Biomedical subjects

K Zacharowski

Publications and source records attributed to K Zacharowski.

24 records · Page 2Linked to original sources

PubMed1999

Effects of the prostanoid EP3-receptor agonists M&B 28767 and GR 63799X on infarct size caused by regional myocardial ischaemia in the anaesthetized rat.

1. This study investigates the effects of two agonists of the prostanoid EP3-receptor (M&B 28767 and GR 63799X) on the infarct size caused by regional myocardial ischaemia and reperfusion in the anaesthetized rat. 2. One hundred and sixty-seven, male Wistar rats were anaesthetized (thiopentone, 120 mg kg(-1) i.p.), ventilated (8-10 ml kg(-1), 70 strokes min(-1), inspiratory oxygen concentration: 30%; PEEP: 1-2 mmHg) and subjected to occlusion of the left anterior descending coronary artery (LAD, for 7.5, 15, 25, 35, 45 or 60 min) followed by reperfusion (2 h). Infarct size was determined by staining of viable myocardium with a tetrazolium stain (NBT), histological evaluation by light and electron microscopy and determination of the plasma levels of cardiac troponin T. 3. M&B 28767 (0.5 microg kg(-1) min(-1), i.v., n=7) or GR 63799X (3 microg kg(-1) min(-1), i.v., n=7) caused significant reductions in infarct size from 60+/-3% (25 min ischaemia and 2 h reperfusion; saline-control, n=8) to 39+/-6 and 38+/-4% of the area at risk, without causing a significant fall in blood pressure. Pretreatment of rats with 5-hydroxydecanoate (5-HD), an inhibitor of ATP-sensitive potassium channels, attenuated the cardioprotective effects of both EP3-receptor agonists. The reduction in infarct size afforded by M&B 28767 was also abolished by glibenclamide and the protein kinase C (PKC) inhibitors staurosporine and chelerythrine. 4. Thus, M&B 28767 and GR 63799X reduce myocardial infarct size in the rat by a mechanism(s) which involves the activation of PKC and the opening of ATP-sensitive potassium channels.

Alprostadil↗

PubMed1999

Reduction of myocardial infarct size with sCR1sLe(x), an alternatively glycosylated form of human soluble complement receptor type 1 (sCR1), possessing sialyl Lewis x.

1 This study investigated the effects of soluble complement receptor type 1 (sCR1) or sCR1sLex, agents which function as a complement inhibitor or as a combined complement inhibitor and selectin adhesion molecule antagonist, respectively, on the infarct size and cardiac troponin T (cTnT) release caused by regional myocardial ischaemia and reperfusion in the rat. 2 Eighty-two, male Wistar rats were subjected to 30 min occlusion of the left anterior descending coronary artery (LAD) followed by 2 h of reperfusion. Haemodynamic parameters were continuously recorded and at the end of the experiments infarct size (with p-nitro-blue tetrazolium) and cTnT release were determined. 3 Infusion of sCR1 (1, 5 or 15 mg kg-1, each n=7) or sCR1sLe(x) (1, 5 or 15 mg kg-1, n=7, 13 or 13, respectively) 5 min prior to LAD-reperfusion caused a reduction in infarct size from 59+/-2% (PBS - control, n=12) to 46+/-6%, 25+/-9% and 37+/-6% or 42+/-6%, 35+/-6% and 35+/-4%, respectively. 4 Infusion of sCR1 (15 mg kg-1, n=5) or sCR1sLe(x) (15 mg kg-1, n=5) also reduces the myocardial TnT release from 80+/-20 ng ml-1 (control) to 13+/-7 or 4+/-1 ng ml-1, respectively. 5 Thus, sCR1 or sCRsLe(x) significantly reduce infarct size and cardiac TnT release caused by 30 min of regional myocardial ischaemia and 2 h of reperfusion in the rat. The mechanisms of the cardioprotective effects of sCR1 or sCR1sLe(x) are not entirely clear, but may be due complement inhibition and/or prevention of the adhesion and activation of neutrophils.

Animals↗

PubMed1999

Identification of copper/zinc superoxide dismutase as a novel nitric oxide-regulated gene in rat glomerular mesangial cells and kidneys of endotoxemic rats.

To define the mechanism of nitric oxide (NO) action in the glomerulus, we attempted to identify genes that are regulated by NO in rat glomerular mesangial cells. We identified a Cu/Zn superoxide dismutase (SOD) that was strongly induced in these cells by treatment with S-nitroso-glutathione as a NO-donating agent. Bacterial lipopolysaccharide (LPS) acutely decreased Cu/Zn SOD mRNA levels. The LPS-mediated decrease in Cu/Zn SOD is reversed by endogenously produced NO, as LPS also induced a delayed strong iNOS expression in these cells in vitro, which is accompanied by increased Cu/Zn SOD expression. NO dependency of Cu/Zn SOD mRNA recovery could be demonstrated by inhibition of this process by L-NG-monomethylarginine, an inhibitor of NOS enzymatic activity. To demonstrate the in vivo relevance of our observations, we have chosen LPS-treated rats as a model for induction of a systemic inflammatory response. In these animals, we demonstrate a direct coupling of Cu/Zn SOD expression levels to the presence of NO, as Cu/Zn SOD mRNA levels declined during acute inflammation in the presence of a selective inhibitor of iNOS. We propose that the up-regulation of Cu/Zn SOD by endogenous NO may serve as an adaptive, protective mechanism to prevent the formation of toxic quantities of peroxynitrite in conditions associated with iNOS induction during endotoxic shock.

Animals↗

PubMed1999

Selective activation of the prostanoid EP(3) receptor reduces myocardial infarct size in rodents.

