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PubMed2002

Long-term administration of nicorandil abolishes ischemic and pharmacologic preconditioning of the human myocardium: role of mitochondrial adenosine triphosphate-dependent potassium channels.

BACKGROUND: Acute administration of mitochondrial adenosine triphosphate-dependent potassium channel openers preconditions the heart, but whether their long-term administration induces a permanent state of protection is unknown. These studies investigate the effect of long-term treatment with the mitochondrial adenosine triphosphate-dependent potassium channel opener nicorandil on the response of the human myocardium to ischemia and preconditioning. METHODS: Right atrial tissue obtained from patients regularly treated with or without nicorandil (mean of 20 mg/d for 18.6 +/- 2.5 months) and undergoing cardiac surgery was sliced and equilibrated for 30 minutes and then subjected to 90 minutes of simulated ischemia, followed by 120 minutes of reoxygenation. In study 1 the following groups were studied to investigate the effect of nicorandil on the susceptibility of the myocardium to ischemia and on the protective effect of ischemic and pharmacologic preconditioning: (1) aerobic control; (2) simulated ischemia and reoxygenation alone; (3) ischemic preconditioning with 5 minutes of simulated ischemia and 5 minutes of reoxygenation; and (4) phenylephrine (0.1 micromol/L) for 5 minutes and 5 minutes' washout before simulated ischemia and reoxygenation. In study 2 the following groups were studied to investigate the effect of nicorandil on the responsiveness of mitochondrial adenosine triphosphate-dependent potassium channels: (1) aerobic control; (2) simulated ischemia and reoxygenation; (3) ischemic preconditioning; (4) diazoxide (100 micromol/L) for 10 minutes before simulated ischemia and reoxygenation, and (5) 5-hydroxydecanoate (1 mmol/L) for 10 minutes before simulated ischemia and reoxygenation. In study 3 the following groups were included to investigate the effect of the long-term administration of nicorandil on the kinase pathway involved in preconditioning: (1) aerobic control; (2) simulated ischemia and reoxygenation alone; (3) ischemic preconditioning; (4) phorbol 12-myristate 13-acetate (1 micromol/L), a protein kinase C activator, for 10 minutes before simulated ischemia and reoxygenation; and (5) anisomycin (1 nmol/L), a p38 mitogen-activated protein kinase activator, for 10 minutes before simulated ischemia and reoxygenation. At the end of each protocol, the leakage of creatine kinase (in units per gram wet weight) and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide into insoluble formazan dye (in millimoles per gram wet weight) were measured. RESULTS: In study 1 the leakage of creatine kinase and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide induced by simulated ischemia and reoxygenation were similar in the groups with or without nicorandil (creatine kinase, 3.4 +/- 0.1 and 3.5 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 74.6 +/- 3.9 and 67.9 +/- 7.3, respectively; P >.2 in each instance). Ischemic preconditioning and pharmacologic preconditioning protected the myocardium from patients without nicorandil (creatine kinase, 2.3 +/- 0.1 and 2.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 131.4 +/- 4.9 and 128.4 +/- 5.6, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) but not the myocardium from patients receiving nicorandil (creatine kinase, 3.3 +/- 0.1 and 3.3 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 89.7 +/- 6.5 and 86.4 +/- 5.2, respectively; P >.2 vs simulated ischemia and reoxygenation alone in each instance). In study 2 the administration of diazoxide had identical protection to that of ischemic preconditioning in the myocardium of patients not receiving nicorandil (creatine kinase, 2.1 +/- 0.2 and 2.3 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 141.4 +/- 7.4 and 131.4 +/- 4.9, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) but failed to precondition the myocardium from patients treated with nicorandil (creatine kinase, 3.3 +/- 0.2 and 3.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 90.1 +/- 7.2 and 86.4 +/- 5.2, respectively; P > 0.2 vs simulated ischemia and reoxygenation alone in each instance). In study 3 phorbol 12-myristate 13-acetate or anisomycin given for 10 minutes before simulated ischemia and reoxygenation afforded similar protection to that of ischemic preconditioning in the myocardium from patients with (creatine kinase, 1.5 +/- 0.3 and 1.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 147.0 +/- 4.9 and 160.0 +/- 16.1, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) and without nicorandil (creatine kinase, 1.7 +/- 0.4 and 1.4 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 160.3 +/- 13.6 and 158.3 +/- 11.8, respectively; P <.001 vs simulated ischemia and reoxygenation alone in each instance). CONCLUSION: The myocardium of patients chronically treated with nicorandil cannot be preconditioned either by ischemia or pharmacologically, and this is because of unresponsive mitochondrial adenosine triphosphate-dependent potassium channels. However, protection can be obtained by protein kinase C and p38 mitogen-activated protein kinase activation, which are downstream of mitochondrial adenosine triphosphate-dependent potassium channels in the signaling transduction pathway of preconditioning.

