Regional Segment Shortening Research Articles

Effects of HBOC‐201 in a porcine model of impending myocardial infarction produced by severe coronary artery stenosis

Hemoglobin oxygen carrier HBOC‐201 can act as a direct oxygen donor and facilitate diffusive oxygen delivery between red blood cells and tissues to improve tissue oxygenation. Recently we showed that pre‐oxygenated HBOC‐201 infused distal to a coronary occlusion, fully restored aerobic metabolism and myocardial function. Here, we studied the effects of systemic administration of HBOC‐201 on left ventricular (LV) function and infarct size (IS) in pigs with coronary stenosis. A stenosis placed in the left anterior descending coronary artery for 120 min reduced flow by 70±2%. HBOC‐201 (1 g/kg), with or without nitroglycerine (NTG), were infused iv over 30 min, starting 15 min after the onset of ischemia. After 120 min of reperfusion, the area‐at‐ risk (AR), infarct area (IA) and IS=IA/AR•100% were determined. HBOC‐201 did not ameliorate stenosis‐induced loss of regional systolic segment shortening (from 20±1% to −3±1%) in the anterior LV wall and had no effect on IS (33±5%) compared to control (39±5%). To balance the purported scavenging of nitric oxide by HBOC‐201, we co‐infused NTG during HBOC‐201 which prevented systemic and coronary vasoconstriction. However, even in the presence of NTG, HBOC‐201 failed to blunt regional dysfunction or reduce IS (40±6%). Thus, despite the established oxygen transport capacity of HBOC‐201, it failed to afford cardioprotection in the setting of ischemia‐reperfusion in pigs.

Intracoronary infusion of Glucagon‐like peptide 1 acutely enhances myocardial glucose uptake during ischemia in canines

The objective of this study was to examine acute coronary, cardiac and metabolic effects of glucagon-like peptide 1 (GLP-1) in normal and ischemic myocardium. Experiments were conducted in open chest, anesthetized dogs at coronary perfusion pressures (CPP) of 100 and 40 mmHg before and during intracoronary GLP-1 infusion (10 pM - 1 nM). Isometric tension studies were also conducted in isolated coronary arteries. GLP-1 did not affect blood pressure, coronary blood flow (CBF), myocardial oxygen consumption (MVO2) or glucose uptake at CPP = 100 mmHg. Tension of intact and denuded coronary artery rings was also unaffected by GLP-1 (10 pM - 1 nM). At CPP=100 mmHg, GLP-1 (1 nM) reduced cardiac output (2.5 ± 0.7 to 1.9 ± 0.5 L/min) and reduced regional segment shortening by 27 ± 6%. Reducing CPP to 40 mmHg caused expected decreases in CBF (0.50 ± 0.10 to 0.17 ± 0.03 ml/min/g) and MVO2 (287 ± 32 to 165 ± 43 □l O2/min/g), and regional shortening fell by 70 ± 5%. At CPP=40 mmHg GLP-1 had no affect on CBF, MVO2, or regional shortening, but dose-dependently increased myocardial glucose uptake (0.09 ± 0.03 to 0.13 ± 0.03 □mol/min/g (sham – 1nM)). These data indicate that GLP-1 acutely augments glucose metabolism in ischemic myocardium, independent of effects on cardiac contractile function and without altering CBF. These studies suggest GLP-1 may be of therapeutic value in manipulating myocardial fuel selection during ischemia.

Characteristic dysfunction of stunned myocardium induced by 2,3-butanedione monoxime without ischaemia

1. In the present study, we tested the hypothesis that, even in the absence of prior ischaemia, 2,3-butanedione monoxime (BDM), an inhibitor of contraction at the actin-myosin level, could produce the postischaemic dysfunction characteristic of stunned myocardium. 2,3-Butanedione monoxime was injected directly into the left anterior descending coronary artery (LAD) before and again after myocardial stunning produced by 15 min occlusion of the LAD followed by 30 min reperfusion. 2. Regional myocardial force, segment shortening and regional work were measured in both the LAD-perfused area and the area perfused by the circumflex coronary artery, which served as a control area. Regional dysfunction produced by BDM injection or ischaemia-reperfusion was assessed quantitatively by five parameters: end-diastolic length (EDL), shortening onset delay (delay), systolic bulge (bulge), end-shortening time delay (EST) and tail work ratio (TWR). 3. It was found that injection of BDM into the LAD caused dyskinesis similar to that caused by occlusion-reperfusion. Both displayed elevated EDL and marked increases in delay, bulge, EST and TWR; these parameters were significantly higher in the dyskinesis caused by BDM injection. Despite dysfunctional fibre shortening, intracoronary BDM injection did not reduce regional force. 4. Thus, BDM can elicit changes similar to those characteristic of postischaemic dysfunction. Because contractility was not impaired, dysfunction was apparently caused by disrupting the association between contractile force and muscle motion.

