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Adenosine A2a agonist CGS-21680 improves recovery of ventricular function after ischemia-reperfusion in regionally stunned porcine myocardium
S36
Surgical Forum Abstracts
J Am Coll Surg
zation and thereafter in the antegrade working mode to allow for assessment of functional parameters. Results: Phosphorylation of Transcription Factors HR CF dp/dtmax Infarct size (Beats/min) (ml/min) (mm Hg/sec) % Control BL R120 (⫺)Losartan BL R120 (⫹)Losartan BL R120
290 ⫾ 6 272 ⫾ 6
24 ⫾ 1 4367 ⫾ 110 25.2 ⫾ 1 4022 ⫾ 100
JAK
STAT
(Arbitrary Units)
— 3⫾1
— 8⫾1
— 14 ⫾ 2
291 ⫾ 7 285 ⫾ 4
24 ⫾ 1 4479 ⫾ 123 22 ⫾ 2 1715 ⫾ 77*†
— 35 ⫾ 1†
— 79 ⫾ 5†
— 155 ⫾ 5†
292 ⫾ 5 291 ⫾ 5
25 ⫾ 1 4287 ⫾ 92 24 ⫾ 1 2834 ⫾ 111*†
— 20⫹1†
— 14 ⫾ 1.8
— 32 ⫾ 4
BL: baseline; HR: heart rate; CF: coronary flow; dp/dt developed pressure.
max:
maximum first derivative of
* p ⬍ 0.05 vs. BL; †p ⬍ 0.05 vs. control
Conclusions: Our results documented for the first time that losartan induces cardioprotection and blocks the activation of JAK/STAT signaling in the ischemic reperfused myocardium.
Adenosine A2a agonist CGS-21680 improves recovery of ventricular function after ischemia-reperfusion in regionally stunned porcine myocardium M. Salik Jahania MD, Robert Lasley Ph.D., Prakash Narayan Ph.D., Timothy W. Mullett MD, Juan A Sanchez MD, FACS, Robert M Mentzer, Jr, MD, FACS. Department of Surgery, University of Kentucky, Lexington, KY, M. Salik Jahania, MD, Univ. of Kentucky Chandler Medical Center, C421, 800 Rose Street, Lexington, KY 40536, USA. E-mail: [email protected]. Phone: 606-323USA.1335. Fax: 606-323-1700. Introduction: The use of the adenosine (ADO) A2a agonist CGS-21680 (CGS) after ischemia/reperfusion is usually accompanied by systemic hypotension and tachycardia. The purpose of this study was to test the hypothesis that low dose CGS would attenuate myocardial stunning independent of changes in coronary blood flow (CBF) and avoid changes in systemic blood pressure (SBP) and heart rate (HR). Methods: Open chest pigs underwent 15 minute left anterior descending coronary artery (LAD) ischemia followed by 3.5 hours of reperfusion (RP). Control animals (n ⫽ 6) received 0.9 N NaCl (saline) intracoronary (ic) during RP. Treated animals (n ⫽ 6) received saline for the first 2 hr RP, followed by CGS (0.05– 0.1 mg/kg/min, ic) for 1 hour and saline for last 30 minutes. Regional stunning was assessed using sonomicrometry to measure load-insensitive preload recruitable stroke work area (PRSWA). Results: There was no difference in PRSWA between the two groups before or after ischemia until the low dose CGS infusion was initiated whereupon the A2a agonist significantly increased PRSWA (93 ⫾ 10% compared to 51 ⫾ 4% of preischemic values, p ⬍0.01). Although CGS infusion was accompanied by a 2-fold increase in LAD CBF, it did not alter PRSWA in the nonstunned myocardium. Moreover, the improved functional recovery persisted long after the cessation of the CGS infusion and return of CBF to preinfusion levels. Low dose CGS was not associated with changes in SBP or HR. Conclusions: These results indicate that low dose CGS infusion during RP avoids significant changes in SBP and HR and attenuates myocardial stunning independent of increases in CBF. ADO A2a agonist treatment may be beneficial after acute ischemia-reperfusion episodes which occur during off pump coronary artery bypass surgery.
␦ Selective opioid agonist based cardioprotection is mediated by potassium-ATP channels Christopher D Nicholas MD, M Salik Jahania MD, Julia Wedge BS, Meera Govindaswami Ph.D., Peter Oeltgen Ph.D., Robert M Mentzer, Jr. MD, FACS, Juan A Sanchez MD, FACS: M Salik Jahania, MD.