Adenosine Triphosphate↗

PubMed1991

Altered load dependence of postischemic myocardium.

Intermittent myocardial ischemia can produce areas of postischemic ("stunned") myocardium in the heart of the human with coronary artery disease. These areas are no longer ischemic, but have diminished contractile performance. Although the effects of loading conditions on systolic contraction of normal, ischemic, and failing myocardium have been investigated in great detail, the way in which load affects contraction of postischemic myocardium is not known. The aim of this study was to determine in anesthetized dogs how loading conditions affect the systolic function of a region of myocardium after 10 min of ischemia and 1 h of reperfusion. Sets of piezoelectric crystals were implanted in a test zone and in a remote zone of myocardium. Measurements of systolic wall thickening were made during nine combinations of left atrial pressure (3, 6, and 9 cmH2O) and mean arterial pressure (70, 90, and 110 mmHg). One set of measurements was made under baseline conditions, and a second set was made after 10 min of coronary occlusion and 1 h of reperfusion. Ischemia and reperfusion reduced wall thickening in the test zone 36 +/- 3% and diminished the response to increases in preload. In contrast, the response of the test zone to changes in afterload was unchanged. An interaction between the test zone (in which depressed contraction was observed) and the surrounding myocardium (in which enhanced function was observed) produced the appearance of a regional wall motion abnormality as afterload increased. These results emphasize that the load dependence of postischemic myocardium differs from that of normal myocardium and must be taken into account in clinical studies in which regional contraction is used to monitor the heart for ischemia.

Animals↗

PubMed1999

Interregional differences in the systolic and diastolic response of nonischemic myocardium to remote coronary occlusion.

BACKGROUND: Previous work showed a twofold increase in stiffness of nonischemic myocardium at the base during ischemia of the left anterior wall. Whether the diastolic response of nonischemic myocardium to remote ischemia depends on the localization of the ischemic or the nonischemic area is unknown. METHODS: In dogs with open chests, regional function in ischemic and nonischemic myocardium was assessed (sonomicrometry) before and 5 min after occlusion of the left anterior descending coronary artery (LAD; n = 7) or the left circumflex coronary artery (LCX; n = 7). RESULTS: In nonischemic myocardium at the base, left anterior descending and left circumflex coronary artery occlusion both resulted in a twofold increase in chamber stiffness, whereas contractility and peak lengthening rate remained unchanged. In nonischemic myocardium of the posterior wall, left anterior descending coronary artery occlusion resulted in a significant (P<0.05 vs. control, P<0.05 vs. base) increase (mean+/-SD) in chamber stiffness (25+/-6%), contractility (17+/-5%), and peak lengthening rate (28+/-6%). In nonischemic myocardium at the apex, left circumflex coronary artery occlusion resulted in a significant (P<0.05 vs. control, P<0.05 vs. base) increase in chamber stiffness (15+/-5%), contractility (16+/-4%), and peak lengthening rate (19+/-6%). CONCLUSIONS: Stiffening of remote nonischemic myocardium occurs regardless of the localization of the ischemic and nonischemic area. The systolic and diastolic responses of nonischemic myocardium are not necessarily homogenous but may vary among different regions.

Animals↗

PubMed2005

Impaired resting perfusion in viable myocardium distal to chronic coronary stenosis in rats.

Chronic coronary artery stenosis results in patchy necrosis in the dependent myocardium and impairs global and regional left ventricular (LV) function in rats in vivo. The aim of the present study was to compare regional myocardial blood flow (RMBF) and function (F) in poststenotic myocardium by using magnetic resonance imaging (MRI) and to compare MRI blood flow changes to histological alterations to assess whether RMBF in the viable poststenotic tissue remains normal. MRI was performed in 11 anesthetized Wistar rats with 2-wk stenosis of the left coronary artery. Postmortem, the extent of fibrotic tissue was quantified. Poststenotic RMBF was significantly reduced to 2.21 +/- 0.30 ml.g(-1).min(-1) compared with RMBF in the remote myocardium (4.05 +/- 0.50 ml.g(-1).min(-1)). A significant relationship between the poststenotic RMBF (%remote area) and the poststenotic F (%remote myocardium) was calculated (r = 0.61, P < 0.05). Assuming perfusion in scar tissue to be 32 +/- 5% of perfusion of remote myocardium, as measured in five additional rats, and that in remote myocardium to be 114 +/- 25% of that in normal myocardium, as assessed in five sham rats, the calculated perfusion in partially fibrotic tissue samples (35.7 +/- 5.2% of analyzed area) was 2.88 +/- 0.18 ml.g(-1).min(-1), whereas measured MRI perfusion was only 1.86 +/- 0.24 ml.g(-1).min(-1) (P < 0.05). These results indicate that resting perfusion in viable poststenotic myocardium is moderately reduced. Alterations in global and regional LV function are therefore secondary to both patchy fibrosis and reduced resting perfusion.