Uncoupling of Muscle Shortening from Contractile Force in Intact Heart

It is well accepted that myocardial segment shortening is preceded by, and dependent upon, development of isometric force. In other words, muscle shortening is coupled in both time and amplitude to force; therefore it is assumed that dysfunctional contraction (e.g., in stunned myocardium) must be due to depressed contractility. However, it is also possible that dysfunctional shortening would result from poor coupling between force and shortening. This study was designed to test this hypothesis, and to show that it is possible to reversibly dissociate shortening from force development under certain conditions. In open-chest anesthetized dogs, 2,3-butanedione monoxime (BDM), acetylcholine and dobutamine were each injected directly into the left anterior descending coronary artery (LAD). The LAD was then ligated for 10 min to produce local myocardial ischemia, followed by reperfusion. In addition to global hemodynamics, regional myocardial force and segment shortening were measured in both the LAD-perfused area and that perfused by the circumflex coronary artery which served as a control area. It was found that both BDM and postischemic reperfusion produced significantly reduced fiber shortening (from 17.1± 1.5% to 5.4± 1.1% and 6.5± 2.3% respectively), but regional force was not depressed (from 11.1± 1.3 to 22.5± 2.6 g and 16.6± 2.7 g). This led to a decrease in the ratio of shortening/force (from 100 to 14.8± 2.5% and 28.2± 6.4%). Dyskinesis produced by BDM and ischemia reperfusion was also manifested by elevated end-diastolic length (EDL), prolonged delay to shortening, systolic bulge, elevated end-shortening time delay, and tail work ratio. In contrast, intracoronay acetylcholine produced a similar decrease in both force (from 11.1± 1.3 to 7.4± 1.4 g) and muscle shortening (from 17.1± 1.5 to 9.3± 1.6%); and dobutamine caused comparable increases in both force (from 11.1± 1.3 to 20.0± 3.6 g) and shortening (from 17.1± 1.5 to 24.0± 3.1%). The ratio of shortening/force was relatively unchanged. It is concluded that uncoupling of force/shortening may produce regional dysfunction, even in the presence of normal contractility. Thus, assessment of wall motion alone may not always be an accurate estimation of myocardial contractile mechanisms.

Blunted functional responses to pre- and postjunctional sympathetic stimulation in hibernating myocardium

Regional reductions in norepinephrine-tracer uptake are found in pigs with hibernating myocardium. Clinical studies would suggest that this is evidence for denervation; however, the functional responses to sympathetic stimulation have not been evaluated, and our previous studies with beta-adrenergic stimulation have not suggested denervation hypersensitivity. Therefore, pigs were chronically instrumented to produce hibernating myocardium characterized by chronic regional dysfunction and histological viability. Open-chest studies were performed to determine changes in regional function in response to both pre- and postjunctional stimulation. Regional segment shortening was reduced at rest in hibernating myocardium compared with controls (13 +/- 3% vs. 27 +/- 3%, P = 0.004). During stellate ganglion stimulation, regional function increased in both groups of animals (P = 0.008 vs. baseline), but the increase in hibernating myocardium was blunted compared with controls (Delta%, 3 +/- 2% vs. 8 +/- 3%, P = 0.04). Similar results occurred with intracoronary tyramine (10 mug/kg). Functional improvement during intravenous epinephrine infusion (0.35 mug.kg(-1).min(-1)) was also blunted in hibernating myocardium compared with controls (Delta%, 7 +/- 1% vs. 15 +/- 2%, P = 0.04). Even when the improvement in function was expressed relative to the reduced baseline, there was no evidence for catecholamine-mediated hypersensitivity in hibernating myocardium. We therefore conclude that functional responses to both pre- and postjunctional sympathetic stimulation are blunted in pigs with hibernating myocardium. In contrast to previous studies of infarcted, denervated, and acutely stunned myocardium, there is no catecholamine-induced hypersensitivity in hibernating myocardium. These data suggest a downregulation in functional responses to stimulation that would protect hibernating myocardium from demand-induced ischemia at the expense of contractile reserve during sympathetic stimulation.

