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PKG pathway fails to limit infarct size in hearts from hyperlipidaemic rats
S214
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S190–S218
plasma levels with time in almost all patients. This elevation started approximately after 24 h of arrivals. Obtained results might bring to light the importance of A1AT in the monitoring, treatment and prognosis of AMI patients. Keywords: Infarction; Enzymes doi:10.1016/j.yjmcc.2007.03.645
Cardioprotective effect of phosphodiesterase inhibitor ‘ordonofil’ compared to that of Sildeanfil Said Y. Khatib, Tariq R. Tamimi. Jordan University of Science & Technology, Faculty of Medicine. Irbid, Jordan Phosphodiesterase type-5 (PDE-5) inhibitors, Sildenafil (SILD), Vardenafil (VAR) and Ordonafil (ORD), have been developed for erectile dysfunction. Recently SILD and VAR were shown to have cardioprotective effect by reducing the infarct size in ischemic/reperfusion injury. To support the suggestion that this effect is a generalized “class” effect we decided to test the cardioprotective effect of ORD and to compare it to that of SILD. Isolated rabbit's hearts, perfused using Langendorff system, were subjected to 30 min of global ischemia followed by 2 h of reperfusion. At end of perfusion the heart was sliced into 5–6 cuts, 2 mm thick and incubated in 1% triphenyltetrazolium chloride. The area of infarction and the whole left ventricle (LV) were measured by computer morphometry using image tool software. The infarct size was expressed as % of LV. Creatine kinase enzyme (CK) as a marker of infarction, was determined in the perfusate pre- and post-ischemia by enzyme bioassay. The drugs, SILD or ORD at 1 mg/L, perfused the heart for 5 min before induction of ischemia. The results of both drugs showed significant cardioprotective effect and the infarct size (as % of LV) was reduced from 38 ± 12% in the control group to 5 ± 2 and 9 ± 6%, mean ± SD, n = 6–8, P < 0.004 for ORD and SILD, respectively. Similarly the increase in CK was attenuated from 32 times increase in the control group to 20 times and 26 times for ORD and SILD, respectively. These results support the notation that the class of PDE-5 inhibitors has protective effect in the ischemic heart beside their effect in the treatment of erectile dysfunction. Keywords: Cardioprotection; Myocardial infarction; Phosphodiesterase inhibitors doi:10.1016/j.yjmcc.2007.03.646
Activation of cyclic GMP/PKG pathway fails to limit infarct size in hearts from hyperlipidaemic rats Z. Giricz, D.S. Burley, P. Ferdinandy, G.F. Baxter. Cardiovascular Res. Group, Univ of Szeged, Hungary. The Royal Vet Coll, Univ of London, UK
Elevation of intracellular cGMP as a result of soluble guanylate cyclase activation by NO or particulate guanylate cyclase activation by B-type natriuretic peptide (BNP) increases resistance to ischaemia–reperfusion injury. The downstream signalling pathways and effectors of protection are unclear but could include PKG. In hyperlipidaemia, attenuation of vascular cGMP production has been reported. Therefore, we investigated the cardioprotective efficacy of cGMP-elevating agents in hearts from normal and hyperlipidemic rats. Male Wistar rats were fed with normal or 2% cholesterol-enriched chow for 12 weeks. The hearts were subjected to 30 min occlusion of the left main coronary artery, followed by 120 min reperfusion and the infarct size was determined. Treatment with the cGMP analogue 8-BrcGMP (CG), the NO-donor S-nitroso-N-acetylpenicillamine (SNAP), or BNP from 10 min prior to coronary occlusion until 10 min after reperfusion decreased infarct size in normal chow-fed rat hearts. The protective action of BNP was abolished by PKG inhibitors KT5823 or 8-pCPT-PET-cGMPS. In hearts from hyperlipidemic rats, CG, SNAP, or BNP failed to decrease infarct size. These data confirm that diverse cGMPelevating agents are protective against ischemia–reperfusion injury and suggest that PKG is a key downstream component of BNP's cardioprotective signalling pathway. Defects in the cardioprotective cGMP/PKG pathway may be a critical biochemical anomaly in chronic hyperlipidemia (Supported by the Wellcome Trust). Keywords: BNP; Hyperlipidemia doi:10.1016/j.yjmcc.2007.03.647
Coenzyme Q10-loaded liposomes effectively protect the myocardium in rabbits with an acute experimental myocardial infarction D.D. Verma, W. Hartner, T. Levchenko, V. Torchilin. Department of Pharmaceutical Sciences, Northeastern University, Boston, USA We assessed whether the intracoronary infusion of Coenzyme Q10-loaded liposomes (Q10-L) will reduce the fraction of the irreversibly damaged myocardium in rabbits with an experimental myocardial infarction. Q10-L, empty liposomes (EL), or Krebs-Henseleit (KH) buffer were administered by intracoronary infusion, followed immediately by 30 min of occlusion and 3 h of reperfusion. Unisperse Blue dye's presence was used to demarcate the size of the occlusion-induced ischemic zone (area at risk), and nitroblue tetrazolium staining was used to detect the final fraction of the irreversibly damaged myocardium within the total area at risk. The total size of the area at risk in all experimental animal groups was approximately 20–27 wt.% of the left ventricle. The irreversible damage in Q10-L-treated (containing 36 mg of CoQ10 in perfused liposome solution) animals was only ca. 31% of the total area at risk as compared with ca. 59% in the group treated