Animals↗

PubMed1987

Effects of left circumflex Ameroid constrictor placement on adrenergic innervation of myocardium.

We evaluated the adrenergic innervation of the swine and canine myocardium after placement of an Ameroid constrictor around the left circumflex coronary artery (LCX). Fluorescent histochemistry was used to identify adrenergic nerve terminals in the myocardium and coronary vasculature. Ameroid occlusion of the proximal LCX in 10 pigs for 3 wk resulted in 6 +/- 1% infarction as well as myocardial ischemia in the left circumflex region of pigs studied during exercise. However, placement of the Ameroid constrictor did not significantly alter the surface density of the nerve terminals in the LCX region of myocardium when compared with innervation of control hearts. Histological examination of the coronary arterial adrenergic innervation in Ameroid-occluded pigs revealed that coronary vessels in the circumflex region of the heart were innervated. Similarly, in seven LCX Ameroid-occluded dogs, no significant decrease in adrenergic innervation of the LCX region of myocardium was observed when compared with control dogs. In contrast LCX Ameroid-occluded pigs demonstrated significant (P less than 0.01) denervation of the left anterior descending (LAD) region of myocardium when compared with control animals. The close proximity of adrenergic nerve bundles in the proximal LAD region indicates that denervation of the myocardium supplied by the LAD may result from the dissection and/or fibrosis associated with placement of the Ameroid constrictor on the proximal LCX. Our results suggest that placement of an Ameroid constrictor on the proximal LCX does not significantly alter the adrenergic innervation of the LCX-perfused myocardium or its associated coronary vasculature. However, denervation of LAD-perfused myocardium and its vasculature may result.

Adrenergic Fibers↗

PubMed1976

Observations on the ultrastructure of developing myocardium of rat embryos.

Timed pregnancies were obtained in Sprague-Dawley rats and early ultrastructural differentiation of myocardium of embryos of 10, 11, 12, 13, and 14 days were investigated and compared with that of newborn. Ten-day myocardium is characterized by loosely packed cells; the cytoplasm is typified by a dearth of organelles. Both thick (myosin) and thin (actin) filaments become identifiable for the first time in the 10-day myocardium where the heart is pulsating but circulation is not established. These filaments are not visible in the embryos of 9-day-old myocardium. The formation of these filaments is observed to continue throughout the period covered in this investigation. Concomitant with the appearance of the myofilaments is the synthesis of Z band material. By the eleventh day of gestation and during the subsequent days there is a rapid proliferation and differentiation of most of the organelles. The myofilaments become organized into fully formed striated fibrils. Intercalated discs appear as small wavy lines on the eleventh day and become plicated in later stages and serve as cell boundaries and points of attachment for myofilaments and fibrils. There is a perceptible change in the number and morphology of mitochondria from the tenth to eleventh day and later stages of development when the heart becomes functional. Similarly, there is a rapid proliferation and differentiation of granular endoplasmic reticulum and Golgi bodies. Large quantities of free ribosomes are dispersed in the cytoplasm of 10-day myocardium; however, in later stages there is a progressive reduction in the distribution of these particles. An intimate association of ribosomes and polysomes with the developing myofibrils is discernible. The T-system and sarcoplasmic reticulum begin to appear in 11-day myocardium. The embryonic myocardium displays intense mitotic activity throughout its development and a unique feature of embryonic myocardial cells is the simultaneous occurrence of myofilament synthesis and mitotic activity within the same cells.

Animals↗

PubMed1997

Beta-adrenergic receptor signalling in stunned myocardium of conscious pigs.