Hemodynamic Interactions of Propofol and Dantrolene in Chronically Instrumented Dogs

The hemodynamic interaction of dantrolene, a specific drug for malignant hyperthermia, and propofol which appears to be safe in malignant hyperthermia-susceptible patients, has not been investigated. We performed this study to examine the hemodynamic actions of dantrolene at a therapeutic dose during propofol anesthesia. Ten dogs were chronically instrumented for the measurements of systemic and coronary hemodynamics. The dogs were assigned to receive propofol with vehicle or dantrolene in a random manner on separate experimental days. Propofol significantly decreased mean arterial blood pressure, left ventricular systolic and end-diastolic pressure, the maximal rate of increase in left ventricular pressure, and left ventricular regional segment shortening. Coronary blood flow (CBF) was unchanged but coronary vascular resistance (CVR) decreased. Dantrolene reversed the decrease in mean arterial blood pressure and left ventricular systolic pressure caused by propofol, and significantly increased heart rate. However, left ventricular end-diastolic pressure, cardiac output, maximal rate of increase in left ventricular pressure, and segment shortening were unchanged. CBF was significantly increased with a decrease in CVR. These results suggest that dantrolene reverses the hypotensive action produced by propofol and causes an increase in CBF with a decrease in CVR, but does not significantly change the negative inotropic effects. Thus, dantrolene exerts favorable hemodynamic effects during propofol anesthesia. Our study suggests that dantrolene reverses the hypotensive action produced by propofol and causes an increase in coronary blood flow with a decrease in coronary vascular resistance, but does not significantly change the negative inotropic effects.

Selective opening of mitochondrial ATP-sensitive potassium channels during surgically induced myocardial ischemia decreases necrosis and apoptosis.

Mitochondrial ATP-sensitive potassium channels have been proposed to be myoprotective. The relevance and specificity of this mechanism in cardiac surgery was unknown. The purpose of this study was to examine the effects of the mitochondrial potassium ATP-sensitive channel opener diazoxide on regional and global myocardial protection using a model of acute myocardial infarction. Pigs (n=19) were placed on total cardiopulmonary bypass and then subjected to 30 min normothermic regional ischemia by snaring the left anterior descending coronary artery (LAD). The aorta was then crossclamped and cold blood Deaconess Surgical Associates cardioplegia (DSA; n=6) or DSA containing 50 microM diazoxide (DZX; n=6) was delivered via the aortic root and the hearts subjected to 30 min hypothermic global ischemia. The crossclamp and snare were removed and the hearts reperfused for 120 min. No significant differences in preload recruitable stroke work relationship, Tau, proximal, distal or proximal/distal coronary flow, regional or global segmental shortening, systolic bulging or post-systolic shortening were observed within or between DSA and DZX hearts during reperfusion. Infarct was present only in the region of LAD occlusion in both DSA and DZX hearts. Infarct size (% of area at risk) was 33.6+/-2.9% in DSA and was 16.8+/-2.4% in DZX hearts (P<0.01 versus DSA). Apoptosis as estimated by TUNEL positive nuclei was 120.3+/-48.8 in DSA and was significantly decreased to 21.4+/-5.3 in DZX hearts. Myocardial infarct was located centrally within the area at risk in both DSA and DZX hearts but was significantly increased at borderline zones within the area at risk in DSA hearts. The addition of diazoxide to cardioplegia significantly decreases regional myocardial cell necrosis and apoptosis in a model of acute myocardial infarction and represents an additional modality for achieving myocardial protection.

The Novel Glycolipid RC-552 Attenuates Myocardial Stunning and Reduces Infarct Size in Dogs

The novel glycolipid RC-552 shares common structural features with the natural products lipid A and the previously described cardioprotectant monophosphoryl lipid A. RC-552 administered to dogs as a bolus intravenous dose (35-70 microg/kg) either 24 h or 10 min prior to 60 min of regional myocardial ischemia and 3 h of reperfusion significantly (P<0.05 v control) reduced infarct size (IS) as assessed by triphenyltetrazolium staining from 27.0+/-2.3% of the area-at-risk (AAR) to 13.3+/-2.2% and 15.0+/-3.0%, respectively. Administration of the non-specific inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (30 mg/kg, subcutaneously) 1 h prior to ischemia blocked the ability of RC-552 (35 microg/kg, 24 h pretreatment) to reduce infarct size. Intravenous pretreatment with RC-552 (35 microg/kg) either 24 h or 10 min prior to five 5 min repetitive cycles of ischemia and reperfusion significantly improved regional myocardial segment shortening (percentage of control) at all time points during 2 h of reperfusion in dogs. These effects of RC-552 in either cardiac injury model occurred independent of differences in AAR, transmural blood flow during ischemia or hemodynamics throughout the experiment. In contrast with monophosphoryl lipid A (MLA), which has also been reported to be cardioprotective at similar doses in dogs, RC-552 was approximately 100 times less prone to cause fever in the USP rabbit pyrogen test. Likewise, RC-552 did not induce secretion of the proinflammatory cytokines TNF, IL-6 or IL-8 from THP-1 cells or alter the expression of adhesion molecules on human neutrophils at concentrations up to 10 microg/ml. MLA was active in these systems at concentrations in the range 0.1-1.0 microg/ml. In conclusion, RC-552 reduces myocardial infarct size and stunning in dogs in the absence of residual immunomodulatory activity.

