Percent Segment Shortening Research Articles

Direct Protective Effects of Dexmedetomidine Against Myocardial Ischemia-Reperfusion Injury in Anesthetized Pigs

Systemic administration of α2-adrenergic agonists has been shown to protect ischemic myocardium, but the direct effects on ischemia-reperfused myocardium have not yet been clarified. This study was carried out to determine the effects of intracoronary dexmedetomidine (DEX) on the myocardial ischemia-reperfusion injury in anesthetized pigs. In open-chest pigs, the left anterior descending coronary artery was perfused through an extracorporeal circuit from the carotid artery. They received intracoronary infusion of DEX at a rate of 1 ng · mL(-1) (group LD, n = 9), 10 ng · mL(-1) (group MD, n = 9), or 100 ng · mL(-1) (group HD, n = 9) of coronary blood flow or vehicle (group C, n = 12) for 30 min before ischemia. Myocardial stunning was produced by 12-min ischemia of the perfused area of left anterior descending coronary artery and 90-min reperfusion. The effect on reperfusion-induced arrhythmias was evaluated using the incidence of ventricular tachycardia or fibrillation after reperfusion. Regional myocardial contractility was evaluated with segment shortening (%SS). Dexmedetomidine significantly reduced the incidence of reperfusion-induced ventricular arrhythmias. Dexmedetomidine significantly improved the recovery of percentage segment shortening at 90 min after reperfusion (32.6% ± 3.1% in group C, 58.2% ± 2.1% in group LD, 61.1% ± 1.8% in group MD, and 72.0% ± 2.0% in group HD). Dexmedetomidine suppressed the increase in plasma norepinephrine concentration after reperfusion. The results indicate that DEX would exert the protective effect against ischemia-reperfusion injury by the direct action on the myocardium, which is not mediated through the central nervous system.

The Effect of Pimobendan on Myocardial Mechanical Function and Metabolism in Dogs: Comparison with Dobutamine

The effect of pimobendan, a newly developed cardiotonic agent, on myocardial mechanical function and energy metabolism has been examined in the dog heart, and compared with that of dobutamine. Either saline, vehicle for pimobendan, dobutamine (0.3 and 1 microgram kg-1), or pimobendan (0.3 and 1 mg kg-1) was injected intravenously. Dobutamine and pimobendan both increased the first derivative of left ventricular pressure and percent segment shortening, indicating their positive inotropic action. After 2 min of dobutamine injection, or after 20 min of pimobendan injection, the myocardium was removed, and used for determination of the tissue levels of metabolites of energy and carbohydrate metabolism. In general, all metabolic parameters measured were not changed by either dobutamine or pimobendan injection. In animals with aortic constriction for 10 months, dobutamine and pimobendan injections did not alter the myocardial energy and carbohydrate metabolism. Although dobutamine and pimobendan increased the cardiac mechanical function, they did not disturb the myocardial energy and carbohydrate metabolism.

Postischemic infusion of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, protects against myocardial stunning in swine

It seems controversial whether or not neutrophil elastase inhibitors are effective in attenuating myocardial ischemia/reperfusion injury. We thus investigated possible protective effects of sivelestat, a neutrophil elastase inhibitor, against myocardial stunning i.e., prolonged myocardial dysfunction following a brief episode of ischemia. Swine were divided into control group (group C), low-dose sivelestat group (group L), and high-dose sivelestat group (group H) (n = 7 for each group). All the swine were subjected to myocardial ischemia through ligation of the left anterior descending (LAD) coronary artery for 12-min, followed by 90-min reperfusion. Sivelestat was infused intracoronally at concentrations of 6 and 60 mg/ml throughout the reperfusion period in groups L and H, respectively, while saline was infused in the group C. Heart rate (HR), left ventricular developed pressure (LVdP), maximum rate of LVdP (LVdP/dt (max)), LV end-diastolic pressure (LVEDP), percentage of segment shortening (%SS, an index of regional myocardial contractility), and coronary venous interleukin-6 concentration in the LAD perfusion area were measured before ischemic induction and during reperfusion. The ischemia/reperfusion insult did not cause any significant changes in HR, LVdP, LVdP/dt (max), and LVEDP in all groups. However, it significantly reduced %SS in the LAD perfusion area and increased the interleukin-6 concentration in group C. Those changes in %SS and the interleukin-6 concentration were both greatly attenuated, but not prevented, in groups L and H. Sivelestat presumably attenuates myocardial contractile dysfunction due to myocardial stunning by inhibiting neutrophil-derived elastase, thereby suppressing the production of interleukin-6 in activated neutrophils.

