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This study was carried out to determine the relative importance of alpha 1- and alpha 2-adrenergic vasoconstriction in opposing the increase in coronary blood flow, which occurs during exercise. The response of left circumflex coronary artery blood flow was examined during treadmill exercise in 16 chronically instrumented dogs during control conditions, after selective alpha 1-adrenergic blockade with intracoronary prazosin, and after alpha 2-blockade with intracoronary idazoxan. During control conditions, graded treadmill exercise resulted in progressive increases of coronary blood flow and decreases of coronary vascular resistance. Prazosin produced highly selective alpha 1-adrenergic blockade; coronary blood flow was significantly higher and coronary vascular resistance significantly lower during all but the heaviest exercise stage after prazosin. Idazoxan produced highly effective, but only moderately selective, alpha 2-adrenergic blockade. However, after idazoxan, coronary blood flow and coronary vascular resistance during exercise were not significantly different from control. Combined alpha 1- and alpha 2-adrenergic blockade was not more effective in increasing coronary blood flow during exercise than was alpha 1-adrenergic blockade alone. These data support a role for alpha 1-adrenergic coronary vasoconstriction in limiting the increase in coronary blood flow, which occurs during exercise, but do not support a role for alpha 2-mediated coronary vasoconstriction during exercise.

This study tested the hypothesis that for similar degrees of left ventricular hypertrophy, subendocardial blood flow would be facilitated by the increased diastolic coronary perfusion pressure associated with arterial hypertension, as compared with hypertrophy produced by banding the ascending aorta. Left ventricular hypertrophy was produced with perinephritic hypertension in seven adult dogs and by banding the ascending aorta in nine adult dogs. Left ventricular/body weight ratios were 6.15 +/- 0.59 g/kg in the hypertensive animals and 6.87 +/- 0.47 g/kg in dogs with aortic banding, as compared with 4.23 +/- 0.23 g/kg in seven normal dogs (p less than .01). Studies were performed at rest and during two stages of treadmill exercise to achieve heart rates of 195 and 260 beats/min. Diastolic aortic pressure was increased in animals with hypertension but not in dogs with aortic banding. Systolic ejection period was prolonged in dogs with aortic banding but not in hypertensive dogs. Mean blood flow per gram of myocardium measured with microspheres was similar at rest and during light exercise in all three groups of animals, whereas during heavy exercise blood flow was significantly greater than normal in both groups with hypertrophy. In normal dogs subendocardial/subepicardial (endo/epi) flow ratios did not change significantly during exercise. In both groups with hypertrophy, endo/epi ratios were normal at rest but decreased significantly during exercise. During heavy exercise the endo/epi ratio decreased to 0.73 +/- 0.08 in dogs with aortic banding as compared with 1.07 +/- 0.12 in hypertensive dogs (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of a proximal coronary artery stenosis on transmural myocardial blood flow during exercise was studied in nine dogs with electromagnetic flowmeter probes and hydraulic occluders on the left circumflex coronary artery. Regional myocardial blood flow at rest and during treadmill exercise was estimated with radioactive microspheres 7-10 mum in diameter. Exercise studies were performed during unrestricted coronary artery inflow (control exercise) and during partial inflation of the occluder to a level which did not reduce flow at rest but which limited the increase in flow during exercise to 66 +/- 6% (mild restriction) or 44 +/- 3% (severe restriction) of the value during control exercise. Mean myocardial blood flow at rest was 0.94 +/- 0.06 ml/min per g of myocardium and increased to 2.45 +/- 0.15 ml/min per g during control exercise, with uniform distribution across the wall of the left ventricle. Flow to the subepicardial myocardium was significantly greater during exercise in the presence of a mild restriction than during control exercise, whereas flow to deeper layers of myocardium was progressively decreased below the control level. A similar pattern of redistribution of flow occurred during exercise in the presence of a severe restriction, but flow to all transmural layers was below that during mild restriction, resulting in more marked subendocardial underperfusion. Thus, exercise in the presence of stenosis resulted in transmural redistribution of myocardial blood flow with subendocardial underperfusion in proportion to the degree of restriction of coronary artery inflow.