Isoflurane-enhanced recovery of canine stunned myocardium: role for protein kinase C?

Isoflurane enhances the functional recovery of postischemic, reperfused myocardium by activating adenosine A1 receptors and adenosine triphosphate-regulated potassium channels. Whether protein kinase C is involved in this process is unknown. The authors tested the hypothesis that inhibition of protein kinase C, using the selective antagonist bisindolylmaleimide, attenuates isoflurane-enhanced recovery of stunned myocardium in dogs. Fifty dogs were randomly assigned to receive intracoronary vehicle or bisindolylmaleimide (2 or 8 microg/min) in the presence or absence of isoflurane (1 minimum alveolar concentration). Five brief (5 min) coronary artery occlusions interspersed with 5-min reperfusion periods followed by 180 min of final reperfusion were used to produce myocardial stunning. Hemodynamics, regional segment shortening, and myocardial blood flow (radioactive microspheres) were measured at selected intervals. There were no differences in baseline hemodynamics, segment shortening, or coronary collateral blood flow between groups. Isoflurane significantly (P<0.05) decreased heart rate, mean arterial pressure, rate pressure product, and the maximum rate of increase of left ventricular pressure (+dP/dt(max)) in the presence or absence of bisindolylmaleimide. Sustained contractile dysfunction was observed in dogs that received vehicle (recovery of segment shortening to 12+/-8% of baseline), in contrast to those that received isoflurane (75+/-7% recovery). Bisindolylmaleimide at a dose of 2 microg/min alone enhanced recovery of segment shortening (50+/-7% of baseline) compared with vehicle-pretreated dogs, and isoflurane in the presence of 2 microg/min bisindolylmaleimide further enhanced recovery of contractile function (79+/-8% of baseline). In contrast, 8 microg/min bisindolylmaleimide alone (32+/-12%) or combined with isoflurane (37+/-17%) did not enhance recovery of segment shortening compared with vehicle-pretreated dogs. The results indicate that protein kinase C inhibition using low doses of bisindolylmaleimide alone produces cardioprotection, and isoflurane further enhances this protection. In contrast, high doses of bisindolylmaleimide are not cardioprotective in the presence or absence of isoflurane. A role for protein kinase C during isoflurane-induced recovery of the stunned myocardium cannot be excluded.

Monophosphoryl lipid A attenuates myocardial stunning in dogs: role of ATP-sensitive potassium channels.

Results of previous studies indicate that monophosphoryl lipid A (MLA) reduces myocardial infarct size when administered 24 but not 1 h before a prolonged period of regional ischemia in dogs and rabbits. This cardioprotective effect of MLA could be reversed by the administration of the adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) blockers, glibenclamide, or 5-hydroxydecanoate. MLA also was shown to attenuate myocardial stunning in dogs; however, its mechanism in this model remains unknown. Therefore the major aim of our study was to determine the dose-related effect of MLA to enhance contractile function in stunned myocardium and to determine the role of the K(ATP) channel in mediating its cardioprotective effect. To produce myocardial stunning, barbital-anesthetized dogs were subjected to five cycles of 5 min of left anterior descending (LAD) coronary artery occlusion interspersed with 10 min of reperfusion and finally followed by 2 h of reperfusion. Regional segment shortening (%SS) was determined by sonomicrometers implanted in the subendocardium of the ischemic region. Single intravenous doses of MLA in the range of 10-35 microg/kg given 24 h before ischemia resulted in an improvement in %SS over a 2-h reperfusion period. Similar to results obtained in the canine and rabbit infarct models, cardioprotection against stunning with MLA appears to require activation of K(ATP) channels during ischemia, because glibenclamide (50 microg/kg, 15 min before ischemia) completely blocked the effect of MLA to improve regional %SS during reperfusion. Cardioprotective doses of MLA were without effect on systemic hemodynamics, blood gases, and pH throughout the experiment. No treatment-related effects on regional myocardial blood flow were observed during ischemia or reperfusion. These results suggest that MLA improves %SS at doses of 10-35 microg/kg by an ATP-sensitive potassium channel-dependent process, and that MLA may mimic the antistunning effects observed during the second window of ischemic preconditioning.

Simultaneous evaluations of contractility and energy metabolism of stunned myocardium using 31P magnetic resonance spectroscopy.