Department of Surgery, University of Kentucky, Lexington, KY; Univ. of Kentucky Chandler Medical Center, C421, 800 Rose Street, Lexington, KY 40536 USA. E-mail: [email protected]. Phone: 606-323-1335. Fax: 606-323-1700. Introduction: Opioid agonists have been shown to reduce myocardial ischemia-reperfusion injury but the exact mechanism is unknown. We tested the hypothesis that opioid mediated cardioprotection may be linked to K⫹-ATP channels which can be abolished by glibenclamide. Methods: Isolated, oxygenated KHB perfused rat hearts (350 – 400 g) underwent 20 min global ischemia and 120 min reperfusion, at 37° C in modified Langendorff mode. Coronary perfusion pressure was maintained at 70 mm Hg by regulating coronary flow. Hearts were paced at 5.5 Hz except during ischemia. Left ventricular (LV) developed pressure (DP) and LV end diastolic pressure (LVEDP) was measured with a saline filled balloon. Treated animals (Group Z, n ⫽ 6) received ZGI-04 (a ␦-2 selective agonist 2 mg/kg) via tail vein 24 hrs prior to cardiectomy. Control hearts (Group C, n ⫽ 6) received saline. In another set of experiments, ZGI-04 treated animals received 1mg/kg glibenclamide (GB) at 24.5 hrs (Group G1 n ⫽ 6) or .5 hrs (Group G2, n ⫽ 6) prior to cardiectomy. Infarct size was measured with TTC staining and expressed as percent of region at risk. Data were analyzed using paired Student’s t-Test and expressed as mean ⫾ SEM (p ⬍ 0.05 ⫽ significant). Results: ZGI-04 treatment caused a decrease in infarct size (12 ⫾ 3 % Group Z vs, 27 ⫾ 5 % Group C, p ⫽ 0.04). GB abolished the infarct reduction by ZGI-04 (23 ⫾ 5% Group G1, 20 ⫾ 2% GroupG2, p ⫽ NS vs Group C). The reduction in LVEDP at 5 min of reperfusion by ZGI-04 (38 ⫾ 6mmHg Group C vs 8 ⫾ 4 mmHg ZGI, p ⫽ 0.003)) was blocked by GB treatment (23 ⫾ 4 mmHg group G1 vs 38 ⫾ 6mmHg Group C, p ⫽ NS). Conclusions: These data suggest that the cardioprotective effect of opioid agonists may be mediated by activation of K⫹-ATP channels.
Targeted disruption of the heme oxygenase gene impairs myocardial preservation and preconditioning Daniel T Engelman, MD, Richard M Engelman, MD, FACS, John A Rousou, MD, FACS, Joseph E Flack, MD, David W Deaton, MD, FACS, Nilanjana Maulik, PhD, Tetsuya Yoshida, MD, Ye-Shih Ho, PhD, Dipak K Das, PhD. Dept. Surgery, Baystate Medical Center, 759 Chestnut St., Springfield, MA, 01107, USA (413) 794-5550, and Univ. Connecticut Sch. of Med., Farmington, CT, and Institute of Toxicology, Wayne State Univ., Detroit, MI USA. Introduction: We sought to determine whether targeted disruption of the gene for heme oxygenase (HO-1), an intracellular antioxidant, would adversely affect myocardial preservation and preconditioning. Methods: A heterozygous knockout mouse (HO-1⫹/⫺) was created by cloning the XhoI fragment of the HO-1 gene to the targeting vector pPNT with subsequent subcloning. The vector was then transfected and recombinant ES clones identified. Male chimeric mice, generated by microinjecting C57BL/6 blastocytes, were bred with C57BL/6 females and cell line 183 knockout mice (HO-1⫹/⫺) were created. Twenty-four wild-type control (HO-1⫹/⫹) and 24 HO-1⫹/⫺ mice were divided into four groups (n ⫽ 12). Group A (control), Group B (HO-1⫹/⫺): standard Langendorff perfusion, 30 min normothermic ischemia, 2 hrs reperfusion; Group C (control), Group D (HO-1⫹/⫺): ischemic preconditioning (three 5 min periods of ischemia/5 min reperfusion) followed by 30 min normothermic ischemia, 2 hrs reperfusion. CK release, malonaldehyde generation, myocardial contractility and infarct size were all measured. Results: A 40% reduction of HO-1 protein was found in the HO-1⫹/⫺ hearts compared to wild-type controls. The HO-1⫹/⫺ hearts displayed significantly (p ⬍ 0.05) reduced postischemic recovery, increased CK release, infarct size, and malonaldehyde generation. Preconditioned HO-1⫹/⫺ hearts had only a minimal improvement in function, CK release, infarct size, and oxidative stress. Conclusions: Genetic engineering can produce mice with a deficient HO-1 gene that are more susceptible to ischemia/reperfusion
Surgical Forum Abstracts
J Am Coll Surg
zation and thereafter in the antegrade working mode to allow for assessment of functional parameters. Results: Phosphorylation of Transcription Factors HR CF dp/dtmax Infarct size (Beats/min) (ml/min) (mm Hg/sec) % Control BL R120 (⫺)Losartan BL R120 (⫹)Losartan BL R120
290 ⫾ 6 272 ⫾ 6
24 ⫾ 1 4367 ⫾ 110 25.2 ⫾ 1 4022 ⫾ 100
JAK
STAT
(Arbitrary Units)
— 3⫾1
— 8⫾1
— 14 ⫾ 2
291 ⫾ 7 285 ⫾ 4
24 ⫾ 1 4479 ⫾ 123 22 ⫾ 2 1715 ⫾ 77*†
— 35 ⫾ 1†
— 79 ⫾ 5†
— 155 ⫾ 5†
292 ⫾ 5 291 ⫾ 5
25 ⫾ 1 4287 ⫾ 92 24 ⫾ 1 2834 ⫾ 111*†
— 20⫹1†
— 14 ⫾ 1.8
— 32 ⫾ 4
BL: baseline; HR: heart rate; CF: coronary flow; dp/dt developed pressure.
