Regional myocardial blood flow in awake dogs.

The objectives of this study were to test the hypothesis in awake dogs that during control conditions endocardial vessels are maximally dilated and to determine whether variables introduced by general anesthesia and thoracotomy modify distribution of myocardial blood flow or impair capacity for augmentation of flow in response to a coronary vasodilator stimulus. Myocardial blood flow was measured in relatively small, 2-3 g, left ventricular epicardial and endocardial samples by using 7-10-mum radioisotope-labeled microspheres during control conditions and during infusion of adenosine in dosages which produced maximum increases in coronary blood flow. Measurements were made initially in awake resting animals and were repeated after pentobarbital anesthesia, thoracotomy, and pericardiotomy. Blood flow (mean+/-SEM) in the epicardium and endocardium, respectively, was 0.75+/-0.06 and 0.83+/-0.06 during control conditions and 4.98+/-0.28 and 4.49+/-0.27 cm(3)/min/g during adenosine. These data demonstrate considerable capacity for vasodilation in both myocardial layers and thus refute the hypothesis that endocardial vessels are maximally dilated during control conditions. During control conditions blood flow within epicardial and endocardial layers was essentially homogeneous around the circumference of the left ventricle. In contrast to previous studies in anesthetized animals, however, transmural gradients were present in most regions, i.e., endocardium: epicardium ratio (endo/epi) 1.06-1.16. During adenosine, circumferential epicardial flows were homogeneous; however, circumferential endocardial flows were inhomogeneous and increased less than epicardial flows, endo/epi 0.81-0.99.Anesthesia, thoracotomy, and pericardiotomy increased epicardial and endocardial flow, mean values 1.08+/-0.10 and 1.11+/-0.08 cm(3)/min/g, respectively. Transmural gradients remained in only papillary muscle regions. Adenosine increased epicardial flow comparably before and after anesthesia. Although adenosine increased endocardial flow three- to fourfold after anesthesia, the increase was considerably less than epicardial flow, i.e., endo/epi 0.63-0.78.

Myocardial blood flow distribution during ischemia-induced coronary vasodilation in the unanesthetized dog.

This study was designed to determine whether coronary vasodilation distal to a flow-limiting coronary artery stenosis could result in redistribution of myocardial blood flow to produce subendocardial underperfusion. Studies were performed in 10 awake dogs chronically prepared with electromagnetic flow-meters and hydraulic occluders on the left circumflex coronary artery. Regional myocardial blood flow was measured using radionuclide-labeled microspheres, 7-10 mum in diameter, injected into the left atrium. A 5(-s) coronary artery occlusion was followed by reactive hyperemia with excess inflow of arterial blood effecting 375+/-20% repayment of the blood flow debt incurred during occlusion. When, after a 5(-s) occlusion, the occluder was only partially released to hold arterial inflow to the preocclusion level for 20 s before complete release, the delayed reactive hyperemia was augmented (mean blood flow repayment = 610+/-45%, P < 0.01). This augmentation of the reactive hyperemia suggested that ischemia was continuing during the interval of coronary vasodilation when coronary inflow was at the preocclusion level. Measurements of regional myocardial blood flow demonstrated that endocardial flow slightly exceeded epicardial flow during control conditions. When arterial inflow was limited to the preocclusion rate during vasodilation after a 5(-s) total coronary artery occlusion, however, flow to the subepicardial myocardium was increased at the expense of underperfusion of the subendocardial myocardium. Thus, in the presence of a flow-limiting proximal coronary artery stenosis, ischemia-induced coronary vasodilation resulted in redistribution of myocardial blood flow with production of subendocardial ischemia in the presence of a net volume of arterial inflow which, if properly distributed, would have been adequate to prevent myocardial ischemia.

Effect of exercise on perfusion of collateral-dependent myocardium in dogs with chronic coronary artery occlusion.