A canine model of postischemic myocardial dysfunction (15 min ischemia, 60 min reperfusion) was used to evaluate the relationship between energy metabolism and myocardial contractile function by on-line measurements of ECG, left ventricular pressure, coronary blood flow and regional segment shortening (%SS) with the continuous acquisition of 31PMR spectra. Two groups emerged from these studies; the first (n = 7) in which regional myocardial %SS remained significantly depressed after 60 min of reperfusion (stunned) and the second (n = 5) in which regional %SS returned to control levels after 60 min of reperfusion (non-stunned). Both groups exhibited rapid, similar decreases in %SS and parallel rapid decreases in the phosphocreatine to inorganic phosphate (PCr/Pi) ratio with the onset of ischemia. The PCr/ATP ratio exceeded control levels in the stunned group immediately upon reperfusion and remained significantly above control after 60 min of reperfusion. Measurements of tissue myocardial creatine kinase (CK) revealed a significant decrease in total tissue CK activity in stunned myocardium compared to control. A significant inverse relationship (r = -0.904, p < 0.003) was found between myocardial tissue CK specific activity and the PCr/ATP ratios. We postulate that the elevated PCr/ATP ratio caused by the impairment of energy transfer to the contractile apparatus constitutes a contractile dysfunction in the postischemic heart.

Blockade of nitric oxide synthesis reduces myocardial oxygen consumption in vivo.

Although cardiac myocytes and coronary vascular endothelium are known to express a constitutive form of NO synthase, the in vivo effects of tonic endogenous production of NO on myocardial O2 consumption and contractile performance remain unclear. The effects of blockade of NO synthase were determined in intact dogs. Myocardial O2 consumption decreased systematically over a wide range of hemodynamic demand after the systemic administration of N omega-nitro-L-arginine methyl ester (L-NAME) or N omega-nitro-L-arginine. Decreases after doses of 1 and 10 mg/kg L-NAME averaged 23 +/- 3.8% and 34 +/- 7.2% at a heart rate of 90 bpm in open-chest animals. Similar reductions occurred after the administration of L-NAME and N omega-nitro-L-arginine in chronically instrumented animals and were unaffected by beta-adrenergic blockade. Intracoronary infusion of L-NAME in chronically instrumented animals reduced both myocardial O2 consumption and regional segment shortening, even at a dose that did not increase systemic arterial pressure. The blockade of NO synthesis reduces myocardial O2 consumption in vivo. The decrease in O2 consumption is accompanied by a decrease in segment shortening. It involves a direct myocardial action of NO, is unaffected by beta-blockade, and is consistent with in vitro studies indicating that low levels of NO augment contractile performance by inhibition of a cGMP-dependent phosphodiesterase.

Effect of hypertonic saline/dextran on post-stenotic myocardial perfusion, metabolism, and function during resuscitation from hemorrhagic shock in anesthetized pigs.

Resuscitation using small volumes of hypertonic saline solutions normalizes cardiac output without fully restoring arterial pressure. This study compared the efficacy of either 7.2% saline/10% dextran 60 (HSDex) or the identical sodium load of normal saline (NS) to improve regional myocardial blood flow (MBF), contractile function, and oxygen metabolism in the presence of a critical coronary stenosis. Fourteen anesthetized, open-chest pigs (25 +/- 3.6 kg) were instrumented to assess left anterior descending coronary artery (LAD) flow, post-stenotic oxygen, and lactate metabolism, regional myocardial segment shortening (SS, sonomicrometry), and MBF (radioactive microspheres). After implementation of a critical LAD-stenosis, shock was induced by hemorrhage (mean arterial pressure (MAP) 45-50 mmHg for 75 min). Resuscitation was started by infusion (2 min) of either HSDex (n = 7,10% of blood loss) or NS (n = 7, 80% of blood loss); 30 min later 6% dextran 60 (10% of blood loss) was administered in both groups. The LAD-stenosis did not affect myocardial metabolism, SS, or MBF at rest. After hemorrhage, MBF remained unchanged from baseline in non-stenotic but decreased by 53% in post-stenotic myocardium (p < .05). The endo-epicardial flow ratio fell below 1.0 in both areas. SS decreased by 10-15% only in post-stenotic myocardium (p < .05). Resuscitation with both HSDex and NS restored cardiac index (CI) but not MAP. MBF increased above baseline values with either solution in non-stenotic while it remained at shock levels in post-stenotic myocardium, where ischemia persisted as evidenced by lactate production and depressed SS. Neither in non-stenotic nor in post-stenotic myocardium was the epi-endocardial flow ratio normalized upon resuscitation with HSDex or NS. We conclude that in the presence of a flow-limiting coronary stenosis, initial fluid resuscitation with both HSDex and the identical sodium load of NS failed to restore perfusion pressure, redistributed MBF in favor of normally perfused myocardium, and did not reverse ischemia in post-stenotic myocardium.

