential of defibrotide which appears to involve endothelial protection from granulocyte-derived noxious compounds and a long-lasting stimulation of PGI2 production.
Animals↗
Inotropic actions of eicosanoids.
Eicosanoids (prostaglandins, leukotrienes, thromboxane A2 and other metabolites of C-20 polyunsaturated fatty acids) have numerous effects in the cardiovascular system. Direct inotropic actions have been repeatedly described, but appear in only very few cases to be due to direct modification of the inotropic state of the heart. Specific eicosanoid receptors have been identified on the surface of the sarcolemmal membrane. Signal transduction pathways in the cardiac myocyte involve the adenylate cyclase/cAMP system or stimulation of the phospholipase C/IP3 pathway. In general, concentrations of eicosanoids which affect myocardial contractility are higher as the response is less predictable than the effects on platelet function or vessel tone. Therefore, eicosanoid-induced extracardiac effects may be superimposed to more direct changes in the contractile state of the intact heart in vitro or in vivo. In contrast to non-failing hearts, there is a significant improvement of the contractile function in contractile failure ("stunning", ischemia, congestive heart failure) by vasodilating prostaglandins (e.g., PGI2). The mechanism of this action is still unknown.
Animals↗
Adenosine-induced increase in myocardial ATP: are there beneficial effects for the ischaemic myocardium?
The adenosine triphosphate (ATP) content of isolated Langendorff-perfused rat hearts may be increased by more than 40% above the normal value by a 2-h perfusion with adenosine (15 mumol/l). This metabolic manipulation was used to investigate the hypothetical relationship between total tissue ATP content and ischaemia-induced contractile failure, ischaemic contracture and post-ischaemic functional recovery. Adenosine perfused hearts were submitted to 20 min of normothermic ischaemia and reperfused for 45 min with or without adenosine. Control experiments were performed with adenosine-free preischaemic perfusion. In identically designed experiments the tissue-protective effect of diltiazem (0.5 mumol/l) was determined and compared with the experiments with adenosine. At the end of 120 min of preischaemic perfusion, the ATP content of the adenosine treated hearts was 34.3 +/- 1.8 mumol/g dry weight (control = 23.6 +/- 1.9 mumol/g, p less than 0.01). After a period of 20 min of normothermic ischaemia, the ATP content of the adenosine hearts decreased to 13.3 +/- .4 mumol/g, whereas ATP fell to 8.3 +/- 1.6 mumol/g in the control hearts. The creatine phosphate (CP) levels of adenosine hearts were significantly lower than those of the control group before ischaemia, but did not show major differences following ischaemia. During ischaemia, the contractile activity measured via an intraventricular balloon catheter, as well as ischaemic contracture did not differ between the adenosine and control hearts. The inclusion of diltiazem into the perfusate significantly delayed the onset of contracture. After 45 min of reperfusion, ATP contents of adenosine and control hearts reached similar values (8.4 +/- 2.3 and 8.3 +/- 2.9 mumol/g, respectively). Inclusion of adenosine (15 mumol/l in the reperfusion perfusate of the adenosine experiments prevented a further decrease, but did not increase tissue ATP content. CP values of all groups showed a partial recovery upon reperfusion, they did not differ significantly. Contractile recovery was equal in all experimental groups except for the diltiazem treated hearts, which showed during the first 10 min of reperfusion an improved mechanical performance. It is concluded that total tissue ATP is not necessarily a good indicator of functional capabilities under conditions of normothermic ischaemia and reperfusion in the isolated rat heart.
Adenosine↗
Improvement of epidermal adhesion by surface modification of craniofacial abutments.
Craniofacial implants may present peri-implant inflammation because there is no close adhesion of the epithelium to abutments and because of bacteria infiltrating the subcutaneous tissue through the gap. Therefore an attempt was made to improve adhesion of epithelium to abutments. In an in vitro model, adhesion of epithelial cells (HaCat cells) to nonmodified and 3 modified Brånemark System abutment surfaces was quantified. It was found that more cells were adherent in sequence at silicone-coated surfaces, sandblasted surfaces, and collagen-coated (Types I and IV) surfaces than on nonmodified abutments. It was concluded that it is possible to improve epidermal adhesion to abutments through modification of abutment surfaces.
Bacterial Physiological Phenomena↗
[Thrombocyte prostacyclin receptors in gestational hypertension and pre-eclampsia].
OBJECTIVE: To determine prostacyclin (PGI2) receptor characteristics in pregnancies complicated by hypertension and to assess any relation to the clinical outcome. METHODS: Radioligand binding studies with [3H]-Iloprost were performed to measure receptor capacity (Bmax) and affinity (Kd-1) using platelet membranes from patients with preeclampsia, gestational hypertension or normal pregnancy. RESULTS: PGI2 receptor capacity did not differ between the patient groups. In contrast, PGI2 receptor affinity was diminished in gestational hypertension and considerably reduced in preeclampsia compared to normal pregnancy. A similar pattern was found in fetal growth (normal pregnancy > gestational hypertension > preeclampsia). Furthermore, the rate of low Apgar scores and acidosis was increased in preeclampsia. CONCLUSIONS: In preeclampsia reduced platelet PGI2 receptor affinity was found as well as poor pregnancy outcome in comparison with normal pregnancy, whereas these differences were less pronounced in gestational hypertension. This suggests a role of PGI2 and its receptor in gestational hypertension and in particular in preeclampsia.
Adolescent↗