Since the ability of mature intercoronary collateral channels to increase myocardial blood flow in response to drug-induced coronary vasodilation has been questioned, the present study was undertaken to evaluate the response of coronary collateral circulation to the stress of exercise. Studies were performed at rest and during two levels of treadmill exercise in six dogs a minimum of 6 mo after placement of an Ameroid constrictor on the left circumflex coronary artery. Regional myocardial blood flow was estimated in normally perfused anterior and predominantly collateral-dependent posterior left ventricular wall with left atrial injections of radio-nuclide-labeled microscheres 7-10 mum in diameter. At rest, heart rate was 87 +/- 7 beats/min and mean myocardial blood flow was comparable in control and collateral-dependent regions (0.96 +/- 0.13 and 0.97 +/- 0.14 ml/min-g, respectively). During exercise, heart rates increased to 180 +/- 13 and 228 +/- 14 beats/min and myocardial blood flow (MBF) in the anterior control region increased linearly with heart rate (HR), (MBF = 0.133 HR - 0.202, r = 0.88). MBF to the posterior collateral-dependent region was similarly augmented during exercise (MBF = 0.140 HR - 0.252, r = 0.89), so that the linear correlation between HR and MBF was similar for the control and collateral-dependent regions. In addition, the transmural distribution of MBF was uniform at rest and during exercise in both the anterior control and posterior collateral-dependent regions. Thus, not only could the mature intercoronary collateral vasculature supply adequate flow at rest, but when subjected to the natural stress of exercise, the increase in flow to the predominantly collateral-dependent area was similar to that in the normally perfused area.

Persistence of regional left ventricular dysfunction after exercise-induced myocardial ischemia.

To determine whether regional myocardial dysfunction occurring after exercise-induced ischemic might be caused by continued abnormalities of myocardial blood flow in the post-exercise period, nine dogs were instrumented with ultrasonic microcrystals for determination of circumferential segment shortening, circumflex artery electromagnetic flow probes, and hydraulic coronary artery occluders. Dogs performed treadmill exercise during partial inflation of the coronary artery occluder. When the stenosis was maintained after exercise (persistent stenosis), subendocardial flow = 0.79 +/- 0.42 ml/min per g vs. 1.39 +/- 0.43 ml/min per g control), and this was associated with continued dysfunction in the ischemic zone (segment shortening 45.4 +/- 36.9% of resting control). When the stenosis was released immediately after exercise (temporary stenosis), however, flow was markedly increased 1 min post-exercise (mean transmural flow 4.24 +/- 1.22 ml/min per g; subendocardial flow 4.18 +/- 1.52 ml/min per g), and this was associated with a transient increase in segment shortening to 104.5 +/- 9.3% of resting control. 5 min after exercise, however, moderate reductions in ischemic segment shortening were noted after both temporary stenosis and persistent stenosis runs, and these persisted for 30 min post-exercise. It is concluded that regional left ventricular dysfunction may persist for a significant period of time after exercise-induced ischemia. Furthermore, early after exercise, dysfunction is related to persistent abnormalities of myocardial blood flow, whereas late after exercise it is independent of primary reductions in myocardial blood flow.

Regional myocardial blood flow during graded treadmill exercise in the dog.

Regional myocardial blood flow was measured in nine dogs at rest and during three levels of treadmill exercise by using left atrial injections of 7-10-mum radioactive microspheres. At rest, heart rate was 76 plus or minus 3 beats/min (mean plus or minus SEM), mean left ventricular myocardial flow was 0.94 plus or minus 0.09 ml/min/g and endocardial flow (endo) exceeded epicardial flow (epi) in all regions (endo/epi equals 1.12-1.33). When treadmill exercise was regulated to increase heart rates from 152 plus or minus 3 to 190 plus or minus 3 to 240 plus or minus 6 beats/min, myocardial blood flow (MBF) to all regions of the left ventricle increased linearly with heart rate (HR) from 1.83 plus or minus 0.11 to 2.75 plus or minus 0.22 to 3.90 plus or minus 0.26 ml/min/g (MBF EQUALs 0.0175 HR - 0.523 PLUS OR MINUS 0.614, R EQUALS 0.87). Exercise abolished the gradient of blood flow favoring the left ventricular endocardium at rest, so that the endo/epi flow ratios were not significantly different from 1.00. Right ventricular flows were consistently less than corresponding left ventricular flows, but showed a similar linear increase with heart rate. Right ventricular endo/epi ratios were not different from 1.00 either at rest or during exercise. Thus, exercise resulted in increased myocardial blood flow to all regions of the left and right ventricles with maintenance of subendocardial flow equal to subepicardial flow.

Role of K+ ATP channels and adenosine in the regulation of coronary blood flow during exercise with normal and restricted coronary blood flow.