939-78 Selective Angiotensin II Receptor Antagonism Does not Influence Myocardial Stunning but Augments Ischemic Pre-conditioning in the Pig Heart

The effects of a new angiotensin II receptor antagonist (EXP 3174, an active carboxylic acid analog of the selective angiotensin II receptor antagonist DuP 753) on infarct size and regional contractile function in an open-chest pig model of ischemia and reperfusion were evaluated. Ischemic preconditioning (PC) was performed by twice 10 min LAD occlusion (CO) and 30 min reperfusion (RP) followed by 1 hour CO and 1.5 hour RP Infarct size (IS) in the left ventricle in % of risk area (RA) was determined by tetrazolium salts and regional segment shortening (%SS) by subendocardial implanted ultrasonic crystals in the LAD supplied area. Group (Gp) 1 = control (1 h CO + 1.5 h RP), Gp 2 = control + EXP 1 mg/kg iv, Gp 3 = PC, Gp 4 = PC + EXP 0.3 mg/kg iv, group 5 = PC + EXP 1 mg/kg iv. %SS after PC was 22.2 ± 7.2 in Gp 3,19.9 ± 0.9 in Gp 4, and 17.1 ± 4.5 in Gp 5 (p &gt; 0.05) Gp n= RA/LV(%) IS/RA(%) 1 5 16.1 ± 2.2 71.3 ± 3.8 2 4 22.3 ± 3.3 57.5 ± 3.1 3 7 16.9 ± 1.3 36.5 ± 4 * 4 4 15.9 ± 3.8 40.3 ± 5.2 * 5 5 13.6 ± 6.3 6.7 ± 3.1 ** LV = left ventricle * p &lt; 0.05 vs Gp 1 ** vs Gp 3 Administration of EXP 3174 neither alters IS in controls nor %SS after brief periods of ischemia, however, IS after PC are dosedependent significantly reduced, indicating a supportive role of angiotensin II receptor activation for infarct size limiting effects of ischemic preconditioning in our pig model

Effects of Regional Myocardial Lidocaine Infusion on High Energy Phosphates

High energy phosphates [phosphocreatine (PCr) and adenosine triphosphate (ATP)] are maintained in the heart under conditions of altered myocardial contractility and under certain conditions of maintained in the heart under conditions of altered myocardial contractility and under certain conditions of myocardial ischemia (such as hibernating myocardium). However, the metabolic consequences of reduced regional contractility have not been investigated. This study was designed to test the hypotheses that (1) under conditions of normal blood flow, reduction in regional contractility does not result in changes in PCr or ATP and (2) under conditions of reduced blood flow, reduction in regional contractility prevents the expected decline in high energy phosphates usually seen in regional ischemia. An in situ open chest swine preparation was used in which regional contractility was reduced with the administration of intracoronary lidocaine. High energy phosphates were measured using phosphorus-31 magnetic resonance spectroscopy (NMR) under conditions of normal flow and reduced flow. Intracoronary lidocaine infusion in 9 animals did not change blood flow from basal levels, but significantly reduced regional segment shortening from 0.16 +/- 0.02 to 0.02 +/- 0.01. The ratio of PCr/ATP did not change with lidocaine infusion (control: 1.53 +/- 0.09; lidocaine: 1.59 +/- 0.11), but oxygen content in the anterior interventricular vein increased from 8.25 +/- 0.69 to 9.83 +/- 0.91 ml/O2/100 ml blood in parallel studies (P = 0.04). While the lidocaine infusion was maintained, subsequent coronary stenosis significantly reduced subendocardial blood flow from 0.91 +/- 0.06 to 0.41 +/- 0.06 ml/min/g without significantly altering high energy phosphates (PCr/ATP = 1.51 +/- 0.15). In contrast to the 29% decline in PCr previously seen with regional ischemia, PCr was unchanged with this degree of flow reduction in the presence of lidocaine. Thus, PCr and ATP are unchanged under conditions of reduced contractility, consistent with equilibrium of energy synthesis and utilization. In addition, factors which reduce myocardial contractility, either pharmacologically or endogenously, protect against the metabolic consequences of reduced flow by reducing MVO2.

C5a-induced myocardial ischemia: role for CD18-dependent PMN localization and PMN-platelet interactions.