max:
maximum first derivative of
* p ⬍ 0.05 vs. BL; †p ⬍ 0.05 vs. control
Conclusions: Our results documented for the first time that losartan induces cardioprotection and blocks the activation of JAK/STAT signaling in the ischemic reperfused myocardium.
Adenosine A2a agonist CGS-21680 improves recovery of ventricular function after ischemia-reperfusion in regionally stunned porcine myocardium M. Salik Jahania MD, Robert Lasley Ph.D., Prakash Narayan Ph.D., Timothy W. Mullett MD, Juan A Sanchez MD, FACS, Robert M Mentzer, Jr, MD, FACS. Department of Surgery, University of Kentucky, Lexington, KY, M. Salik Jahania, MD, Univ. of Kentucky Chandler Medical Center, C421, 800 Rose Street, Lexington, KY 40536, USA. E-mail: [email protected]. Phone: 606-323USA.1335. Fax: 606-323-1700. Introduction: The use of the adenosine (ADO) A2a agonist CGS-21680 (CGS) after ischemia/reperfusion is usually accompanied by systemic hypotension and tachycardia. The purpose of this study was to test the hypothesis that low dose CGS would attenuate myocardial stunning independent of changes in coronary blood flow (CBF) and avoid changes in systemic blood pressure (SBP) and heart rate (HR). Methods: Open chest pigs underwent 15 minute left anterior descending coronary artery (LAD) ischemia followed by 3.5 hours of reperfusion (RP). Control animals (n ⫽ 6) received 0.9 N NaCl (saline) intracoronary (ic) during RP. Treated animals (n ⫽ 6) received saline for the first 2 hr RP, followed by CGS (0.05– 0.1 mg/kg/min, ic) for 1 hour and saline for last 30 minutes. Regional stunning was assessed using sonomicrometry to measure load-insensitive preload recruitable stroke work area (PRSWA). Results: There was no difference in PRSWA between the two groups before or after ischemia until the low dose CGS infusion was initiated whereupon the A2a agonist significantly increased PRSWA (93 ⫾ 10% compared to 51 ⫾ 4% of preischemic values, p ⬍0.01). Although CGS infusion was accompanied by a 2-fold increase in LAD CBF, it did not alter PRSWA in the nonstunned myocardium. Moreover, the improved functional recovery persisted long after the cessation of the CGS infusion and return of CBF to preinfusion levels. Low dose CGS was not associated with changes in SBP or HR. Conclusions: These results indicate that low dose CGS infusion during RP avoids significant changes in SBP and HR and attenuates myocardial stunning independent of increases in CBF. ADO A2a agonist treatment may be beneficial after acute ischemia-reperfusion episodes which occur during off pump coronary artery bypass surgery.
␦ Selective opioid agonist based cardioprotection is mediated by potassium-ATP channels Christopher D Nicholas MD, M Salik Jahania MD, Julia Wedge BS, Meera Govindaswami Ph.D., Peter Oeltgen Ph.D., Robert M Mentzer, Jr. MD, FACS, Juan A Sanchez MD, FACS: M Salik Jahania, MD.