Regulation of coronary vasomotor tone during exercise is incompletely understood. We investigated the contributions of K+ ATP channels and adenosine to the coronary vasodilation that occurs during exercise in the normal heart and in the presence of a coronary artery stenosis. Dogs that were chronically instrumented with a Doppler flow probe, hydraulic occluder, and indwelling catheter on the left anterior descending coronary artery were exercised on a treadmill to produce heart rates of approximately 200 beats/min. By graded inflation of the occluder to produce a wide range of coronary stenosis severities, we determined the coronary pressure-flow relation. K+ atp channel blockade with intracoronary glibenclamide (10-50 microgram/kg per min) decreased coronary blood flow during exercise at coronary pressures within and below the autoregulatory range, indicating that coronary K+ ATP channel activation is critical for producing coronary vasodilation with either normal arterial inflow or when flow is restricted by a coronary artery stenosis. Adenosine receptor blockade with intravenous 8-phenyltheophylline (5 mg/kg) had no effect on coronary flow at pressures within the autoregulatory range but decreased flow at pressures < 55 mmHg. In contrast, in the presence of K+ ATP channel blockade, the addition of adenosine receptor blockade further decreased coronary flow even at coronary pressures in the autoregulatory range, indicating increased importance of the vasodilator influence of endogenous adenosine during exercise when K+ atp channels are blocked. Intracoronary adenosine (50 microgram/kg per min) increased coronary flow at perfusion pressures both within and below the autoregulatory range. In contrast, selective K+ ATP channel activation with intracoronary pinacidil (0.2-5.0 microgram/kg per min) increased flow at normal but not at lower coronary pressures (< 55 mmHg). This finding demonstrates that not all K+ ATP channels are activated during exercise at pressures in the autoregulatory range, but that most K+ ATP channels are recruited as pressures approach the lower end of the autoregulatory plateau. Thus, K+ ATP channels and endogenous adenosine play a synergistic role in maintaining vasodilation during exercise in normal hearts and distal to a coronary artery stenosis that results in myocardial hypoperfusion during exercise.

Local effects of acute cellular injury on regional myocardial blood flow.

This study was designed to examine local effects of acute cellular injury on regional myocardial blood flow. Studies were carried out in awake dogs chronically prepared with indwelling catheters in the aorta and left atrium and an occluder on the left circumflex coronary artery. Regional myocardial blood flow was measured by using 7-10-mum radioisotope-labeled microspheres after reestablishing inflow to a region subjected to a 2-h complete coronary occlusion. Microspheres were injected 15 s, 15 min, 4 h, and 3 days after reperfusion to assess effects of cell injury at varying intervals after reperfusion. Effects of acute cellular injury on blood flow were assessed by determining the relationship between regional blood flow and the extent of subsequent cellular necrosis measured in multiple tissue samples, weight 1-2 g, from the entire ischemic zone. The extent of cellular necrosis was determined from histological sections of each tissue sample. Prolonged ischemia effected local tissue responses which altered perfusion as a function of the interval after reperfusion and the subsequent extent of myocardial necrosis. Although the net response in each region immediately after reperfusion was vasodilation, the hyperemia in regions which subsequently suffered cellular necrosis was attenuated in direct proportion to the extent of subsequent infarction. Blood flow to acutely injured regions remained equal to, or in excess of, flow to nonischemic regions 15 min after reperfusion, but at 4 h and 3 days after reperfusion, flow was significantly decreased in regions with greater than 50% infarction. Thus, these data indicate that prolonged ischemia initiates tissue responses which progressively reduce myocardial perfusion after reperfusion. These effects on tissue perfusion may result from normal responses to irreversible injury and (or) abnormal responses to reversible and thus, potentially alterable, ischemic injury.

Endogenous adenosine mediates coronary vasodilation during exercise after K(ATP)+ channel blockade.