Coronary vascular responses in regions of reversible postischemic myocardial contractile dysfunction (stunned myocardium) were examined in chronically instrumented, awake dogs. Left anterior descending coronary artery blood flow and oxygen extraction, aortic and left ventricular pressures, and regional myocardial segment shortening were determined. Regional myocardial blood flow was measured with microspheres. Coronary reactive hyperemia and vasodilator reserve, and regional myocardial oxygen consumption were determined. Three sequential 10-minute left anterior descending coronary artery occlusions separated by 30-minute reperfusion periods resulted in progressive postischemic dysfunction so that 1 hour after the final coronary artery occlusion, myocardial segment shortening was reduced to 37% of baseline. Despite this decrease in contractile function, left anterior descending artery flow (19.6 +/- 2.6 vs. 18.4 +/- 3.0 ml/min), myocardial blood flow and the transmural distribution of flow measured with microspheres, and regional myocardial oxygen consumption were unchanged. Although the coronary vasodilator reserve in response to adenosine was unaltered (63 +/- 9 vs. 70 +/- 15 ml/min), the reactive hyperemia response to a 10-second coronary occlusion was decreased in intensity (debt repayment ratio = 474 +/- 78% vs. 322 +/- 74%; p less than 0.05) and duration (57 +/- 9.1 vs. 35 +/- 4.5 seconds; p less than 0.05), while the peak flow response was unchanged (57 +/- 6.8 vs. 60 +/- 7.1 ml/min). Thus, in the intact awake animal postischemic myocardial contractile dysfunction was not associated with decreased myocardial oxygen consumption and did not impair the normal relation between coronary blood flow and myocardial oxygen utilization. Although coronary vessels showed a normal ability to vasodilate in response to adenosine, coronary reactive hyperemia was reduced.

Studies were performed to compare the effects of alpha 1-adrenergic blockade with indoramin and nonselective alpha-adrenergic blockade with phentolamine on coronary blood flow and myocardial oxygen consumption during exercise. Nine dogs trained to run on a motor-driven treadmill were instrumented with electromagnetic flowmeter probes on the left circumflex coronary artery, and aortic and coronary sinus catheters for determination of myocardial arteriovenous oxygen difference. During control conditions, myocardial oxygen consumption and coronary blood flow increased as a direct function of heart rate during exercise. Phentolamine caused a significant decrease in blood pressure, while heart rate, coronary blood flow, and myocardial oxygen consumption were significantly increased at rest and during all exercise stages. Although alpha 1-adrenergic blockade with indoramin caused a similar reduction of arterial pressure, heart rate was unaltered both at rest and during exercise. Coronary blood flow and myocardial oxygen consumption were unchanged by alpha 1-adrenergic blockade at rest and during light exercise: however, during the heaviest exercise stages alpha 1-blockade caused a significant decrease in myocardial oxygen consumption. These findings are in agreement with the concept that phentolamine, by blocking presynaptic alpha 2-adrenoceptors which normally modulate norepinephrine release, increases sympathetic activity during exercise while indoramin, by acting as a selective alpha 1-adrenergic blocker, does not produce this effect.

Coronary stenosis results in transmurally non-uniform blood flow with the inner layers of the left ventricular wall typically suffering a more severe hypoperfusion relative to the outer layers. Coupled with numerous other transmural non-uniformities such as systolic tension development and oxygen needs, the heterogeneous blood flow distribution in the presence of coronary stenosis is expected to result in transmurally heterogeneous ischemia. All previous NMR spectroscopy studies of myocardial metabolism and bioenergetics under normal and ischemic conditions treated the organ as a homogeneous tissue. We have utilized spatially localized 31P NMR spectroscopy together with non-NMR measurements of regional blood flow to study the myocardium with transmural spatial differentiation under normal and flow-restricted conditions. 31P NMR and blood flow data obtained concurrently on each heart revealed that sustained coronary artery stenosis resulted in transmurally non-uniform ischemia which largely paralleled the hypoperfusion pattern. The reduction in creatine phosphate content (with consequent elevation of Pi) and hypoperfusion was tightly correlated in the subendocardium for flow rates less than approximately 0.7 mL/min per g wet myocardium. The high energy phosphate and Pi content of the epicardium, however, was responsive not only to the flow to this region but also to the extent of ischemia in the subendocardial layers. These results document the utility of localized NMR spectroscopy in physiologic research and suggest potential biomedical applications due to the tight correlation noted between alterations in blood flow and changes in the phosphorylated metabolite levels detected by 31P NMR.