The cardioprotective effects of E-type prostaglandins (EPs) have been attributed to vasodilatation, inhibition of platelet and neutrophil function (EP(2) mediated), and an unknown "cytoprotective effect." We have hypothesized that selective activation of EP(3) receptors may cause cardioprotection. The prostanoid derivative ONO-AE-248 selectively binds to murine EP(3alpha) receptors expressed in Chinese hamster ovary (CHO) cells (K(i), 15 nmol/L) and prevents the rise in cAMP caused by forskolin in CHO cells (IC(50) approximately 1 nmol/L) in which the EP(3alpha) receptor had been expressed. In anesthetized rats subjected to regional myocardial ischemia for 25 or 45 minutes and 2 hours of reperfusion, infusion of ONO-AE-248 (5 microg kg(-1). min(-1) IV) caused a significant reduction in infarct size, from 60+/-3% (n=8) to 36+/-6% (n=7) and from 78+/-2% (n=11) to 58+/-4% (n=9), respectively. The reduction in infarct size caused by ONO-AE-248 in rats subjected to 25 minutes of ischemia and reperfusion was abolished by a selective inhibitor of ATP-sensitive potassium (K(ATP)) channels, 5-hydroxydecanoate (n=6), and the protein kinase C inhibitors staurosporine (n=6) and chelerythrine (n=6). In anesthetized rabbits subjected to coronary artery occlusion for 45 or 60 minutes and 2 hours of reperfusion, infusion of ONO-AE-248 (5 microg. kg(-1). min(-1) IV) caused a significant reduction in infarct size, from 61+/-2% (n=10) to 36+/-4% (n=8) and from 63+/-4% (n=7) to 42+/-4% (n=7), respectively. The reduction in infarct size caused by ONO-AE-248 in the rabbit was also abolished by 5-hydroxydecanoate. The cardioprotective effect of ONO-AE-248 in rats or rabbits was not associated with any hemodynamic effects. Selective activation of the prostanoid EP(3) receptor reduces myocardial infarct size in rodents by a mechanism(s) that may involve the activation of protein kinase C and the opening of K(ATP) channels.

Animals↗

PubMed1999

Endotoxin induces a second window of protection in the rat heart as determined by using p-nitro-blue tetrazolium staining, cardiac troponin T release, and histology.

Pretreatment of rats with small doses of lipopolysaccharide (LPS), eg, for 24 hours, attenuates the cardiac dysfunction caused by subsequent period of myocardial ischemia. This phenomenon of enhanced tolerance to an ischemic insult has been termed "second window of protection." Although the cardioprotective effects of LPS were first reported in 1989, it is still unclear whether the observed attenuation by LPS of the ischemia-induced cardiac dysfunction is indeed secondary to the protection of cardiac myocytes against ischemic cell injury and death. This study was designed to investigate the effects of "preconditioning" with LPS on cell injury caused by regional myocardial ischemia and reperfusion in the anesthetized rat. Thirty-five Wistar rats were subjected to 25 minutes occlusion of the left anterior descending coronary artery followed by 2 hours of reperfusion. Hemodynamic parameters were continuously recorded, and at the end of the experiments, infarct size (using p-nitro-blue tetrazolium staining), cardiac troponin T release, and histological markers of cell injury and death were determined. In rats pretreated with a bolus of saline (vehicle for LPS) 2 or 24 hours before left anterior descending coronary artery occlusion and reperfusion, the infarct size was 59+/-4% (2 hours saline-control, n=6) and 61+/-3% (24 hours saline-control, n=6), respectively. Pretreatment of animals with a bolus of LPS (1 mg/kg IP) 24 hours before the onset of myocardial ischemia and reperfusion reduced both infarct size (to 18+/-7%; P<0.05, n=6) as well as histological signs of cell injury. Pretreatment (24 hours, as above) of rats with LPS also reduced the release of cardiac troponin T from 58+/-13 ng/mL (saline-control) to 16+/-9 ng/mL. In contrast, pretreatment of rats with LPS (2 hours, as above) did not affect infarct size (56+/-8%, n=6), cardiac troponin T release, or the histological parameters of cell injury. These data provide the first conclusive evidence that pretreatment of rats with a bolus of LPS 24 hours before intervention reduces the cell injury and death caused by a subsequent period of myocardial ischemia and reperfusion.

Animals↗

PubMed1997

[Local drug delivery and gene therapy].

One of the most important problems in clinical cardiology is still unresolved, i.e., the development of a restenosis following coronary balloon angioplasty. Our knowledge about the sequelae of pathophysiologic events occurring during neointima formation is still far from complete (Figure 1) and numerous therapeutic trials using systemic administration of drugs with different mechanisms of action have failed. Possible innovative strategies are the local administration of high doses of drugs into the coronary arteries and local gene therapeutic interventions to inhibit neointima formation by reducing the proliferation of vascular smooth muscle cells. Numerous catheter devices were developed (Figure 2) in order to enable the local application of high doses of a drug or DNA. Additionally, galenic techniques are being developed to guarantee a steady release of locally administered drugs, e.g. from drug containing liposomes or microcarriers (Figure 3). There are already several animal models in which the development of a neointima was reduced by injecting antisense oligonucleotides directed towards the RNA encoding cell cycle regulatory proteins or peptides. Alternatively, the transfer of cDNA encoding proteins or protein products which inhibit the cellular proliferation and migration are being tested in vitro and in vivo with the help of reporter genes (Figure 4). Although, gene transfer techniques are believed to offer great therapeutic options for the future, the clinical data available today regarding this method are very limited and are derived from studies in patients with peripheral arterial disease. Thus, it is still questionable if gene transfer techniques will ever be able to become an integral part of our standard treatment for patients with vascular diseases.

Coronary Disease↗