The primary goal of this study was to compare the effects of isoproterenol which stimulates beta-adrenergic receptors and forskolin, and NKH 477, a water soluble derivative of forskolin, which stimulate adenylyl cyclase in stunned myocardium of conscious pigs, previously instrumented for measurements of left ventricular pressure and dP/dt, arterial pressure, and wall thickening. Ten min of coronary artery occlusion induced transmural reductions in blood flow (radioactive microspheres) in subepicardium (-98 +/- 2%) and subendocardium (-99 +/- 1%). Wall thickening (piezoelectric crystals) fell from 2.50 +/- 0.26 mm to -0.26 +/- 0.26 mm and remained depressed at 1.37 +/- 0.19 mm after 20-30 min coronary artery reperfusion, reflecting myocardial stunning. At that time, isoproterenol (0.2 microgram/kg) increased wall thickening in stunned myocardium (+1.40 +/- 0.16 mm, P < 0.05) more than in control (+0.71 +/- 0.22 mm), while forskolin elicited the opposite effects. NKH 477 (30 micrograms/kg), which does not penetrate the blood-brain barrier, increased systolic wall thickening similarly before (+0.95 +/- 0.25 mm) and during (+1.01 +/- 0.24 mm) myocardial stunning. The reflex inotropic responses to inferior vena caval occlusion on wall thickening were diminished, P < 0.05, in the stunned myocardium (+0.53 +/- 0.05 mm) compared with control (+0.95 +/- 0.07 mm). beta-adrenergic receptor density, which was quantitated with 125I-cyanopindolol binding, was increased transmurally in stunned myocardium compared with non-ischemic myocardium (subepicardium: +23 +/- 5%, subendocardium: +34 +/- 13%, P < 0.05). Basal and forskolin-stimulated adenylyl cyclase activities were decreased slightly, but significantly, in the stunned subendocardium but not in the subepicardium, while isoproterenol stimulation of adenylyl cyclase activity showed no differences. In summary, paradoxical responses to beta-adrenergic receptor stimulation were observed in stunned myocardium, with pharmacological stimulation with isoproterenol evoking enhanced responses, and neural stimulation with inferior vena caval occlusion eliciting depressed responses. The diminished responses to forskolin in vivo, in stunned myocardium were out of proportion to the biochemical measurements, and may be attributed to neurally mediated cardiac effects of forskolin, since the responses to direct stimulation of adenylyl cyclase by NKH 477 were preserved.

Adenylyl Cyclases↗

PubMed2002

Basic fibroblast growth factor is upregulated in hibernating myocardium.

BACKGROUND: Ischemia is known to be a potent stimulus for the upregulation of angiogenic growth factors, such as basic fibroblast growth factor (bFGF). While previous investigations have shown that many angiogenic growth factors are upregulated in animal models of myocardial ischemia, the models used are limited in their ability to produce stable ischemia beyond a few weeks. Our laboratory uses a stable model of hibernating myocardium where later time points may be examined. Therefore, the goal of this study was to examine bFGF protein levels in the myocardium at baseline and 3 or 6 months following the onset of myocardial ischemia. METHODS: A total of 18 miniswine were studied. Basal endogenous levels of bFGF were measured in control animals (n = 6) immediately following sacrifice, while 12 other pigs underwent a 90% left circumflex artery occlusion with documented hibernating myocardium by positron emission tomography ((13)N-ammonia) and dobutamine stress echocardiography. These animals were studied at 3 (n = 7) and 6 months (n = 5) postoperatively. At sacrifice, six 3 x 3 mm samples were harvested from the left circumflex (hibernating) myocardium. Basic FGF levels (picograms per microgram of protein) were determined using ELISA kits. RESULTS: Basic FGF protein levels 3 months after the creation of hibernating myocardium were three times greater than in nonischemic control animals (P < 0.05), while levels at 6 months were increased sixfold compared to control animals (P < 0.05 versus both control and 3-month groups). CONCLUSIONS: Endogenous bFGF production is upregulated at 3 and 6 months in hibernating porcine myocardium. The angiogenic effects of exogenous bFGF delivered into ischemic myocardium with varying levels of endogenous growth factors must be determined.

Animals↗

PubMed1995

The ryanodine binding sarcoplasmic reticulum calcium release channel in nonfailing and in failing human myocardium.