Administration of the Rho-Kinase Inhibitor Fasudil Before Ischemia or just After Reperfusion, but not 30 min After Reperfusion, Protects the Stunned Myocardium in Swine

We assessed the effect of administration time for fasudil treatment of the stunned myocardium in 40 anesthetized open chest swine. All swine were subjected to 12 min ischemia followed by reperfusion to generate stunned myocardium. Group A (n = 11) received saline in place of fasudil both before ischemia and after reperfusion. Group B (n = 10) received 30 min intravenous fasudil at a rate of 13 mug/kg/min starting 45 min before ischemia and received saline after reperfusion. Groups C (n = 10) and D (n = 9) received saline before ischemia, and received fasudil at a rate of 13 microg kg(-1) min(-1) starting just before reperfusion in group C and 30 min after reperfusion in group D. In both groups, treatment lasted 30 min. Myocardial contractility was assessed by percent segment shortening (%SS). Three swine in group A, 2 swine in each of groups B and C, and one swine in group D had ventricular fibrillation or tachycardia after reperfusion and were excluded from further analysis. The changes of %SS from baseline at 90 min after reperfusion in groups B and C were 68 +/- 8% and 75 +/- 8%, respectively, which were significantly higher than in group A or D (47 +/- 10% or 43 +/- 8%). We conclude that fasudil administered before ischemia or just after reperfusion, but not 30 min after reperfusion, protects the stunned myocardium.

Milrinone Administered Before Ischemia or Just After Reperfusion, Attenuates Myocardial Stunning in Anesthetized Swine

We assessed the dose or timing effect of milrinone administered against myocardial stunning in 37 anesthetized open-chest swine. All swine were subjected to 12-min ischemia followed by reperfusion to produce myocardial stunning. Group A (n = 12) received saline in place of milrinone both before and after ischemia. Group B (n = 9) and C (n = 9) received intravenous milrinone at a rate of 5 microg/kg/min for 10 min followed by 0.5 microg/kg/min for 10 min and 10 microg/kg/min for 10 min followed by 1 microg/kg/min for 10 min, respectively, until 30 min before coronary occlusion. Group D (n = 7) received the same dose of milrinone as group B starting 1 min after reperfusion. Myocardial contractility was assessed by percentage segment shortening (%SS). Five swine in group A and two swine in groups B and C each had ventricular fibrillation or tachycardia after reperfusion, and were thus excluded from further analysis. The percentage changes of %SS from the baseline 90 min after reperfusion in groups B, C, and D were 78 +/- 9%, 82 +/- 13%, and 79 +/- 7%, respectively, which were significantly higher than those in group A (43 +/- 13%). We conclude that milrinone administered before ischemia or just after reperfusion attenuates myocardial stunning.

Sequential deformation and physiological considerations in unipolar right or left ventricular pacing

To determine the effects of ventricular pacing on the normal contraction sequence of the helical ventricular myocardial band, and its' impact on left ventricular function. Ten pigs (25-68 kg) underwent analysis of percent segmental shortening (%SS) by sonomicrometry, with crystals placed along the fiber orientation of the ascending and descending segments, and posterior LV wall of the geometry of the helical heart. Unipolar pacing electrodes stimulated either the right atrium (RA), right ventricular apex (RVA) and outflow tract (RVOT), or posterior LV wall. Systemic hemodynamics, QRS-interval, cardiac index (CI), systolic and diastolic LV function and pressure-dimension (P-D) loops were analyzed and cardiac motion was monitored by video analysis. Normal sinus heart rate (NSR) was elevated from 84+/-15 beats/min to 113+/-22 beats/min by pacing (p<0.05). The variables of NSR were not changed by atrial pacing. Conversely, compared with NSR, ventricular pacing (RVA, RVOT, LV) significantly (p<0.05) prolonged the QRS-interval (94-111 ms vs 52+/-7 ms, p<0.05) decreased mean arterial pressure (46-47 mmHg vs 62+/-11 mmHg), CI (2.7-3.4 L/(min m2) vs 4.9+/-0.9L/(min m2)) and systolic LV pressure (56-61 mmHg vs 92+/-10 mmHg). Furthermore, ventricular pacing decreased peak +dP/dt and -dP/dt (p<0.05) and lowered PRSW to 59-77%, with most profound change after RVA pacing (p<0.05). Each ventricular pacing intervention decreased SS% significantly in the descending, ascending, and posterior LV segments compared with NSR. Disruption of the normal NSR sequence of shortening (progression from descending to posterior to ascending regions) followed each pacing intervention. Changes were characterized by premature stimulation of the segment adjacent to the pacer stimulus, with associated (1) decrease of pressure-dimension loop area, (2) desynchronization of P-D loops and (3) consistent loss of the twisting pattern of visible cardiac motion. Ventricular pacing disrupts the natural sequence of shortening along the myocardial band, and the resultant dyssynchrony impairs LV function.