The mechanism of coronary vasodilation produced by exercise is not understood completely. Recently, we reported that blockade of vascular smooth muscle K(ATP)+ channels decreased coronary blood flow at rest, but did not attenuate the increments in coronary flow produced by exercise. Adenosine is not mandatory for maintaining basal coronary flow, or the increase in flow produced by exercise during normal arterial inflow, but does contribute to coronary vasodilation in hypoperfused myocardium. Therefore, we investigated whether adenosine opposed the hypoperfusion produced by K(ATP)+ channel blockade, thereby contributing to coronary vasodilation during exercise. 11 dogs were studied at rest and during exercise under control conditions, during intracoronary infusion of the K(ATP)+ channel blocker glibenclamide (50 micrograms/kg per min), and during intracoronary glibenclamide in the presence of adenosine receptor blockade. Glibenclamide decreased resting coronary blood flow from 45 +/- 5 to 35 +/- 4 ml/min (P < 0.05), but did not prevent exercise-induced increases of coronary flow. Glibenclamide caused an increase in myocardial oxygen extraction at the highest level of exercise with a decrease in coronary venous oxygen tension from 15.5 +/- 0.7 to 13.6 +/- 0.8 mmHg (P < 0.05). The addition of the adenosine receptor antagonist 8-phenyltheophylline (5 mg/kg intravenous) to K(ATP)+ channel blockade did not further decrease resting coronary blood flow but did attenuate the increase in coronary flow produced by exercise. This was accompanied by a further decrease of coronary venous oxygen tension to 10.1 +/- 0.7 mmHg (P < 0.05), indicating aggravation of the mismatch between oxygen demand and supply. These findings are compatible with the hypothesis that K+ATP channels modulate coronary vasomotor tone both under resting conditions and during exercise. However, when K(ATP)+ channels are blocked, adenosine released from the hypoperfused myocardium provides an alternate mechanism to mediate coronary vasodilation in response to increases in oxygen demand produced by exercise.

Bioenergetic abnormalities associated with severe left ventricular hypertrophy.

Transmurally localized 31P-nuclear magnetic resonance spectroscopy (NMR) was used to study the effect of severe pressure overload left ventricular hypertrophy (LVH) on myocardial high energy phosphate content. Studies were performed on 8 normal dogs and 12 dogs with severe left ventricular hypertrophy produced by banding the ascending aorta at 8 wk of age. Spatially localized 31P-NMR spectroscopy provided measurements of the transmural distribution of myocardial ATP, phosphocreatine (CP), and inorganic phosphate (Pi); spectra were calibrated from measurements of ATP content in myocardial biopsies using HPLC. Blood flow was measured with microspheres. In hypertrophied hearts during basal conditions, ATP was decreased by 42%, CP by 58%, and the CP/ATP ratio by 32% in comparison with normal. Increasing myocardial blood flow with adenosine did not correct these abnormalities, indicating that they were not the result of persistent hypoperfusion. Atrial pacing at 200 and 240 beats per min caused no change in high energy phosphate content in normal hearts but resulted in further CP depletion with Pi accumulation in the inner left ventricular layers of the hypertrophied hearts. These changes were correlated with redistribution of blood flow away from the subendocardium in LVH hearts. These findings demonstrate that high energy phosphate levels and the CP/ATP ratio are significantly decreased in severe LVH. These abnormalities are proportional to the degree of hypertrophy but are not the result of persistent abnormalities of myocardial perfusion. In contrast, depletion of CP and accumulation of Pi during tachycardia in LVH are closely related to the pacing-induced perfusion abnormalities and likely reflect subendocardial ischemia.

Effects of nitroglycerin on transmural myocardial blood flow in the unanesthetized dog.

This study was designed to determin the effect of nitroglycerin upon transmural distribution of myocardial blood flow in the awake dog during normal conditions and in the presence of ischemia-induced coronary vasodilation. Studies were performed in chronically prepared dogs with electromagnetic flowmeters and hydraulic occluders on the left circumflex coronary artery. Regional myocardial blood flow was estimated by using radionuclide-labeled microspheres, 7-10 mum in diameter, injected into the left atrium. During control conditions endocardial flow (0.86 plus or minus SEM 0.05 ml/min per g) slightly exceeded epicardial flow (0.72 plus or minus 0.03 ml/min per g, P smaller than 0.05), and this distribution of flow was not significantly altered by nitroglycerin. After a 5-s coronary artery occlusion, reactive hyperemia occurred with excess inflow of arterial blood effecting 360 plus or minus 15% repayment of the blood flow debt incurred during occlusion. When arterial inflow was limited to the preocclusion rate during coronary vasodilation after a 5-s total coronary artery occlusion, flow to the subepicardial myocardium was increased at the expense of underperfusion of the subendocardial myocardium, and the delayed reactive hyperemia was markedly augmented (mean blood flow debt repayment =775plus or minus 105%, P smaller than 0.01). Tese data suggested that subendocardial underperfusion during the interval of coronary vasodilation in the presence of a flow-limiting proximal coronary artery stenosis caused continuing subendocardial ischemia which resulted in augmentation of the reactive hyperemic response. In this experimental model both the redistribution of myocardial blood flow which occurred during an interval of restricted arterial inflow after a 5-s coronary artery occlusion and augmentation of the subsequent reactive hyperemic response were returned toward normal by nitroglycerin. This effect of nitroglycerin may have resulted, at least in part, from its ability to vasodilate the penetrating arteries which deliver blood from the epicardial surface to the subendocardium.