The calcium entry-blocking drugs produce effects on the coronary vasculature that might be expected to exert anti-ischemia activity. Although these agents cause little vasodilation of the epicardial coronary arteries during basal conditions, they block vasoconstriction that can increase stenosis severity during isometric exercise and interrupt coronary artery spasm in patients with variant angina. Administration of the calcium blockers causes transient vasodilation of the coronary resistance vessels, followed by decreased responsiveness to a brief ischemic stimulus. This results in decreased coronary reactive hyperemia after transient coronary occlusion. By preventing excessive ischemic vasodilation of the resistance vessels, these agents can enhance perfusion of the subendocardium distal to a flow-limiting coronary stenosis. The calcium entry blockers have relatively little effect on the immature coronary collateral vessels that exist at the time of acute coronary occlusion. Diltiazem, however, has been demonstrated to increase collateral blood flow in animals in which chronic coronary occlusion has resulted in growth of moderately well-developed collateral vessels.

This study was designed to quantitate transmural myocardial blood flow when coronary arterial inflow was limited to systole and during the subsequent reactive hyperemic response. Studies were performed in 10 awake dogs chronically prepared with electromagnetic flowmeters and pneumatic occluders on the left circumflex coronary artery. Intermittent coronary perfusion, confined to the interval of left ventricular systole or an equivalent period during diastole, was effected by an R wave-triggered solenoid valve connected to the occluder. To measure regional myocardial blood flow we injected radionuclide-labeled microspheres, 7-10 mum in diameter, into the left atrium. When arterial inflow was limited to systole, flow was normal in the subepicardial layers and was decreased as a linear function of tissue depth in the subendocardial layers. When coronary arterial inflow was limited to an equivalent interval in diastole, the transmural distribution of flow was uniform. When coronary flow was confirmed to systole for more than 20 seconds, the blood flow debt incurred elicited a reactive hyperemia similar to that following a total occlusion of equivalent blood flow debt. However, regional myocardial blood flow during the peak of reactive hyperemia following systolic perfusion was preferentially directed to the subendocardium, where underperfusion was most marked, whereas reactive hyperemia flow following a total occlusion of equivalent blood flow debt was distributed more evenly across the left ventricular wall. Thus, when coronary inflow was limited to systole, ventricular contraction produced a transmural gradient in myocardial blood flow resulting in subendocardial underperfusion.

Cardiac glycosides have previously been shown to constrict small coronary resistance vessels. This study evaluated the effect of a bolus intravenous dose of ouabain (20 micrograms/kg) on large left circumflex coronary arterial diameter measured by sonomicrometry in nine awake chronically instrumented dogs. Between 5 and 10 min after ouabain administration external circumflex coronary diameter decreased (3.87 +/- 0.21 to 3.83 +/- 0.21 mm, p less than 0.05). Twenty minutes after ouabain administration, coronary diameter had returned to control. At the time of the peak decrease in coronary diameter, heart rate had decreased (104 +/- 7 to 82 +/- 7 beats/min, p less than 0.05), circumflex coronary blood flow had decreased (45 +/- 7 to 38 +/- 6 ml/min, p less than 0.05), total circumflex coronary resistance had increased (2.7 +/- 0.4 to 3.5 +/- 0.6 U, p less than 0.05) and aortic pressure was unchanged (108 +/- 4 to 113 +/- 4 mm Hg). Alpha-adrenergic blockade with phentolamine did not prevent the decrease in circumflex coronary arterial diameter in each of five dogs (3.67 +/- 0.28 to 3.60 +/- 0.28 mm, p less than 0.05). Therefore, intravenous ouabain caused vasoconstriction of large coronary arteries. These vasocontrictor effects were not mediated by alpha-adrenergic mechanisms. This constriction could have important consequences in the presence of coronary stenoses.