The ryanodine-sensitive Ca2+ release channel (RyaCRC) of the sarcoplasmic reticulum plays a key role in the intracellular Ca2+ handling in cardiomyocytes. Altered expression of the RyaCRC has been supposed to contribute to abnormal cellular Ca2+ handling and to myocardial dysfunction in dilated and ischemic cardiomyopathy. In the present study the 3H-ryanodine binding site in human myocardial homogenates was characterized and the density of the RyaCRC (which corresponds to the cardiac ryanodine receptor) was determined in nonfailing and in failing human myocardium. Homogenates were prepared from nonfailing left ventricular myocardium from the hearts of 5 organ donors (NF) and from failing myocardium from 14 explanted hearts of transplant recipients with end-stage heart failure resulting from dilated (DCM, n = 5) or ischemic (ICM, n = 9) cardiomyopathy. Radioligand saturation binding experiments revealed a specific, high-affinity 3H-ryanodine binding site (Kd-values: NF: 0.65 +/- 0.11 nmol/l, DCM: 0.66 +/- 0.09 nmol/l, ICM: 0.88 +/- 0.18 nmol/l; n.s.) in all preparations. Specific 3H-ryanodine binding depended on the free Ca2+ concentration in the assay. It was maximal at 3-100 micro mol/l Ca2+. The binding was inhibited by the RyaCRC antagonists ruthenium red (Ki-value: 0.32 [0.18-0.56] micromol/l, n = 5) and Mg2+ (Ki-value: 2.95 [1.23-7.11] mmol/l, n = 5). The RyaCRC density was 103.5 +/- 11.9 fmol/mg protein in nonfailing myocardium. There was no significant change in the RyaCRC density in dilated or ischemic cardiomyopathy (112.4 +/- 17.1 and 122.7 +/- 13.9 fmol/mg protein) compared to nonfailing control myocardium. In summary, 3H-ryanodine binds specifically and with high-affinity to the RyaCRC in human myocardium. There is no change in the RyaCRC density in failing myocardium of patients with DCM or ICM in comparison to non-failing controls.

Adult↗

PubMed1998

Assessment of reperfused myocardium using a new ischaemia-avid imaging agent, technetium-99m HL91: comparison with myocardial glucose uptake.

We evaluated the efficacy of a new ischae-mia-avid imaging agent, technetium-99m labelled 4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime (99mTc- HL91) as a marker of myocardial viability in ischaemic and reperfused myocardium. The left coronary artery of rats was ligated for 15 or 60 min and released. The myocardium was reperfused for 60 min [stunned myocardium, or acute myocardial infarction (MI)] or 7 days (subacute MI). Thereafter, 99mTc-HL91 and carbon-14 2-deoxyglucose (DG) were co-injected 30 min before sacrifice. We evaluated the myocardial accumulation of 99mTc-HL91 and DG by dual-tracer ex vivo autoradiography. The uptake of each tracer in the myocardial region was normalized by that in the septum (control), and expressed as percent uptake (%HL or %DG, respectively). Individual hearts were also histopathologically examined. The %HL in the stunned myocardium (n = 8) and in the septum were identical (101%+/-15%, mean+/-SD, P = ns), whereas the %DG was significantly increased (149%+/-27%, P<0.05) compared with that in the septum. These results suggest that 99mTc-HL91 cannot visualize stunned myocardium, whereas DG can. In acute MI (n = 7), the %HL (423%+/-96%, P<0.005) and the %DG (318%+/-91%, P<0.001) in the non-infarcted area at risk were significantly augmented compared with those in the septum. The %DG (181%+/-17%) in the infarcted area was also augmented (P<0.001), whereas the %HL (106%+/-25%) in the infarcted area was identical to that in the septum (P = ns). These results indicate that 99mTc-HL91 detected viable myocardium in the area at risk. In subacute MI (n = 8), the%HL in the infarcted area (101%+/-45%) and in the septum was identical, whereas %DG (292%+/-57%) was significantly higher than that in the non-infarcted risk area or the septum (P<0.0001). These findings suggest that DG detected viable myocardium in the area at risk, but that 99mTc-HL91 was not retained. We conclude that 99mTc-HL91 is a potent marker of myocardial viability when used during the early acute phase after reperfusion.

Animals↗

PubMed2005

Late gadolinium-enhanced magnetic resonance imaging in acute and chronic myocardial infarction. Improved prediction of regional myocardial contraction in the chronic state by measuring thickness of nonenhanced myocardium.