Cyclic nucleotide phosphodiesterase type 5 activity limits blood flow to hypoperfused myocardium during exercise.

BACKGROUND: Nitric oxide (NO) causes vasodilation by stimulation of guanylate cyclase in vascular smooth muscle to produce cGMP. The resultant vasodilator effect is regulated by a family of cGMP phosphodiesterases (PDEs). Sildenafil, a selective inhibitor of PDE5 used for treatment of erectile dysfunction, has been found to cause relaxation of isolated epicardial coronary artery segments. The present study examined the effects of sildenafil on coronary blood flow and hemodynamics during exercise in normal and ischemic heart. METHODS AND RESULTS: In chronically instrumented normal dogs, sildenafil 2 mg/kg PO caused a slight but significant increase in left anterior descending (LAD) coronary blood flow during resting conditions, with a nonsignificant trend toward increased coronary flow during treadmill exercise. Exercise in the presence of LAD stenosis that decreased distal coronary pressure to 57+/-2 mm Hg reduced LAD flow during exercise from 69+/-8 to 41+/-7 mL/min (P:<0. 05), with hypoperfusion most severe in the subendocardium. At the same distal coronary pressure, sildenafil increased LAD flow in the ischemic region to 50+/-11 mL/min (P:<0.05). Increase in ischemic region blood flow produced by sildenafil was uniform across the LV wall, given that no change occurred in the transmural distribution of perfusion. CONCLUSIONS: Inhibition of PDE5 with sildenafil caused vasodilation of coronary resistance vessels with an increase of blood flow into an ischemic myocardial region during exercise in the presence of coronary artery stenosis.

Coronary nitric oxide production in response to exercise and endothelium-dependent agonists.

BACKGROUND: Endothelium-derived nitric oxide (NO) contributes to epicardial coronary artery vasodilation during exercise. However, blockade of NO production does not impair the increase in coronary blood flow (CBF) during exercise, suggesting that NO is not obligatory for exercise-induced coronary resistance vessel dilation. In contrast, the increases in CBF produced by endothelium-dependent agonists are decreased after NO blockade. Consequently, this study was performed to determine whether the increase in coronary NO production in response to agonists is greater than that which occurs during exercise. METHODS AND RESULTS: We measured the oxidation products of NO (nitrate+nitrite=NO(x)) in aortic and coronary sinus plasma using chemiluminescence to assess NO(x) production across the coronary circulation in chronically instrumented dogs during a 3-stage treadmill exercise protocol and in response to intracoronary administration of the endothelium-dependent agonists acetylcholine (37.5 microg/min) and bradykinin (3.0 microg/min). No coronary NO(x) production could be detected at rest or during the first 2 stages of exercise; only at the highest level of exercise was a small increase in coronary NO(x) production measured. In contrast, coronary production of NO(x) was significantly increased in response to endothelium-dependent agonists. CONCLUSIONS: Coronary NO production in response to endothelium-dependent agonists is greater than in response to the increase in shear stress associated with exercise. These findings support previous studies suggesting that NO is not required for the coronary vasodilation that occurs in the normal heart during exercise.

Myocardial oxygen consumption during exercise in the presence of left ventricular hypertrophy secondary to supravalvular aortic stenosis.