Department of Surgery, University of Kentucky, Lexington, KY; Univ. of Kentucky Chandler Medical Center, C421, 800 Rose Street, Lexington, KY 40536 USA. E-mail: [email protected]. Phone: 606-323-1335. Fax: 606-323-1700. Introduction: Opioid agonists have been shown to reduce myocardial ischemia-reperfusion injury but the exact mechanism is unknown. We tested the hypothesis that opioid mediated cardioprotection may be linked to K⫹-ATP channels which can be abolished by glibenclamide. Methods: Isolated, oxygenated KHB perfused rat hearts (350 – 400 g) underwent 20 min global ischemia and 120 min reperfusion, at 37° C in modified Langendorff mode. Coronary perfusion pressure was maintained at 70 mm Hg by regulating coronary flow. Hearts were paced at 5.5 Hz except during ischemia. Left ventricular (LV) developed pressure (DP) and LV end diastolic pressure (LVEDP) was measured with a saline filled balloon. Treated animals (Group Z, n ⫽ 6) received ZGI-04 (a ␦-2 selective agonist 2 mg/kg) via tail vein 24 hrs prior to cardiectomy. Control hearts (Group C, n ⫽ 6) received saline. In another set of experiments, ZGI-04 treated animals received 1mg/kg glibenclamide (GB) at 24.5 hrs (Group G1 n ⫽ 6) or .5 hrs (Group G2, n ⫽ 6) prior to cardiectomy. Infarct size was measured with TTC staining and expressed as percent of region at risk. Data were analyzed using paired Student’s t-Test and expressed as mean ⫾ SEM (p ⬍ 0.05 ⫽ significant). Results: ZGI-04 treatment caused a decrease in infarct size (12 ⫾ 3 % Group Z vs, 27 ⫾ 5 % Group C, p ⫽ 0.04). GB abolished the infarct reduction by ZGI-04 (23 ⫾ 5% Group G1, 20 ⫾ 2% GroupG2, p ⫽ NS vs Group C). The reduction in LVEDP at 5 min of reperfusion by ZGI-04 (38 ⫾ 6mmHg Group C vs 8 ⫾ 4 mmHg ZGI, p ⫽ 0.003)) was blocked by GB treatment (23 ⫾ 4 mmHg group G1 vs 38 ⫾ 6mmHg Group C, p ⫽ NS). Conclusions: These data suggest that the cardioprotective effect of opioid agonists may be mediated by activation of K⫹-ATP channels.
Targeted disruption of the heme oxygenase gene impairs myocardial preservation and preconditioning Daniel T Engelman, MD, Richard M Engelman, MD, FACS, John A Rousou, MD, FACS, Joseph E Flack, MD, David W Deaton, MD, FACS, Nilanjana Maulik, PhD, Tetsuya Yoshida, MD, Ye-Shih Ho, PhD, Dipak K Das, PhD. Dept. Surgery, Baystate Medical Center, 759 Chestnut St., Springfield, MA, 01107, USA (413) 794-5550, and Univ. Connecticut Sch. of Med., Farmington, CT, and Institute of Toxicology, Wayne State Univ., Detroit, MI USA. Introduction: We sought to determine whether targeted disruption of the gene for heme oxygenase (HO-1), an intracellular antioxidant, would adversely affect myocardial preservation and preconditioning. Methods: A heterozygous knockout mouse (HO-1⫹/⫺) was created by cloning the XhoI fragment of the HO-1 gene to the targeting vector pPNT with subsequent subcloning. The vector was then transfected and recombinant ES clones identified. Male chimeric mice, generated by microinjecting C57BL/6 blastocytes, were bred with C57BL/6 females and cell line 183 knockout mice (HO-1⫹/⫺) were created. Twenty-four wild-type control (HO-1⫹/⫹) and 24 HO-1⫹/⫺ mice were divided into four groups (n ⫽ 12). Group A (control), Group B (HO-1⫹/⫺): standard Langendorff perfusion, 30 min normothermic ischemia, 2 hrs reperfusion; Group C (control), Group D (HO-1⫹/⫺): ischemic preconditioning (three 5 min periods of ischemia/5 min reperfusion) followed by 30 min normothermic ischemia, 2 hrs reperfusion. CK release, malonaldehyde generation, myocardial contractility and infarct size were all measured. Results: A 40% reduction of HO-1 protein was found in the HO-1⫹/⫺ hearts compared to wild-type controls. The HO-1⫹/⫺ hearts displayed significantly (p ⬍ 0.05) reduced postischemic recovery, increased CK release, infarct size, and malonaldehyde generation. Preconditioned HO-1⫹/⫺ hearts had only a minimal improvement in function, CK release, infarct size, and oxidative stress. Conclusions: Genetic engineering can produce mice with a deficient HO-1 gene that are more susceptible to ischemia/reperfusion