OBJECTIVES: We sought to determine serial changes of enhanced and nonenhanced tissue on late gadolinium-enhanced cardiac magnetic resonance (CMR) imaging in patients with a myocardial infarction (MI) and to assess whether thickness of nonenhanced myocardium can improve the detection of preserved contractile function in the chronic state. BACKGROUND: Previous studies demonstrated that enhancement on late gadolinium-enhanced CMR images indicates myocardial necrosis, and nonenhancement shows the presence of viable myocardium. METHODS: The CMR studies were performed within one week (scan 1) and more than five months (scan 2) after the onset of MI in 18 patients. The area and mean thickness of enhanced tissue and nonenhanced myocardium were measured by using a 30-segment model. Systolic wall thickening on cine CMR at scan 2 was assessed for evaluating regional contractile function. RESULTS: The amount of enhanced tissue significantly decreased from scan 1 to 2 (22.1 +/- 14.0 ml vs. 15.0 +/- 9.3 ml, p < 0.001). The averaged thickness of nonenhanced myocardium in the infarct segments significantly increased from scan 1 to 2 (5.2 +/- 3.0 mm vs. 6.6 +/- 3.2 mm, p < 0.001). Receiver operating characteristic analysis demonstrated that the measurement of thickness of nonenhanced myocardium, compared with measurement of percent transmural enhancement, had better diagnostic accuracy for predicting improved systolic wall thickening form scan 1 to 2 in dysfunctional segments (Az 0.650 vs. 0.594, p < 0.05). CONCLUSIONS: The amounts of enhanced tissue and nonenhanced myocardium significantly altered from the acute to chronic state in MI patients. The diagnostic performance of CMR imaging for detection of preserved contractile function can be significantly improved by measuring thickness of nonenhanced myocardium in MI patients.

Aged↗

PubMed2002

Coronary patency and its relation to contractile reserve in hibernating myocardium.

OBJECTIVES: Recent clinical studies suggest that contractile reserve may occur in a minority of viable, chronically dysfunctional segments with reduced resting flow (hibernating myocardium). We hypothesized that epicardial artery patency might predict which segments have critically reduced subendocardial flow reserve and limited contractile reserve. METHODS: Pigs were chronically instrumented with a fixed stenosis on the left anterior descending coronary artery (LAD) to produce hibernating myocardium. At least 3 months later, flow at rest and during adenosine vasodilation (microspheres), ventricular function and contractile reserve (contrast ventriculography), and (18)F-2-deoxyglucose (FDG) deposition (ex vivo tissue counting) were quantified. RESULTS: Hibernating myocardium (regional dysfunction with reduced resting perfusion) was present in animals with an occluded (n=40) or patent (n=19) LAD. Viability was confirmed by histology and FDG deposition. In collateral-dependent hibernating myocardium, subendocardial flow did not increase above baseline levels during epinephrine or adenosine stimulation, consistent with exhausted subendocardial flow reserve at rest. This was associated with limited contractile reserve and regionally increased FDG deposition. In contrast, subendocardial flow reserve was present in hibernating myocardium distal to a patent artery. Contractile reserve during epinephrine infusion in this group was significantly greater than in animals with an occluded artery. CONCLUSIONS: The physiology and metabolism of hibernating myocardium was dependent upon stenosis severity and its effects on subendocardial flow reserve. In collateral-dependent hibernating myocardium, contractile reserve was limited in the setting of exhausted subendocardial flow reserve, thus supporting the hypothesis that metabolic imaging may be preferable for determining viability distal to a complete occlusion.

Adenosine↗

PubMed1995

Multislice measurement of first-pass transit of gadobenate dimeglumine in normal and ischemic myocardium in dogs.

RATIONALE AND OBJECTIVES: We monitored the differences in the first passage of gadobenate dimeglumine through normal and ischemic myocardium with left anterior descending (LAD) coronary artery occlusion in dogs. METHODS: Dynamic multislice images of the heart were taken on a 1.5-T magnetic resonance (MR) imager. In six normal dogs, inversion recovery (IR)-prepared fast gradient-recalled echo (GRE) images were acquired at five doses of gadobenate dimeglumine (0.005-0.1 mmol/kg). First passage of the contrast medium through normal and acutely ischemic myocardium were monitored in seven dogs subjected to LAD coronary artery occlusion. RESULTS: IR-prepared GRE images showed a dose-dependent increase in the signal intensity (SI) of the myocardium. In dogs with LAD coronary artery occlusion, there was a significant increase in the SI of normal myocardium (p < .01) than in ischemic myocardium after injection of 0.025 mmol/kg gadobenate dimeglumine. CONCLUSION: The first-pass dynamics of gadobenate dimeglumine through normal and ischemic myocardium can be monitored with a multislice acquisition using a clinical MR imager and differentiated between normal and ischemic myocardium in dogs.

Animals↗

PubMed1991

Effects of hypothermic ischemia on purine catabolism in canine, primate, and human myocardium.