The hypothesis that abnormally increased myocardial oxygen demands may contribute to increased vulnerability to ischemia during exercise in the chronically pressure-overloaded hypertrophied left ventricle was tested. Myocardial oxygen consumption was measured during a five stage graded treadmill exercise protocol in eight normal dogs and nine adult dogs in which a 90% increase in left ventricular mass was produced by banding the ascending aorta at 8 weeks of age. Heart rate increased progressively during exercise in both groups of dogs, but was significantly faster than normal in the group with aortic banding. Coronary blood flow increased progressively with exercise in both groups, but was significantly greater than normal in dogs with aortic banding during each exercise stage. Coronary sinus oxygen tension decreased significantly and similarly during exercise in normal and hypertrophied hearts. In dogs with hypertrophy, oxygen consumption per gram of myocardium averaged 52% greater than normal during exercise. This excess myocardial oxygen consumption in dogs with aortic banding resulted from an abnormally large increase in oxygen consumption per beat during exercise and from the faster heart rate in this group of dogs. Measurements of myocardial blood flow with microspheres demonstrated a lower subendocardial/subepicardial blood flow ratio in dogs with hypertrophy; this ratio decreased significantly during exercise in dogs with hypertrophy, but not in normal dogs. These data are consistent with the hypothesis that increased vulnerability to ischemia in the pressure-overloaded hypertrophied left ventricle is the result of both increased myocardial oxygen demands during exercise and abnormalities of myocardial perfusion.

Effects of atrial natriuretic peptide on coronary vascular resistance in the intact awake dog.

Atrial natriuretic peptide has been reported to cause vasoconstriction, vasodilation or no change of coronary vascular resistance in isolated perfused hearts or in open chest animal models. Because general anesthesia and acute surgical trauma may perturb baseline coronary hemodynamics and alter responses to experimental interventions, this study examined the effects of human atrial natriuretic peptide (arginine-102-tyrosine-126) and rat atriopeptin II (serine-103-arginine-125) on the coronary circulation of unsedated, awake dogs. Studies were performed in 12 chronically instrumented animals in which a surgically implanted electromagnetic flow probe and intracoronary catheter allowed measurement of left circumflex coronary blood flow during intraarterial administration of the atrial natriuretic peptides. Bolus doses of both human atrial natriuretic peptide and rat atriopeptin II produced dose-dependent coronary vasodilation; the threshold for coronary vasodilation was 0.2 micrograms/kg body weight for both agents. Coronary vasodilation produced by human atrial natriuretic peptide was not antagonized by adenosine receptor blockade or by cyclooxygenase inhibition with indomethacin. Thus, atrial natriuretic peptides produced dose-dependent coronary vasodilation in intact awake dogs that was not dependent on adenosine-mediated or prostaglandin-mediated mechanisms.

Effect of beta-adrenergic blockade with timolol on myocardial blood flow during exercise after myocardial infarction in the dog.

The effect of beta-adrenergic blockade with timolol (40 micrograms/kg) on myocardial blood flow during rest and graded treadmill exercise was assessed in 12 chronically instrumented dogs 10 to 14 days after myocardial infarction was produced by acute left circumflex coronary artery occlusion. During exercise at comparable external work loads, the heart rate-systolic blood pressure product was significantly decreased after timilol, with concomitant reductions of myocardial blood flow in normal, border and central ischemic areas (p less than 0.001) and increases in subendocardial/subepicardial blood flow ratios (p less than 0.05). In addition to the blunted chronotropic response to exercise, timolol exerted an effect on myocardial blood flow that was not explained by changes in heart rate or blood pressure. At comparable rate-pressure products during exercise, total myocardial blood flow was 24% lower after timolol (p less than 0.02) and flow was redistributed from subepicardium to subendocardium in all myocardial regions. Thus, timolol altered myocardial blood flow during exercise by two separate mechanisms: a negative chronotropic effect, and a significant selective reduction of subepicardial perfusion independent of changes in heart rate or blood pressure with transmural redistribution of flow toward the subendocardium.

Recovery of transmural and subepicardial wall thickening after subendocardial infarction.