The effect of ventricular sequential contraction on helical heart during pacing: high septal pacing versus biventricular pacing

To investigate the effect of biventricular and high septal pacing on the normal contraction sequence of the helical ventricular myocardial band, and its impact on left ventricular function. Ten pigs (25-68 kg) underwent analysis of percent segmental shortening (SS%) by sonomicrometry, with crystals placed along the fiber orientation of the ascending, descending segments, and posterior LV wall within the spatial geometry of the helical heart. Unipolar pacing electrodes stimulated the right atrium (RA) and either the right ventricular apex and left ventricular posterior wall (atrio-biventricular), or the proximal high septum (atrio-high septal). Systemic hemodynamics, QRS-interval, cardiac index (CI), systolic and diastolic LV functions and pressure-dimension loops (P-D) were analyzed and cardiac motion was monitored by video analysis. Pacing increased normal sinus heart rate (NSR) from 77+/-9 beats/min to 98+/-5 beats/min. Atrial pacing did not change the NSR hemodynamic variables. Conversely, atrio-biventricular pacing prolonged the QRS-interval (91+/-14 ms vs 56+/-11 ms at baseline, p<0.05) and decreased mean arterial pressure (50+/-4 mmHg vs 58+/-12 mmHg), CI (3.4+/-0.3 L/(min m2) vs 4.0+/-0.8 L/(min m2)) and PRSW (71+/-25%) compared to NSR (p<0.05). Furthermore, atrio-biventricular pacing decreased SS% in all segments, especially at the LV posterior wall (71% of baseline, p<0.05), and disrupted the NSR shortening sequence (progression from descending to posterior to ascending regions). Changes were characterized by premature stimulation of the posterior wall segment adjacent to the pacer stimulus, with associated (1) decrease of pressure-dimension loop area, (2) desynchronization of P-D loops and (3) consistent loss of the twisting pattern of visible cardiac motion. In contrast, atrio-high septal pacing restored systemic hemodynamics, LV systolic and diastolic functions to baseline values and preserved the normal sequence of shortening of the ventricular myocardial band. (1) Biventricular pacing disrupts of the natural sequence of shortening of the myocardial band and results in impaired LV function. (2) High septal pacing preserves the sequential shortening pattern of the myocardial band and LV function.

Effects of Inotropic Drugs on Mechanical Function and Oxygen Balance in Postischemic Canine Myocardium: Comparison of Dobutamine, Epinephrine, Amrinone, and Calcium Chloride

Brief ischemic episodes that induce myocardial and coronary endothelial dysfunction may alter the responses to inotropic drugs. To determine the effects of inotropic drugs in stunned myocardium, the coronary blood flow (CBF), myocardial oxygen consumption (MVO2), and regional mechanical function in response to intracoronary dobutamine, epinephrine, amrinone, and calcium chloride (CaCl2) were measured before (normal) and 30 min after a 15-min-period occlusion of the left anterior descending artery (stunned) in an open-chest canine model. Percent segment shortening (%SS) and post-systolic shortening (%PSS) were determined. Myocardial extraction of oxygen (EO2) and lactate (Elac) was calculated. The inotropic drugs increased %SS, CBF, and MVO2 in normal myocardium. Epinephrine and amrinone decreased, while dobutamine and CaCl2 did not affect EO2. The ischemia and reperfusion itself significantly reduced %SS and Elac, and increased %PSS. In stunned myocardium, the responses to inotropic drugs were not significantly altered, except that they progressively reduced %PSS and epinephrine did not affect EO2. These findings indicate that a brief episode of ischemia does not affect the mechanical and metabolic coronary flow responses to inotropic drugs, although it abolishes direct vasodilator responses to epinephrine.