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S190–S218
plasma levels with time in almost all patients. This elevation started approximately after 24 h of arrivals. Obtained results might bring to light the importance of A1AT in the monitoring, treatment and prognosis of AMI patients. Keywords: Infarction; Enzymes doi:10.1016/j.yjmcc.2007.03.645
Cardioprotective effect of phosphodiesterase inhibitor ‘ordonofil’ compared to that of Sildeanfil Said Y. Khatib, Tariq R. Tamimi. Jordan University of Science & Technology, Faculty of Medicine. Irbid, Jordan Phosphodiesterase type-5 (PDE-5) inhibitors, Sildenafil (SILD), Vardenafil (VAR) and Ordonafil (ORD), have been developed for erectile dysfunction. Recently SILD and VAR were shown to have cardioprotective effect by reducing the infarct size in ischemic/reperfusion injury. To support the suggestion that this effect is a generalized “class” effect we decided to test the cardioprotective effect of ORD and to compare it to that of SILD. Isolated rabbit's hearts, perfused using Langendorff system, were subjected to 30 min of global ischemia followed by 2 h of reperfusion. At end of perfusion the heart was sliced into 5–6 cuts, 2 mm thick and incubated in 1% triphenyltetrazolium chloride. The area of infarction and the whole left ventricle (LV) were measured by computer morphometry using image tool software. The infarct size was expressed as % of LV. Creatine kinase enzyme (CK) as a marker of infarction, was determined in the perfusate pre- and post-ischemia by enzyme bioassay. The drugs, SILD or ORD at 1 mg/L, perfused the heart for 5 min before induction of ischemia. The results of both drugs showed significant cardioprotective effect and the infarct size (as % of LV) was reduced from 38 ± 12% in the control group to 5 ± 2 and 9 ± 6%, mean ± SD, n = 6–8, P < 0.004 for ORD and SILD, respectively. Similarly the increase in CK was attenuated from 32 times increase in the control group to 20 times and 26 times for ORD and SILD, respectively. These results support the notation that the class of PDE-5 inhibitors has protective effect in the ischemic heart beside their effect in the treatment of erectile dysfunction. Keywords: Cardioprotection; Myocardial infarction; Phosphodiesterase inhibitors doi:10.1016/j.yjmcc.2007.03.646
Activation of cyclic GMP/PKG pathway fails to limit infarct size in hearts from hyperlipidaemic rats Z. Giricz, D.S. Burley, P. Ferdinandy, G.F. Baxter. Cardiovascular Res. Group, Univ of Szeged, Hungary. The Royal Vet Coll, Univ of London, UK
Elevation of intracellular cGMP as a result of soluble guanylate cyclase activation by NO or particulate guanylate cyclase activation by B-type natriuretic peptide (BNP) increases resistance to ischaemia–reperfusion injury. The downstream signalling pathways and effectors of protection are unclear but could include PKG. In hyperlipidaemia, attenuation of vascular cGMP production has been reported. Therefore, we investigated the cardioprotective efficacy of cGMP-elevating agents in hearts from normal and hyperlipidemic rats. Male Wistar rats were fed with normal or 2% cholesterol-enriched chow for 12 weeks. The hearts were subjected to 30 min occlusion of the left main coronary artery, followed by 120 min reperfusion and the infarct size was determined. Treatment with the cGMP analogue 8-BrcGMP (CG), the NO-donor S-nitroso-N-acetylpenicillamine (SNAP), or BNP from 10 min prior to coronary occlusion until 10 min after reperfusion decreased infarct size in normal chow-fed rat hearts. The protective action of BNP was abolished by PKG inhibitors KT5823 or 8-pCPT-PET-cGMPS. In hearts from hyperlipidemic rats, CG, SNAP, or BNP failed to decrease infarct size. These data confirm that diverse cGMPelevating agents are protective against ischemia–reperfusion injury and suggest that PKG is a key downstream component of BNP's cardioprotective signalling pathway. Defects in the cardioprotective cGMP/PKG pathway may be a critical biochemical anomaly in chronic hyperlipidemia (Supported by the Wellcome Trust). Keywords: BNP; Hyperlipidemia doi:10.1016/j.yjmcc.2007.03.647
Coenzyme Q10-loaded liposomes effectively protect the myocardium in rabbits with an acute experimental myocardial infarction D.D. Verma, W. Hartner, T. Levchenko, V. Torchilin. Department of Pharmaceutical Sciences, Northeastern University, Boston, USA We assessed whether the intracoronary infusion of Coenzyme Q10-loaded liposomes (Q10-L) will reduce the fraction of the irreversibly damaged myocardium in rabbits with an experimental myocardial infarction. Q10-L, empty liposomes (EL), or Krebs-Henseleit (KH) buffer were administered by intracoronary infusion, followed immediately by 30 min of occlusion and 3 h of reperfusion. Unisperse Blue dye's presence was used to demarcate the size of the occlusion-induced ischemic zone (area at risk), and nitroblue tetrazolium staining was used to detect the final fraction of the irreversibly damaged myocardium within the total area at risk. The total size of the area at risk in all experimental animal groups was approximately 20–27 wt.% of the left ventricle. The irreversible damage in Q10-L-treated (containing 36 mg of CoQ10 in perfused liposome solution) animals was only ca. 31% of the total area at risk as compared with ca. 59% in the group treated