OBJECTIVES: This study tested the hypothesis that there is preferential recovery of subepicardial wall thickening after nontransmural myocardial infarction. BACKGROUND: Previous studies have demonstrated gradual recovery of mechanical function after reperfusion in acute myocardial infarction. Because myocardial necrosis is primarily subendocardial, it was hypothesized that recovery of mechanical function would occur primarily in the subepicardial layers. METHODS: Eleven mongrel dogs were instrumented with ultrasonic crystals to measure transmural and outer wall thickening. Animals performed treadmill exercise before and 8 days after nontransmural infarction produced by coronary occlusion for 90 min. RESULTS: Coronary artery occlusion reduced myocardial blood flow to inner layers more than that to outer wall layers (mean [+/- SD] 0.19 +/- 0.35 vs. 0.38 +/- 0.38 ml/g per min, p < 0.05). Infarct size (% of risk region) was also greater in subendocardial layers (33.3 +/- 24.3% inner vs. 8.3 +/- 9.7% outer). Rest transmural wall thickening was 22.4 +/- 7.5% versus 14.4 +/- 6.3% for outer wall layers. During coronary artery occlusion, transmural and outer wall thickening decreased similarly (3.2 +/- 7.7% vs. 0.2 +/- 5.9%). Eight days after reperfusion, thickening of the entire wall recovered to 7.5 +/- 4.7%; however, outer wall thickening had only recovered to 0.0 +/- 5.8%. Myocardial blood flow was abnormal during exercise 8 days after reperfusion, with markedly reduced subendocardial perfusion. However, thickening of the inner and outer layers was similar, with transmural thickening of 8.5 +/- 9.3% and outer wall thickening of 1.6 +/- 6.2%. CONCLUSIONS: Despite preferential blood flow and less necrosis, thickening of the outer layer is not preserved 8 days after subendocardial infarction. The severity of subendocardial injury appears to be the major determinant of regional function after nontransmural infarction.

Effect of nifedipine on myocardial blood flow during exercise in dogs with chronic coronary artery occlusion.

The effect of nifedipine, 0.010 mg/kg intravenously, on myocardial blood flow was studied in 15 dogs 4 weeks after placement of an Ameroid constrictor on either the left circumflex or left anterior descending coronary artery to produce total coronary occlusion. Myocardial blood flow was measured with radionuclide-labeled microspheres at rest and during two levels of treadmill exercise to achieve a heart rate of 190 (light exercise) and 230 (heavy exercise) beats/min. During control conditions, increasing exercise resulted in a progressive increase in myocardial blood flow in normally perfused areas, but was associated with worsening subendocardial hypoperfusion in collateral-dependent areas. Nifedipine administration resulted in a transient reduction of arterial pressure and an increase in heart rate. To determine whether nifedipine exerted significant persistent effects on the coronary collateral circulation, measurements of myocardial blood flow were repeated beginning 30 minutes after nifedipine administration, at a time when heart rate and arterial pressure had returned to control levels. In normally perfused areas, nifedipine did not significantly alter myocardial blood flow at rest, but increased mean myocardial blood flow from 2.06 +/- 0.15 to 2.40 +/- 0.20 ml/min per g during light exercise (p less than 0.01), while blood flow during heavy exercise was not significantly altered. In collateral-dependent myocardial areas, the volume and transmural distribution of myocardial blood flow were not significantly altered after nifedipine administration either at rest or during exercise. These results fail to demonstrate persistent vasodilation of the coronary collateral vessels after the systemic hemodynamic effects of nifedipine have subsided.

Effect of serotonin and thromboxane A2 on blood flow through moderately well developed coronary collateral vessels.

This study was performed to determine whether thromboxane A2 (as the analogue U46619) and serotonin can cause vasoconstriction of moderately well developed coronary collateral vessels. Studies were carried out in seven adult mongrel dogs 2 to 4 months after embolic occlusion of the left anterior descending coronary artery had been performed to stimulate collateral vessel growth. At the time of study this artery was cannulated to determine interarterial collateral flow from measurements of retrograde blood flow. Radioactive microspheres were administered during retrograde flow collection to determine continuing tissue flow for evaluation of microvascular collateral communications. Serotonin (50 micrograms/min) resulted in a 48 +/- 11% decrease in retrograde flow (p less than 0.01), with a 36 +/- 10% decrease in total collateral blood flow (p less than 0.02). Infusion of U46619 (0.01 microgram/kg per min) caused a 38 +/- 13% decrease in retrograde blood flow (p less than 0.01), with a 34 +/- 13% decrease in total collateral flow (p less than 0.05). Serotonin caused a significant increase in tissue flow to the subepicardium of the collateral-dependent region, whereas U46619 caused no change in tissue blood flow. These data demonstrate that both serotonin and thromboxane A2 can cause vasoconstriction of interarterial coronary collateral vessels. The findings suggest that platelet activation in coronary arteries from which collateral vessels originate has potential for causing collateral vasoconstriction, thereby compromising blood flow to the dependent myocardium.