Effects of SEA0400, a novel inhibitor of the Na +/Ca 2+ exchanger, on myocardial stunning in anesthetized dogs

Activation of the Na +/Ca 2+ exchanger may contribute to Ca 2+ overload during reperfusion after transient ischemia. We examined the effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a selective inhibitor of Na +/Ca 2+ exchange, on a canine model of ischemia/reperfusion injury (myocardial stunning). Myocardial stunning was induced by a 15-min occlusion of the left anterior descending coronary artery followed by a 4-h reperfusion in anesthetized open-chest dogs. Reperfusion gradually restored myocardial percent segment shortening but remained depressed during a 4-h reperfusion period. A bolus intravenous injection of SEA0400 (0.3 or 1.0 mg/kg), given 1 min before reperfusion, improved significantly the recovery of percent segment shortening in the ischemic/reperfused myocardium. SEA0400 did not affect the hemodynamics and electrocardiogram parameters. In addition, SEA0400 did not affect reperfusion-induced change in coronary blood flow. These results suggest that the Na +/Ca 2+ exchanger is involved in the stunned myocardium of dogs after reperfusion, and that SEA0400 has a protective effect against myocardial stunning in dogs.

Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest

Background Surgical coronary revascularization with cardiopulmonary bypass and cardioplegia has been associated with reperfusion injury. The serine protease inhibitor aprotinin has been suggested to reduce reperfusion injury, yet a clinically relevant study examining regional ischemia under conditions of cardiopulmonary bypass and cardioplegia has not been performed. Methods Pigs were subjected to 30 minutes of regional myocardial ischemia by distal left anterior descending coronary artery occlusion, followed by 60 minutes of cardiopulmonary bypass with 45 minutes of cardioplegic arrest and 90 minutes of post–cardiopulmonary bypass reperfusion. The treatment group (n = 6) was administered aprotinin systemically (40,000 kallikrein-inhibiting units [KIU]/kg intravenous loading dose, 40,000 KIU/kg pump prime, and 10,000 KIU · kg −1 · h −1 intravenous continuous infusion). Control animals (n = 6) received crystalloid solution. Global and regional myocardial functions were analyzed by the left ventricular+dP/dt and the percentage segment shortening, respectively. Left ventricular infarct size was measured by tetrazolium staining. Tissue myeloperoxidase activity was measured. Myocardial sections were immunohistochemically stained for nitrotyrosine. Coronary microvessel function was studied by videomicroscopy. Results Myocardial infarct size was decreased with aprotinin treatment (27.0% ± 3.5% vs 45.3% ± 3.0%, aprotinin vs control; P < .05). Myocardium from the ischemic territory showed diminished nitrotyrosine staining in aprotinin-treated animals versus controls, and this was significant by grade (1.3 ± 0.2 vs 3.2 ± 0.2, aprotinin vs control; P < .01). In the aprotinin group, coronary microvessel relaxation improved most in response to the endothelium-dependent agonist adenosine diphosphate (44.7% ± 3.2% vs 19.7% ± 1.7%, aprotinin vs control; P < .01). No significant improvements in myocardial function were observed with aprotinin treatment. Conclusions Aprotinin reduces reperfusion injury after regional ischemia and cardioplegic arrest. Protease inhibition may represent a molecular strategy to prevent postoperative myocardial injury after surgical revascularization with cardiopulmonary bypass.