After hypothermic cardiac arrest, creatine phosphate (CrP) and adenine nucleotide catabolism was compared in myocardium from dogs (n = 7), baboons (n = 5), and man (n = 7; patients undergoing cardiac transplantation) during cold (0.5 degree C) storage for up to 24 hours. Although hypothermia delayed the catabolism in dog myocardium it still remained very extensive. CrP dropped to virtually nil and ATP fell to below 15% of the total purines within 6 hours. The majority of the adenine nucleotides was broken down to adenosine (ADO; 32% of total purines) and inosine (INO; 21%). Apart from the delay (7 to 9-fold), hypothermia also reversed the ratio between ADO and INO when compared to normothermia, suggesting a profound effect of temperature on the nucleoside transporter. In human myocardium even after 12 hours of hypothermia ATP still contributed more than 60% to the total purines. Concomitantly, nucleoside formation proceeded slowly with almost no intermediate ADO. Under similar conditions, the catabolism of ATP in baboon myocardium occurred at a higher rate than in man but still far below canine metabolism. Irrespective of the relatively higher fall in ATP, ADP and AMP accumulated more in baboon myocardium indicating a limited dephosphorylation of the nucleotides. Only in the baboon myocardium did inosine monophosphate increase above the detection limits. In none of the species did purine catabolism proceed beyond hypoxanthine and even this could hardly be detected in the primates. It is concluded that considerable species differences do exist in the rate as well as in the pattern of nucleotide catabolism even during storage of the myocardium at low temperature.

Adenine Nucleotides↗

PubMed1987

Evaluation of the effect of metoprolol on energy metabolism in the ischaemic myocardium in relation to regional myocardial blood flow.

To evaluate the effect of beta blockade on energy metabolism in ischaemic myocardium metoprolol tartrate in doses of 0.2 or 0.5 mg.kg-1 or saline was injected into 24 anaesthetised dogs 20 min after coronary ligation. Regional myocardial blood flow was measured by the hydrogen gas clearance method, and the heart rate and aortic pressure were recorded. After 60 min coronary occlusion myocardial biopsy specimens were removed from five areas where myocardial blood flow had been recorded to determine their content of adenosine-5'-triphosphate (ATP). Respiratory function and acyl-coenzyme A contents of mitochondria isolated from ischaemic and non-ischaemic myocardium were also measured. In the control group the ATP content in severely ischaemic myocardium where myocardial blood flow was less than 20 ml.min-1.100 g-1 was decreased to 27.5% of that in the non-ischaemic area, whereas the administration of metoprolol 0.5 mg.kg-1 maintained ATP content at 46.3%. In ischaemic myocardium metoprolol inhibited the accumulation of long chain acyl-coenzyme A in mitochondria and significantly preserved their respiratory function. In contrast, metoprolol did not affect myocardial blood flow in myocardium where flow was less than 60 ml.min-1.100 g-1. Heart rate was decreased by metoprolol in proportion to the dose, whereas mean aortic pressure was not changed. These results suggest that beta blockade had beneficial effects on the energy metabolism of ischaemic myocardium and that such effects might be due not only to a reduction in cardiac work but also to a reduction in the vicious circle of fatty acid metabolism in ischaemic myocardium.

Acyl Coenzyme A↗

PubMed1993

Effect of reperfusion on 111In-antimyosin monoclonal antibody uptake by salvaged and necrotic myocardium in the dog.

OBJECTIVE: The aim was to investigate the ability of 111In-antimyosin monoclonal antibody (111In-AMA) to differentiate between salvaged and necrotic myocardium following reperfusion. METHODS: Dogs submitted to a 24 h left anterior descending coronary artery occlusion (group 1, n = 10) or to a 90 min occlusion followed by a 22.5 h reperfusion (group 2, n = 11, group 3, n = 5) were given radiolabelled microspheres and 111In-AMA after 75 min of ischaemia (groups 1 and 2), or after 19.5 h of reperfusion (group 3). After delimiting the area at risk and the infarct by dye perfusion and triphenyltetrazolium chloride, the heart slices were imaged by scintigraphy and dissected into necrotic, viable ischaemic, and normal myocardium. Myocardial blood flow was estimated by microspheres and 111In-AMA uptake was expressed as the ratio of the corresponding non-ischaemic tissue samples taken from opposite ventricular wall. RESULTS: 111In-AMA ratios in necrotic and salvaged myocardium were respectively 5.4(SEM 1.9) and 3.2(0.5) times the normal value, giving a 1.7 to 1 factor between the two areas in dogs with permanent occlusion (group 1). Similar results were obtained in group 3 with ratios of 6.1(1.1) and 3.0(0.3) times normal values. In contrast, ratios of 43.6(5.6) and 5.6(0.9) (p < 0.05) in necrotic and salvaged myocardium, respectively, were found in reperfused group 2, giving a 7.8 to 1 factor between the two tissue areas of the risk territory. Clear delineation between salvaged and necrotic tissue territories could be made on scintigrams only in group 2, which otherwise presented smaller infarcts: 35.1(7.9)% of the risk area v 58.0(8.7)% in non-reperfused animals (p < 0.05). 111In-AMA uptake by necrotic myocardium did not correlate with collateral (group 1) or reperfusion blood flows (group 3), indicating that the greater uptake in reperfused myocardium is flow independent. CONCLUSIONS: 111In-AMA does not clearly identify necrotic from viable ischaemic myocardium within 24 h of injection in a coronary artery occlusion model. Thus it may not be a sensitive enough method to evaluate infarct size progression. However, reperfusion greatly increased 111In-AMA uptake by the infarct in a flow independent manner, this may prove to be useful for clinical assessment of infarct size and reperfusion injury.