Nitric oxide inhibition impairs blood flow during exercise in hearts with a collateral-dependent myocardial region.

OBJECTIVES: We sought to determine the importance of nitric oxide (NO) production in maintaining coronary blood flow during exercise in hearts with collateral-dependent myocardium. BACKGROUND: Coronary collateral vessels demonstrate endothelium-mediated NO-dependent vasodilation in response to agonists such as acetylcholine. However, the contribution of endogenous NO production to maintaining vasodilation of coronary collateral vessels during exercise has not been previously studied. METHODS: Collateral vessel growth was induced in 13 chronically instrumented dogs by intermittent 2-min occlusions, followed by permanent occlusion of the left anterior descending coronary artery (LAD). One week after permanent LAD occlusion, myocardial blood flow was measured with microspheres during rest and treadmill exercise at 6.4 km/h at a 15% grade. Measurements were then repeated after blockade of NO production with N-nitro-L-arginine (LNNA) (20 mg/kg body weight intravenously). RESULTS: LNNA caused a 62 +/- 4% (mean +/- SEM) inhibition of the coronary vasodilation produced by acetylcholine. During rest conditions, LNNA caused a slight decrease in blood flow to the collateral region (p = NS), with no change in normal zone blood flow. During exercise, LNNA caused a decrease in mean blood flow to the collateral region (from 2.24 +/- 0.19 to 1.78 +/- 0.26 ml/min per g after LNNA, p < 0.05). This decrease resulted from a near doubling of the collateral vascular resistance (p < 0.05), with a trend toward an increase in small vessel resistance in the collateral zone. LNNA also reduced myocardial blood flow to the normal region during exercise (from 2.99 +/- 0.24 to 2.45 +/- 0.28 ml/min per g, p < 0.05) as the result of a 44 +/- 13% increase in coronary vascular resistance (p < 0.05). CONCLUSIONS: NO contributes to the maintenance of coronary collateral blood flow during exercise. In contrast to the normal heart, endogenous NO production also maintains blood flow in remote myocardial regions during exercise. These results suggest that control of blood flow during exercise in normal myocardium is altered by the presence of an occluded coronary artery.

Signaling and expression for mitochondrial membrane proteins during left ventricular remodeling and contractile failure after myocardial infarction.

OBJECTIVES: This study was conducted to test hypotheses stating that: 1) altered signaling for mitochondrial membrane proteins occurs during postinfarction remodeling, and 2) successful myocardial adaptation relates to promotion of specific mitochondrial membrane components. BACKGROUND: Abnormalities in high-energy phosphate content and limitations in adenosine 5'-triphosphate (ATP) synthesis rate occur during the transition to contractile failure from compensatory remodeling after left ventricular infarction. The adenine nucleotide translocator (ANT) and F1-ATPase respectively regulate mitochondrial adenosine 5'-diphosphate (ADP)/ATP exchange and ADP-phosphorylation, which are key components of high-energy phosphate metabolism. METHODS: Steady-state mRNA and protein expression for ANT isoform1 and the beta subunit of the F1-ATPase (betaF1) were analyzed in myocardium remote from the infarction zone eight weeks after left circumflex coronary artery ligation in pigs, demonstrating either successful left ventricular remodeling (LVR, n = 8) or congestive heart failure (CHF, n = 4) as determined by clinical and contractile performance parameters. RESULTS: Substantial reductions in steady-state mRNA expression for ANT1 and betaF1 relative to normal (n = 8) occur in CHF, p < 0.01, but not in LVR. Relative expression for both proteins coordinated with their respective steady-state mRNA levels; CHF at 40% normal, p < 0.05 for ANT and 70% normal for betaF1, p < 0.05. CONCLUSIONS: Maintained signaling for major mitochondrial membrane proteins occurs in association with successful remodeling and adaptation after infarction. Reduced expression of these proteins relates to limited ATP synthesis capacity and high energy phosphate kinetic abnormalities previously demonstrated in CHF. These findings imply that mitochondrial processes participate in myocardial remodeling after infarction.