Intracoronary C5a in swine decreases coronary blood flow and regional myocardial segment shortening, responses mediated by thromboxane (Tx) A2-induced coronary vasoconstriction and intramyocardial trapping of granulocytes (PMNs). We sought to determine the origin of TxA2 and to investigate the role of CD18-dependent PMN function by utilizing an anti-CD18 monoclonal antibody, IB4. Isolated C5a-stimulated PMNs or platelets did not produce TxB2. However, together, C5a-stimulated PMNs and platelets produced TxB2. IB4 bound porcine PMN surface CD18 and blocked C5a-induced PMN functions. In vivo, IB4 loading (2 mg/kg) transiently decreased arterial blood pressure and circulating platelet counts in six of nine animals (390 +/- 31 vs. 176 +/- 41 X 10(6)/ml, control vs. IB4; P < 0.002) and significantly ameliorated C5a-induced decreases in coronary venous PMN count (-4.1 +/- 0.6 vs. -1.4 +/- 0.8 X 10(6) cells/ml), coronary artery blood flow (-10 +/- 1 vs. -4 +/- 1 ml/min), and segment shortening (-15 +/- 2 vs. -8 +/- 2%, C5a vs. C5a + IB4). We conclude that 1) production of TxB2 in response to C5a is mediated by a PMN-platelet interaction, 2) IB4 functionally blocks CD18 on porcine PMNs, and 3) C5a-induced myocardial PMN extraction is mediated, in part, by a CD18-dependent mechanism. These results suggest that PMN-platelet interactions and CD18-dependent PMN extraction are important in C5a-induced myocardial ischemia.

L-Propionylcarnitine Does Not Affect Myocardial Metabolic or Functional Response to Chronotropic and Inotropic Stimulation After Repetitive Ischemia in Anesthetized Pigs

In postischemic myocardium, fatty acid oxidation may be deficient owing to depletion of carnitine and citric acid cycle intermediates and fatty acylCoA-induced inhibition of adenine nucleotide translocase. During postischemic stress, the impairment of the fatty acid oxidation may become more apparent. We therefore investigated in open-chest anesthetized pigs the effect of L-propionylcarnitine [100 mg/kg per day orally (p.o.) for 3 days and 50 mg/kg intravenously (i.v.) 2 h before the first occlusion; n = 13] on myocardial function and metabolism of postischemic (two cycles of 10-min occlusion each followed by 30-min reperfusion) myocardium under resting conditions and during chronotropic and inotropic stimulation with dobutamine. Myocardial levels of free carnitine were higher after pretreatment (5.7 +/- 1.4 vs. 4.0 +/- 1.3 mumol/g protein, p < 0.05). The ischemia-reperfusion-induced decreases in free carnitine were similar for both the untreated and treated animals, but in the latter free carnitine was not different from the baseline levels in the control animals. In untreated animals (n = 15), regional systolic segment shortening (SS) was 18.5 +/- 5.5% (means +/- SD) at baseline, but was reduced to 5.1 +/- 5.5% (p < 0.05) at the end of the second reperfusion period. Myocardial ATP levels had decreased by 30% (p < 0.05) in the presence of a maintained energy charge, while myocardial oxygen and lactate consumption had decreased to 61% and 9% of baseline, respectively. During subsequent i.v. infusion of dobutamine (2 micrograms/kg/min), SS and myocardial oxygen consumption per beat increased to 75 and 65% of baseline, respectively, whereas lactate consumption per beat increased to only 25% of baseline. Decreases in myocardial ATP and oxygen and lactate consumption were not different between treated and untreated animals. L-Propionylcarnitine-treated animals displayed slightly better postischemic recovery of systolic SS than did control animals; to 39 and 28% (p = 0.056) of baseline, respectively, probably owing to a reduction in arterial blood pressure (BP), because L-propionylcarnitine prevented the increase in systemic vascular resistance produced by ischemia-reperfusion. L-Propionylcarnitine did not affect myocardial metabolic and contractile functional responses to chronotropic and inotropic stimulation. In a model of repetitive myocardial ischemia, L-propionylcarnitine prevents systemic vasoconstriction in response to ischemia and reperfusion and, probably as a result of the lower afterload, slightly ameliorates postischemic hypofunction, but loss of carnitine apparently does not play a role in myocardial hypofunction after brief repetitive ischemia and reperfusion in pigs.