Effects of Amrinone on Regional Myocardial Function and Oxygen Balance in Stunned Myocardium in Dogs

Background: Brief myocardial ischaemia has been demonstrated to result in mechanical and coronary endothelial dysfunction. We examined whether the mechanical and vascular responses to amrinone are altered in the postischaemic, reperfused myocardium. The effects of amrinone were compared with those of dobutamine. Methods: In an open-chest canine model, coronary blood flow (CBF), myocardial oxygen consumption (MVO2), and regional mechanical function in response to either amrinone (2, 5, 7.5, and 10 g/mL of CBF) or dobutamine (0.05, 0.125, 0.25, 0.375, and 10g/mL of CBF) directly infused into the left anterior descending (LAD) artery were determined before (normal) and 30 min after 15-minperiod of LAD occlusion (stunned). Percent segment shortening (%SS), peak segment lengthening rate (dL/dtmax), and percent post-systolic shortening (%PSS) in the LAD territory was determined using ultrasonic crystals and CBF using Doppler transducer. Myocardial extractions of oxygen (EO2) and lactate (Elac) were calculated. Results: Both amrinone and dobutamine in the normal myocardium caused a dose-dependent increase in mechanical functions (%SS and dL/dtmax) and MVO2 that were comparable (range, 20-40%), but they had no effects on %PSS. Amrinone caused an increase of CBF in excess of MVO2, resulting in a modest decrease in EO2, whereas dobutamine increased CBF in proportion to MVO2, resulting in no changes in EO2. The ischemia and reperfusion insult reduced %SS, dL/dtmax, and Elac, while it did not affect mechanical (%SS and dL/dtmax) and CBF responses to either agent, except for progressive reductions of %PSS. Conclusions: These results indicate that amrinone, similar to dobutamine, exert positive inotropic and lusitropic effects in normal and stunned canine myocardium. It is also indicated that amrinone causes direct coronary vasodilation, which is not affected by an ischemia and reperfusion insult.

Effects of intracoronary calcium chloride on regional oxygen balance and mechanical function in normal and stunned myocardium in dogs

Brief myocardial ischaemia has been demonstrated to result in mechanical and coronary endothelial dysfunction, in which calcium may play a role. We examined whether the mechanical and vascular responses to calcium are altered in postischaemic, reperfused myocardium. Regional myocardial oxygen consumption (MVO2), mechanical function and coronary blood flow (CBF) in response to calcium chloride (0.10, 0.25, 0.50 and 0.75 mg ml(-1) of CBF) directly infused into the left anterior descending (LAD) artery were determined before (normal) and 30 min after a 15-min-period of LAD occlusion (stunned) in an open-chest canine model. Percentage segment shortening (%SS) and percentage postsystolic shortening (%PSS) in the LAD territory were determined using ultrasonic crystals and CBF using a Doppler transducer. Myocardial extraction of oxygen (EO2) and lactate (Elac) was calculated. The infusion of calcium chloride resulted in dose-dependent increases in %SS and MVO2 but did not affect %PSS in normal myocardium. These changes were accompanied by parallel increases in CBF, resulting in no change in EO2. In stunned myocardium, the responses to calcium chloride were not significantly altered, with the exception of a reduction in %PSS. However, ischaemia and reperfusion itself significantly reduced %SS and Elac and increased %PSS. These data suggest that calcium chloride improves regional systolic and diastolic function both in normal and stunned myocardium. Calcium chloride is unlikely to cause direct coronary vasoconstriction or to deteriorate regional mechanical function in postischaemic myocardium.

Hyperlipidemia with Hypoglycemia Reduces Myocardial Oxygen Utilization Efficiency but not Contractile Function During Coronary Hypoperfusion

This study was designed to determine changes in myocardial contractile function and fuel selection during moderate coronary hypoperfusion in the presence of elevated plasma free fatty acid (FFA) at normal and reduced blood glucose concentrations. Coronary perfusion pressure (CPP) was sequentially lowered from 100 to 60, 50, and 40 mmHg in the left anterior descending coronary artery (LAD) of anesthetized, open-chest dogs. Regional glucose uptake (GU), fatty acid uptake (FAU), percentage segment shortening (%SS), and oxygen consumption (MV O2) were determined with normal arterial plasma FFA concentrations (Group 1) or with elevated FFA concentrations (Groups 2 and 3). In Group 3, glucose in the coronary perfusate blood was reduced from 3.53±0.36 to 0.15±0.03 m M by hemodialysis. In Group 1, FAU fell by 85% as CPP was lowered to 60 mmHg and remained depressed as CPP was reduced further; GU did not fall significantly. Hyperlipidemia in Group 2 did not alter GU at any CPP, but maintained FAU at baseline levels until CPP was lowered to 40 mmHg. At 40 mmHg CPP, myocardial function and metabolic variables were similar in Groups 1 and 2. In Group 3 at 40 mmHg, FAU increased four-fold and MV O2doubled v Groups 1 and 2, and GU fell to zero. Despite these metabolic changes, %SS in Group 3 was unchanged relative to Group 2. Addition of glucose to the dialysate prevented the effects of dialysis on FAU, GU, and MV O2. Thus, preferential glucose oxidation sustains myocardial oxygen utilization efficiency [(heart rate × %SS × maximum left ventricular pressure)/MV O2] during hypoperfusion. Blocking preferential glucose oxidation by combined hyperlipidemia and hypoglycemia lowers oxygen utilization efficiency, but does not compromise myocardial contractile function.