This study examined the response to intra-arterial norepinephrine and sympathetic nerve stimulation on perfusion pressure of cannulated dog femoral and left circumflex coronary arteries perfused at constant flow rates. Sympathetic nerve stimulation was delivered through the decentralized inferior cardiac nerve and the lumbar sympathetic chain; beta-adrenergic blockade was maintained with propranolol. In the coronary artery, the vasoconstrictor response to norepinephrine was blunted by alpha 1-adrenergic blockade with prazosin but was abolished by alpha 2-adrenergic blockade with rauwolscine, indicating postsynaptic alpha 2-adrenoceptor-mediated vasoconstriction. In the femoral artery, prazosin decreased norepinephrine-induced vasoconstriction by 20-40%; the subsequent addition of rauwolscine completely abolished vasoconstriction, indicating that both alpha 1- and alpha 2-adrenoceptors contributed to vasoconstriction. Sympathetic nerve stimulation produced frequency-dependent increases of perfusion pressure in both coronary and femoral vascular beds. Prazosin caused approximately 50% reduction in the vasoconstrictor response of the coronary vascular bed and approximately 30% reduction in the femoral bed. The addition of rauwolscine completely blocked the response to sympathetic nerve stimulation in coronary and femoral vascular beds. These studies demonstrate that postsynaptic alpha 2-adrenoceptor-mediated mechanisms participate in vasoconstriction in response to both exogenous norepinephrine and sympathetic nerve stimulation in the canine coronary and femoral vascular beds.

We examined the effects of diltiazem on transmural myocardial blood in the presence of a flow-limiting stenosis and during acute total coronary artery occlusion in awake, chronically instrumented dogs. Regional myocardial perfusion was estimated with left atrial injections of 15-mu-diameter radionuclide labeled microspheres. An electromagnetic flowmeter probe and hydraulic occluder were used to monitor blood flow and produce total and subtotal occlusions of the left circumflex coronary artery. A 10-second total arterial occlusion produced intense coronary vasodilation and a pronounced reactive hyperemic response. When a proximal coronary stenosis prevented reactive hyperemia, ischemic coronary vasodilation after a 10-second arterial occlusion caused transmural redistribution of blood flow toward the subepicardium. resulting in subendocardial underperfusion despite a normal net volume of arterial flow. Although diltiazem did not increase coronary collateral flow during acute arterial occlusion, it did blunt the vasodilation that occurred in response to a 10-second total coronary occlusion, and partially corrected the subendocardial underperfusion that occurred with a proximal flow-limiting coronary stenosis.

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.

Epicardial coronary arteries dilate after release of a transient coronary occlusion in awake chronically instrumented dogs but not in anesthetized dogs studied acutely after surgery. To determine whether anesthesia or surgical trauma is responsible for this lack of reactive dilation, we evaluated the effect of anesthesia on reactive coronary dilation in six chronically instrumented dogs. Circumflex coronary diameter was measured with sonomicrometry. Response to release of a 20- or 30-s coronary occlusion was studied before and after sodium pentobarbital (20 +/- 2 mg/kg) and before and after alpha-chloralose (100 mg/kg) plus either morphine or fentanyl and droperidol. Pentobarbital blunted the peak flow response to release of a transient coronary occlusion (114 +/- 15 vs. 128 +/- 16 ml/min, p less than 0.05) but did not affect the increase in large coronary diameter (before pentobarbital: 3.68 +/- 0.30-3.74 +/- 0.30 mm; after pentobarbital: 3.66 +/- 0.31-3.71 +/- 0.31 mm). alpha-Chloralose blunted the peak flow response to release of a transient coronary occlusion (96 +/- 12 vs. 141 +/- 25 ml/min, p less than 0.05) but did not affect the increase in large coronary diameter (before chloralose: 4.00 +/- 0.28-4.06 +/- 0.28 mm; after chloralose: 3.91 +/- 0.31-3.98 +/- 0.31 mm). Therefore, each drug blunted the peak flow response to release of a transient coronary occlusion, but dilation of large coronary arteries was not impaired. The lack of reactivity of large coronary arteries in acutely studied dogs is probably due to the trauma of recent surgery and not the anesthesia.

This study was performed to examine the effect of alterations of cardiac activity during brief coronary artery occlusions on the subsequent reactive hyperemic response. Reactive hyperemia following coronary occlusions equal in duration to one cardiac cycle were examined in 12 chronically instrumented awake dogs while heart rate was maintained constant by cardiac pacing. During continuous pacing, one-beat coronary occlusions resulted in reactive hyperemia with excess flow equal to 220 +/- 23% blood flow debt repayment. When coronary occlusions of identical duration were performed while a single cycle of pacing was omitted during the interval of occlusion, the subsequent reactive hyperemia was decreased. Conversely, when coronary occlusion was produced during the first potentiated beat following a single cycle of paired ventricular stimulation, the reactive hyperemia was increased. Since, in the absence of coronary occlusion, omitting a single paced beat caused a transient decrease in coronary flow, while a single cycle of paired ventricular stimulation caused a brief increase in coronary flow, the reactive hyperemic responses were corrected for these perturbations in flow. Despite these corrections, the influence of alterations of myocardial activity during the interval of occlusion persisted, with the decreased reactive hyperemia when occlusion occurred during an omitted beat and increased hyperemia when occlusion was performed during a potentiated beat. These data indicate substantial coupling between myocardial activity during coronary occlusions as brief as one cardiac cycle in duration and the subsequent reactive hyperemic response.