Animals↗

PubMedDate not supplied

Effect of dopamine and blockade of dopaminergic and adrenergic receptors on coronary blood flow in ischemic rabbit myocardium.

The effect of a broad dose range of dopamine on coronary blood flow was studied in rabbits with coronary artery occlusion. Dopaminergic and adrenergic receptor blockade was established to distinguish the mechanism of the dopamine-induced increase in coronary blood flow. Dopamine, 10, 100, or 1,000 micrograms/kg/min, was infused in the presence of dopaminergic, beta-, or alpha-adrenergic receptor blockade. Coronary blood flow, as measured by radiolabeled microspheres, and hemodynamic parameters were monitored in 60 anesthetized open-chest rabbits. Dopamine, 1,000 micrograms/kg/min, significantly increased coronary blood flow 157% in normal and 118% in occluded rabbit myocardium. Propranolol (2 mg/kg) prevented the dopamine-induced increases in coronary blood flow within occluded and nonoccluded myocardium. Practolol (2 mg/kg) blunted the coronary blood flow increases within occluded myocardium, but flow within normal myocardium remained significantly elevated. In animals given phenoxybenzamine (2 mg/kg), dopamine infusion produced significant blood pressure reductions along with no change in either occluded or nonoccluded coronary blood flow. Bulbocapnine (8 mg/kg), a dopamine receptor antagonist, did not block blood flow increases in normal myocardium, but prevented significant increases in blood flow within occluded myocardium. It can be concluded that direct or indirect vasodilator receptors (dopaminergic, beta 1-, and beta 2-adrenoceptors) must be stimulated and perfusion pressure must not fall in order for dopamine to produce increases of coronary blood flow within occluded myocardium.

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PubMed1988

Species differences in the negative inotropic response of 1,4-dihydropyridine calcium channel blockers in myocardium.

To determine if species differences exist in myocardial response to 1,4-dihydropyridine (DHP) calcium channel blockers, the binding and pharmacologic responses of a series of DHP compounds were examined in both rat and rabbit myocardium. [3H]Nitrendipine was used to label specific binding sites in myocardial membrane particulates. The results of saturation binding experiments (n = 3) indicated no statistically significant difference in either Kd or Bmax between rat and rabbit myocardial membranes (0.19 +/- 0.02 nM and 157 +/- 29 fmol/mg protein in rat and 0.14 +/- 0.06 nM and 227 +/- 125 fmol/mg protein in rabbit). Furthermore, [3H]nitrendipine binding inhibition experiments using 12 unlabeled DHP analogues yielded Ki values for each compound that were almost identical in myocardium from rat and rabbit, resulting in an excellent 1:1 correlation when data for all of the compounds were compared (r = 0.997, p less than 0.001). The negative inotropic effect of five of these DHP compounds was studied in vitro in isolated right papillary muscles from rabbit and right ventricular strips from rat, and concentration required to displace 50% of ligand binding (IC50) values for inhibition of contraction were determined. The IC50 values were significantly greater in rat myocardium than in rabbit myocardium (p less than 0.003). Therefore, a significantly lower potency of DHP calcium channel blockers has been demonstrated in rat compared with rabbit myocardium, and this species difference cannot be explained by a difference in the DHP binding site. Rat myocardium differs from rabbit myocardium in a number of ways that may explain this lower potency.(ABSTRACT TRUNCATED AT 250 WORDS)

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