Excimer versus carbon dioxide transmyocardial laser revascularization: effects on regional left ventricular function and perfusion

Background. Transmyocardial laser revascularization (TMR) has been established with the carbon dioxide (CO 2) laser. The largely unstudied excimer laser creates channels through chemical bond dissociation instead of thermal ablation, thereby avoiding thermal injury. We sought to compare the effects of CO 2 and excimer TMR in a porcine model of chronic ischemia. Methods. Pigs underwent ameroid constrictor placement on the circumflex artery to create chronic ischemia. TMR was performed with CO 2 (n = 8) or excimer (n = 8) laser 6 weeks later; controls (n = 7) had ameroid placement only. Regional myocardial blood flow (RMBF), determined by radioactive microspheres, and regional myocardial function, determined by percent segmental shortening (%SS), were assessed 18 weeks after ameroid placement. Results. Values are mean ± SD. In the ischemic zone, RMBF (mL/min/g) was improved in the CO 2 (0.73 ± 0.19) and excimer (0.78 ± 0.22) groups when compared with controls (0.55% ± 0.12%, p < 0.05). %SS was also improved in the CO 2 (15.2% ± 5.5%) and excimer (15.3% ± 5.1%) groups when compared with controls (8.0% ± 4.2%, p < 0.05). Conclusions. Excimer and CO 2 TMR significantly improve RMBF and regional function in this porcine model of chronic myocardial ischemia despite fundamentally different tissue interactions.

Participation of angiotensin II and bradykinin in contractile function in dog stunned myocardium

We examined the effects of enalapril and 4′-[(1,4′-dimethyl-2′-propyl-[2,6′-bi-1H-enzimidazole]-1′-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid (BIBR-277), an angiotensin II receptor antagonist, on contractile dysfunction in the stunned myocardium. Dogs were subjected to 20-min ligation of the coronary artery, followed by 60-min reperfusion. Saline, enalapril (1 mg/kg or 3 mg/kg), or BIBR-277 (3 mg/kg) was injected i.v. 10 min before ligation. d-Arginyl- l-arginlyl- l-prolyl- trans-4-hydroxy- l-prolylglycyl-3-(2-thienyl)- l-alanyl- l-seryl- d-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl- l-(2α, 3β, 7aβ)-octahydro-1H-indole-2-carbonyl- l-arginine (Hoe-140), a bradykinin B 2 receptor antagonist, at 300 μg/kg was injected i.v. 10 min before drug injection. Contractile function was assessed on the basis of percentage segment shortening (%SS). ATP levels were measured in 60-min reperfused hearts. %SS significantly decreased during ischemia, and recovered during reperfusion, although the %SS was significantly less than the pre-ischemic level. Both enalapril at either dose and BIBR-277 significantly enhanced %SS recovery during reperfusion, an effect which was associated with a tendency toward energy preservation. Hoe-140 completely abolished the effect of enalapril at either dose, while it did not modify that of BIBR-277. Inhibition of angiotensin II formation and bradykinin breakdown may be separately related to the improvement of myocardial stunning.

The role of ATP-sensitive potassium channels in the mechanism of ischemic preconditioning.