Myocardial dysfunction may occur in areas remote from an acutely occluded coronary artery if those areas are served by a critically stenosed vessel. Although subendocardial hypoperfusion of such remote myocardium has been demonstrated in experimental preparations of this situation, this study was undertaken to determine whether actual reductions in subendocardial perfusion below control levels were necessary for such dysfunction to occur. A 20 mg dose of pentobarbital was injected into the left anterior descending artery (LAD) in 14 anesthetized dogs to create a large anterior regional wall motion abnormality without drawing significant collateral flow from the circumflex vascular bed. Circumflex subendocardial flow was found to rise during injections of pentobarbital and occlusion of the LAD (1.12 +/- 0.38 and 1.17 +/- 0.34 ml/min/g, respectively, vs control 0.91 +/- 0.23 ml/min/g; p less than .05) in the absence of circumflex stenosis. In the presence of circumflex stenosis, circumflex subendocardial flow fell during left anterior descending occlusion (0.59 +/- 0.21 vs 0.89 +/- 0.19 ml/min/g control; p less than .01) but did not change during pentobarbital injections in the LAD (0.77 +/- 0.36 ml/min/g). In the absence of circumflex stenosis, circumflex segment shortening increased during injection of pentobarbital or occlusion of the LAD (14.3 +/- 4.9% and 14.4 +/- 3.5%, respectively, vs 12.3 +/- 3.3% control). In the presence of circumflex stenosis, it did not change (12.5 +/- 4.0% pentobarbital, 11.8 +/- 3.6 LAD occlusion vs 13.1 +/- 4.0% control). We concluded that the presence of large regional wall motion abnormalities may increase the oxygen consumption of remaining myocardium and that dysfunction of that myocardium may result from relative hypoperfusion if blood flow cannot increase appropriately.

This study was performed to test the hypothesis that growth of coronary vasculature would be facilitated if myocardial hypertrophy occurred during the period of normal body growth rather than in mature adult animals. Left ventricular hypertrophy was produced by banding the ascending aorta in eight young dogs 7 wk of age and in nine adult dogs. Adult dogs were studied 2 mo after aortic banding, whereas young dogs were allowed to grow to adulthood before study. Left ventricular weight-to-body weight ratios were increased to 6.88 +/- 0.36 g/kg in the young dogs and 6.64 +/- 0.47 in adult dogs; both were significantly greater than seven normal control animals (4.32 +/- 0.05; each P less than 0.01). Myocardial blood flow per gram measured with microspheres during quiet resting conditions was significantly higher in young dogs with left ventricular hypertrophy than in normal dogs. Myocardial blood flow rates during maximum coronary vasodilation with adenosine (4 mumol X kg-1 X min-1 iv) were similar in all three groups. However, since mean coronary perfusion pressure was higher in the dogs with aortic banding, minimum coronary vascular resistance per gram of myocardium was significantly higher in both young (21.1 +/- 3.1 mmHg X ml-1 X min X g) and adult dogs with left ventricular hypertrophy (21.8 +/- 2.2) than in the normal dogs (16.8 +/- 3.1; each P less than 0.01). Mean coronary vascular resistance for the total left ventricle was similar in all three groups of animals, suggesting that growth of coronary vasculature did not occur as the myocardium underwent hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