Laser-mediated tansmural myocardial channels do not salvage acutely ischemic myocardium

We sought to determine whether the presence of transmural laser-made channels could provide blood flow to ischemic myocardium. Laser-made transmural channels have been used in patients to restore blood flow to ischemic myocardium. Whether such channels actually relieve ischemia is unclear. We therefore tested the concept in an animal model of acute ischemia. Eighteen dogs underwent 6 h of permanent coronary artery occlusion. At 30 min after occlusion, 8 dogs were randomized to the laser-treated group (30 to 40 transmural channels, 1 mm in diameter, were made in the cyanotic area using a holmium: yttrium-aluminum-garnet laser), and 10 were randomized to the control group (no treatment). Transmural blood flow was measured before and after treatment using radiolabeled microspheres. Regional segment shortening and myocardial lactate content were measured in four of the control and two of the laser-treated dogs. Infarct size was measured in all animals using triphenyltetrazolium chloride staining. Laser channels failed to increase blood flow to ischemic tissue. After laser channels were made, mean transmural flow averaged 0.10 +/- 0.03 versus 0.11 +/- 0.03 ml/min per g in treated versus control dogs, respectively. Furthermore, infarct size was similar in both groups (46 +/- 6% vs. 43 +/- 7%, respectively, of the myocardium at risk, p = NS). In addition, the presence of laser channels neither improved regional myocardial function nor enhanced washout of accumulated lactate. Direct laser revascularization of the heart did not provide any immediate benefit to ischemic myocardium in this canine model of coronary artery occlusion. Thus, it is doubtful that direct laser-mediated myocardial revascularization would be of immediate benefit in the treatment of patients with acute ischemia.

Dobutamine restores the reduced efficiency of energy transfer from total mechanical work to external mechanical work in stunned porcine myocardium.

In order to determine whether the relatively high oxygen consumption of stunned myocardium is related to decreased mechanical efficiency, myocardial oxygen consumption (MVO2) and its major determinants were studied in 10 open chest anaesthetised pigs. According to the time varying elastance concept, MVO2 is determined by contractility (Emax) and total mechanical work (PLA), which is the sum of the external work (EW) and potential energy (PE). Mechanical efficiency (EW/MVO2) equals the product of EW/PLA (= efficiency of energy transfer or EET) and PLA/MVO2. Emax is the slope of the end systolic pressure-segment length relationship, determined by gradually clamping the aorta. PLA is the area enclosed by the end systolic pressure-segment length relationship and the pressure-segment length trajectory. EW is the area of the pressure-segment length loop. Systemic haemodynamics, regional segment shortening, and MVO2 were determined at baseline, during stunning (two sequences of 10 min occlusion and 30 min of reperfusion), after a subsequent 50 beats.min-1 increase in heart rate by atrial pacing and additional infusion of 2 micrograms.kg-1.min-1 dobutamine. Stunning decreased segment shortening from 18.2(SEM 1.9)% to 10.2(1.5)%, MVO2 from 4.16(0.27) x 10(-2) to 2.84(0.25) x 10(-2) mumol.beat-1.g-1, and Emax from 47(9) to 23(3) mm Hg.mm-1 (all p < 0.05). PLA decreased by 13(4)%, as EW decreased by 42(6)%, and PE tended to increase. Although EET decreased from 0.58(0.04) to 0.40(0.03) (p < 0.05), there was no decrease in the mechanical efficiency, as an increase in PE caused an increase in PLA/MVO2 which compensated for the decrease in EET. Dobutamine infusion increased Emax and EW per beat to 120(23)% and 67(8)% of baseline, respectively, while MVO2 [4.12(0.53) mumol.beat-1.g-1] and EET [0.57(0.04)] returned to baseline. In stunned myocardium, mechanical efficiency is not decreased despite a decrease in EET. The increase in EET after dobutamine may explain the lack of the excessive increase in MVO2.

Cardiac response to acute coronary artery occlusion in exercise-trained dogs

Exercise training is thought to exert a beneficial effect on cardiovascular function, but its effect in the normal heart following acute coronary artery occlusion is still uncertain. Studies were performed in 12 untrained (UT) and 14 endurance-trained (ET) pentobarbital anesthetized dogs. Left ventricular pressure (LVP), heart rate (HR), percent regional myocardial segmental shortening (%SL), and peripheral coronary pressure (PCP) distal to the occlusion were measured during control conditions and during a 2-min circumflex artery occlusion (CAO). During CAO, LVP, dP/dtmax, and %SL in the ischemic region were significantly reduced in both UT and ET dogs. There was no significant difference between the two groups. In addition, PCP decreased to 27 +/- 5 mm Hg and 26 +/- 9 mm Hg in the UT and ET groups, respectively, during CAO indicating no difference in coronary collateral perfusion between the groups. Regional myocardial blood flow was measured using tracer microspheres in eight of the UT and six of the ET dogs, and the decrease in blood flow to the ischemic zone during CAO was similar in both groups. These results indicate that 12-wk of endurance training does not exert a protective effect on myocardial contractile function or on myocardial perfusion in the central ischemic region during CAO in the anesthetized dog.