We clarified the role of K(ATP) channels in the mechanism of ischemic preconditioning by using K(ATP) channel opener, nicorandil, and K(ATP) channel inhibitor, glibenclamide. Forty anesthetized dogs were divided into five groups: (a) control (C), (b) ischemic preconditioning (PC), (c) intravenous infusion of nicorandil before PC (Ni), (d) glibenclamide pretreated with PC (Gl + PC), and (e) glibenclamide pretreated with Ni (Gl + Ni). All groups were followed by 60-min ischemia and 60-min reperfusion and analyzed by the biochemical procedures. At the end of 60-min reperfusion, percentage of segment shortening in C indicated paradoxic bulging. This value was significantly recovered in PC and Ni, but it was still negative in Gl + PC and Gl + Ni. Ca2+ -adenosine triphosphatase (ATPase) activity of sarcoplasmic reticulum (SR) was significantly decreased in C. In PC and Ni, this activity was significantly maintained; however, in Gl + PC and Gl + Ni, it was similar to that in C. State III respiration of mitochondria showed similarity to the changes in SR. These results indicated that the K(ATP) channel opener enhanced the effects of ischemic preconditioning, and its blockade abolished these phenomena. We conclude that the ATP-sensitive potassium channel may play one of key roles in the mechanisms of ischemic preconditioning in the dog model.

Comparative effects of etomidate, ketamine, propofol, and fentanyl on myocardial contractility in dogs.

The present study was carried out to determine the direct effects of etomidate, ketamine, propofol, and fentanyl on myocardial contractility, and whether fentanyl would enhance the myocardial depression caused by propofol. The anesthetics were injected directly into the circuit that supplied blood to the left circumflex coronary artery (LCX) in anesthetized open-chest dogs. Myocardial contractility was evaluated from measurements of percent segmental shortening (%SS). Etomidate, ketamine, and propofol significantly reduced %SS in a dose-dependent manner. The %SS values with 1.6 and 3.2 mg of etomidate were similar to those with 3.2 and 6.4 mg of ketamine, respectively, and the %SS value with 6.4 mg of propofol was similar to those with 3.2 and 6.4 mg of ketamine. Fentanyl alone had no effects on myocardial performance and did not influence the effect of propofol on %SS. On the basis of clinical doses, the direct myocardial depressant effect of ketamine is more than twice as potent as that of etomidate and slightly more than that of propofol. Fentanyl has no inotropic effect and does not enhance the direct myocardial depressant effect of propofol.

Changes in passive but not active mechanical properties predict recovery of function of stunned myocardium.

The time course of alterations in active and passive mechanical properties of stunned myocardium during ischemia and throughout reperfusion has not been thoroughly quantified. This investigation tested the hypothesis that the amount of injury as well as the rate and extent of recovery of contractile function in postischemic, reperfused myocardium are directly correlated to changes in regional active and passive elastance and viscosity. A modified viscoelastic Voigt model was employed to quantify myocardial mechanical properties. Left ventricular pressure and segment length (in both ischemic and normal regions) were fit to the model consisting of an active elastic spring in parallel with a viscous damper and a passive elastic spring. The mechanical properties of myocardium from dogs which recovered (> or = 50%) baseline regional contractile function as determined by percent segment shortening (n=7) were compared to those from dogs that did not recover function (n=7). Both groups displayed decreased active elastance in the ischemic region during coronary artery occlusion, and this decrease was maintained in the nonrecovery group. Increases in viscosity of ischemic myocardium were observed in both groups during coronary occlusion but returned to control only in the recovery group. The nonrecovery group demonstrated increased passive elastance in the ischemic region during coronary occlusion and throughout the reperfusion period whereas the recovery group remained unchanged. We conclude that functional recovery of stunned myocardium is directly related to alterations in mechanical properties caused by ischemia and that changes in passive elastance during occlusion may predict the ability of ischemic myocardium to recover contractile function.