This study examined the hypothesis that increases in myocardial blood flow during exercise are mediated by adenosine-induced coronary vasodilation. Active hyperemia associated with graded treadmill exercise and coronary reactive hyperemia were examined in chronically instrumented awake dogs during control conditions, after intracoronary infusion of adenosine deaminase (5 units/kg/min for 10 minutes), and after adenosine receptor blockade with 8-phenyltheophylline. Both adenosine deaminase and 8-phenyltheophylline caused a rightward shift of the dose-response curve to intracoronary adenosine; 8-phenyltheophylline was significantly more potent than adenosine deaminase. Adenosine deaminase caused a 33 +/- 7 to 39 +/- 3% decrease in reactive hyperemia blood flow following coronary occlusions of 5-20 seconds duration, respectively, while 8-phenyltheophylline produced a 40 +/- 6 to 62 +/- 8% decrease in reactive hyperemia. Increasing myocardial oxygen consumption during treadmill exercise was associated with progressive increase of coronary blood flow. Neither adenosine deaminase nor 8-phenyltheophylline attenuated the increase in coronary blood flow or the decrease of coronary vascular resistance during exercise. Neither agent altered the relation between myocardial oxygen consumption and coronary blood flow. Thus, although both adenosine deaminase and 8-phenyltheophylline antagonized coronary vasodilation in response to exogenous adenosine and blunted coronary reactive hyperemia, neither agent impaired coronary vasodilation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support a substantial role for adenosine in mediating coronary vasodilation during exercise.

Using the load independent contractility index, end-systolic pressure-volume ratio (Emax), contractility of the hypertrophied left ventricle (LV) from three different models was evaluated in conscious, resting dogs. The experimental animals included 12 dogs with perinephritic hypertension (HYP) (aortic diastolic pressure 130 +/- 5 mm Hg), 12 dogs who underwent aortic banding (AOB) at 6 to 8 weeks of age (resting aortic gradient 110 +/- 15 mm Hg), and 12 dogs with chronic fluid overload from aortocaval fistula (ACF). These were compared with 12 normal dogs (CTL). LV dimension and pressure were measured with ultrasonic tranducers and micromanometers. All three models resulted in hypertrophy with significant (P less than 0.01) increase in LV weight-to-body weight ratio (6.3 +/- 0.4, 8.4 +/- 0.5, 6.3 +/- 0.4, respectively, vs 4.4 +/- 0.1 g/kg). Cardiac output (6908 +/- 740 vs 2424 +/- 276 ml/min) and end-diastolic volume (118 +/- 11 vs 50 +/- 4 ml) were significantly (P less than 0.01) increased in AOB (18 +/- 1 vs 9 +/- 2 mm Hg). dp/dtmax was not significantly different among all groups. Emax (CTL = 5.3 +/- 0.4 mm Hg/ml) was not significantly changed in HYP (9.5 +/- 2.1) but was significantly (P less than 0.01) increased in AOB (14.1 +/- 2.6), and significantly (P less than 0.01) depressed in ACF (2.4 +/- .03). Thus, LV hypertrophy from systemic hypertension (HYP) or proximal aortic hypertension (AOB) is, at least initially, associated with preservation of contractility and normal hemodynamic performance.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this investigation was to examine the distribution of procainamide in the canine heart. Eight anesthetized open-chest dogs received intravenous infusions of 14C-labeled procainamide at 40 micrograms/kg/min for 4 hr. Just prior to the end of the infusion period, 51Cr-labeled microspheres were injected into the left atrium to measure regional myocardial blood flow. The heart was then excised and dissected into regional myocardial sections from each cardiac chamber. Samples from each section were combusted, and the liberated 14CO2 was trapped and counted to determine regional myocardial procainamide concentration. The remainder of each section was analyzed for 51Cr to determine regional myocardial blood flow. Plasma procainamide concentration (mean +/- SE) at the termination of the infusion was 2.68 +/- 0.14 micrograms/ml. Left ventricular procainamide concentration was 6.09 +/- 0.46 micrograms/g. The right ventricular drug concentration was 94% (NS), the left atrial concentration was 85% (p less than 0.005), and the right atrial concentration was 79% (p less than 0.005) of the left ventricular concentration. Within the myocardium of each cardiac chamber there was no correlation between drug concentration and blood flow. We conclude that these concentration differences are insufficient to explain differences in procainamide efficacy between ventricular and atrial arrhythmias.