Effect of sialyl Lewis x oligosaccharide on myocardial and cerebral injury in the pig

Background. Although administration of the sialyl Lewis x oligosaccharide may reduce myocardial injury after ischemia–reperfusion, its effect on coronary and cerebral microvascular regulation and its clinical application during cardiac operation have not been examined. Methods. Pigs were placed on normothermic cardiopulmonary bypass after 30 minutes of left anterior descending coronary artery occlusion. The hearts were then arrested with cold high potassium cardioplegia. After 1 hour the cross-clamp was removed and the pigs were weaned from cardiopulmonary bypass and perfused for an additional 1 hour. CY-1503 (a sodium salt of the sialyl Lewis X oligosaccharide, n = 6) was administered before reperfusion. Six other pigs received saline vehicle. Endothelium-dependent relaxation of precontracted coronary and brain arterioles (70 to 180 μm) to adenosine 5′-diphosphate and endothelium-independent relaxation to sodium nitroprusside were studied in vitro with videomicroscopy. Control values were obtained from uninstrumented pigs. Myeloperoxidase activity in the myocardium and brain was measured to quantify neutrophil infiltration. Cardiac function and perfusion were assessed by left ventricular systolic pressure, maximum rate of increase of left ventricular pressure, left anterior descending coronary artery blood flow and percent segmental shortening, and cerebral vascular resistance, internal carotid artery blood flow, and the constitutively expressed and inducible isoform of nitric oxide synthase mRNA were measured. Results. The impaired myocardial contractile function after ischemia and cardioplegia was not improved by administration of CY-1503. The reduced endothelium-dependent relaxation responses of coronary and brain arterioles during ischemia followed by cardioplegia and cardiopulmonary bypass were improved with CY-1503, but the altered pattern of organ perfusion was not improved. Myeloperoxidase activity was increased in the heart after ischemia–cardioplegia and in the brain after cardiopulmonary bypass. CY-1503 reduced myeloperoxidase activity in both the myocardium and in the brain. Expressions of myocardial inducible isoform or constitutively expressed nitric oxide synthase were not altered in the heart. Conclusions. Although the sialyl Lewis x oligosaccharide does reduce neutrophil infiltration and endothelial injury in the coronary and cerebral microcirculation after cardiopulmonary bypass, it does not have significant beneficial acute effects on organ perfusion or function in the myocardium or brain.

Anti-C5a monoclonal antibody reduces cardiopulmonary bypass and cardioplegia-induced coronary endothelial dysfunction

Objective: Because C5a induces tissue injury by activating polymorphonuclear leukocytes, the hypothesis was that inhibition of C5a activity would reduce cardioplegia-related injury. Methods: Pigs were placed on cardiopulmonary bypass. The hearts were arrested for 1 hour with hyperkalemic cardioplegia. Pigs were then separated from bypass, and the hearts were reperfused for 2 hours. Anti-porcine C5a monoclonal antibody (1.6 mg/kg, intravenously; n = 6) was administered 20 minutes before the onset of cardiopulmonary bypass. Six pigs received saline solution vehicle. Reactivity of coronary arterioles was studied in vitro with videomicroscopy. Microvessels from uninstrumented pigs served as controls for vascular studies. Results: Endothelium-dependent relaxation to adenosine diphosphate (percent relaxation of precontraction) was reduced after cardioplegic reperfusion (63% ± 14% vs 77% ± 10% in control at 10 μmol/L; P = .01). This impairment in endothelium-dependent relaxation was improved with anti-porcine C5a monoclonal antibody (80% ± 22%; P = .01 vs saline solution), as was the impaired endothelium-dependent relaxation to clonidine (64% ± 12% control; 26% ± 17% saline solution; 55% ± 24% anti-porcine C5a monoclonal antibody at 10 μmol/L; P = .01 saline solution vs control or anti-porcine C5a monoclonal antibody). Myeloperoxidase activity was significantly decreased (0.2 ± 0.2 units/g protein; P = .04) in the anti-porcine C5a monoclonal antibody group compared with 5.2 ± 2.7 in the saline solution group. CH 50 2 hours after bypass was not statistically different (0.57 ± 0.41 unit and 0.65 ± 0.41 unit, respectively) between the anti-porcine C5a monoclonal antibody and saline solution groups. Despite less myocardial polymorphonuclear leukocyte infiltration after C5a inhibition, maximum rate of rise of left ventricular pressure, percent segmental shortening, and blood flow through the left anterior descending coronary artery were similar in the anti-porcine C5a monoclonal antibody and saline solution groups. Conclusions: Inhibition of C5a limits neutrophil-mediated impairment of endothelium-dependent relaxation after cardiopulmonary bypass and cardioplegic reperfusion, but it has no effect on short-term myocardial functional preservation. (J Thorac Cardiovasc Surg 1998;116:1060-8)