The effect of 100% oxygen inhalation on regional transmural myocardial blood flow following 45 s of actue total left circumflex coronary artery occlusion was studied in six awake dogs chronically instrumented with a coronary occluder and catheters in the aorta and left atrium. After inhalation of either room air or 100% oxygen for at least 30 min and following the 45-s occlusion, transmural myocardial blood flow was determined with radioactive microspheres (7--10 micrometers). Each dog underwent two occlusions of the left circumflex coronary artery; one during inhalation of rrom air and the other during 100% oxygen. During room air inhalation, mean regional myocardial blood flow to nonischemic, intermediate, and ischemic regions was 0.92 +/- 0.05, 0.51 +/- 0.08, and 0.10 +/- 0.02 ml . min-1 . g-1, respectively. During 100% oxygen administration, flow was significantly diminished in each region to 0.75 +/- 0.04, 0.41 +/- 0.07, and 0.06 +/- 0.01 ml . min-1 . g-1, respectively. Transmural blood flow to each layer was uniformly reduced in all regions. These data indicate that 100% oxygen further reduces myocardial blood flow to ischemic regions.

This study was made to evaluate the relative importance of alpha 1- and alpha 2-adrenergic vasoconstrictor influences in opposing the increase in coronary blood flow that occurs during exercise. The effects of selective alpha 1-adrenergic blockade with prazosin were compared with nonselective alpha-adrenergic blockade with phentolamine on coronary hemodynamics during exercise in chronically instrumented dogs. During control conditions, graded treadmill exercise resulted in progressive increases of myocardial oxygen consumption; this was associated with increased coronary blood flow as well as with increased myocardial oxygen extraction. Although prazosin and phentolamine caused similar reductions of arterial pressure, phentolamine increased heart rate, myocardial oxygen consumption, and coronary blood flow at equivalent exercise levels, and prazosin did not significantly alter these variables. These effects of phentolamine appeared to result from blockade of presynaptic alpha 2-adrenergic receptors, which normally modulate norepinephrine release, that resulted in increased sympathetic effects on the heart. However, at comparable levels of myocardial oxygen consumption, prazosin and phentolamine resulted in similar significant increases of coronary venous PO2 and decreases of coronary vascular resistance. These data support a modest role for alpha 1-adrenergic coronary vasoconstriction during exercise but fail to document an additional role for postsynaptic alpha 2-adrenergic coronary vasoconstriction during exercise.

To determine whether function is depressed in areas of myocardium adjacent to an area of myocardial ischemia, 16 open-chest dogs were studied with both two-dimensional echocardiography and ultrasonic microcrystals. Regional myocardial blood flow was measured with radioactive microspheres during control periods and after coronary arterial ligation. Segments of myocardium adjacent to the area of ischemia were found to have no significant change in transmural blood flow (1.02 +/- 0.38 ml/g/min control vs 0.95 +/- 0.3 ml/g/min after ligation) or subendocardial flow (1.18 +/- 0.41 ml/g/min control vs. 1.19 +/- 0.37 ml/g/min after ligation). Regional function assessed echocardiographically as percent change in segment area was significantly depressed in these normally perfused adjacent areas (69.5 +/- 18.8% control vs 52.5 +/- 19.8% after ligation; p less than .01). There was a significant relationship between proximity to border of infarction and degree of adjacent dysfunction (r = .50, p less than .01 for echocardiography; r = .70, p less than .01 for ultrasonic microcrystals). It is concluded that systolic performance is depressed in nonischemic myocardium directly adjacent to the lateral border of an area of acute myocardial ischemia.

This study tested the hypothesis that an acute increase in right ventricular pressure would result in selective impedance of blood flow into the right ventricular subendocardium (ENDO) similar to that seen normally in the left ventricle. Since tachycardia (reduces diastolic time) and vasomotor paralysis will reveal impedence to blood flow by a decrease in ENDO to subepicardial (EPI) myocardial blood flow (MBF) ratio, MBF was measured with microspheres in eight awake dogs during rapid pacing at 176 +/- 2 beats . min-1 (mean +/- SE) after acute pulmonary artery constriction (PAC) before and during adenosine (A) infusion (1.00 mg . kg-1 . min-1). AP was held constant by aortic constriction. During control pacing the ENDO/EPI ratios were 1.38 +/- 0.08 and 1.46 +/- 0.12 in the RV and LV, respectively. During adenosine infusion the ENDO/EPI decreased to 0.85 +/- 0.08 (P less than 0.05) in the LV but did not change in the RV (1.17 +/- 0.10). During PAC and pacing alone the RV ENDO/EPI was 1.24 +/- 0.05 (NS vs control), but during adenosine fell to 0.88 +/- 0.07 (P less than 0.05). Transmural blood flow to the interventricular septum (IVS) was also affected by increased RV pressure. During control the ratio of blood flow to the left and right side (LV/RV) of the IVS was 1.32 +/- 0.12. PAC alone caused a redistribution of MBF toward the right side and the LV/RV fell to 0.66 +/- 0.06 (P less than 0.05). During PAC and adenosine, however the LV/RV rose to 1.38 +/- 0.08. These data demonstrate that increased RV systolic pressure produces systolic impedance to blood flow to the right ventricular ENDO and the right side of the interventricular septum.

The alterations in regional diastolic mechanics that occur during regional myocardial ischemia (creep and increased myocardial stiffness) may be the result of interactions between the ischemic and surrounding nonischemic myocardium rather than the direct result of ischemia. Thus similar changes may not occur when the entire left ventricle is ischemic. Thus similar changes may not occur when the entire left ventricle is ischemic. To investigate this proposition, left ventricular diastolic mechanics were studied in seven chronically instrumented conscious dogs during global left ventricular ischemia. The anterior-posterior, septal-free wall, and base-apex axes of the left ventricle were measured with ultrasonic dimension transducers. Left and right ventricular pressures were measured with micromanometers. Myocardial blood flows were measured with left atrial injections of 15 microns radioactive microspheres. Global left ventricular ischemia was induced by hydraulic constriction of the left main coronary artery, which resulted in a 54% decrease in mean left ventricular subendocardial blood flow. Left ventricular volume, midwall circumference, and midwall circumferential stress were calculated from ellipsoidal shell theory. To construct pressure-strain and stress-strain relationships from diastolic data collected during vena caval occlusions, all measured and calculated dimensions were normalized to Lagrangian strains (fractional extension from unstressed dimension). During ischemia, creep (elongation of unstressed dimension) occurred in each of the three left ventricular axes. The mean unstressed dimension of the anterior-posterior axis increased from 5.39 +/- 0.53 to 5.85 +/- 0.50 cm ( p less than or equal to .05); the septal-free wall unstressed dimension increased from 5.11 +/- 0.53 to 5.72 +/- 0.80 cm (p less than or equal to .05); and the base-apex unstressed dimension increased from 7.04 +/- 0.61 to 7.25 +/- 0.65 cm (p less than or equal to .05). The relationship between diastolic midwall circumferential stress and strain shifted upward and to the left with ischemia, indicating that an increase in intrinsic myocardial stiffness had occurred. As a result of these mechanical alterations, there was a decrease in left ventricular chamber compliance that was manifested by a leftward shift of the diastolic pressure-volume strain relationship. Neither systolic bulging nor dysynchronous systolic shortening occurred in any of the three left ventricular spatial axes during ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Phasic coronary flow and transmural myocardial perfusion were studied during coronary artery constriction in 10 dogs with electromagnetic flowmeters and hydraulic occluders on the left circumflex coronary artery. Regional blood flow was estimated using left atrial injections of radionuclide-labeled microspheres 9 micron in diameter. During control conditions, 14+/-0.7% of coronary flow occurred in systole and subendocardial (endo) flow exceeded subepicardial (epi) flow in the region of the posterior papillary muscle (endo/epi=1.16). Immediately following partial inflation of the occluder to reduce coronary inflow 39+/-3%, systolic flow was unchanged while diastolic flow fell 42+/-3%, thereby increasing the portion of flow in systole to 22+/-1.4%. At this time blood flow was reduced nearly uniformly across the wall of the left ventricle. When coronary constriction was maintained for 30 s, an additional shift of flow from diastole to systole occurred (systolic flow=29+/-2.3% of total inflow), and transmural perfusion was redistributed from subendocardium to subepicardium (endo/epi=0.37). This redistribution of flow was accompanied by a fall in coronary pressure distal to the occluder, indicating vasodilation of the distal coronary vasculature.

Because of the previous suggestion that subendocardial perfusion may be inadequate in the hypertrophied heart, this study was carried out to examine the response of transmural myocardial blood flow to pacing induced tachycardia in dogs with chronic left ventricular hypertrophy. Myocardial hypertrophy, produced by banding the ascending aorta of puppies at 5-6 wk of age, resulted in an 87% average increase in relative left ventricular mass compared with the control dogs. Myocardial blood flow was examined during ventricular pacing at heart rates of 100, 200, and 250 beats/min using radionuclide-labeled microspheres. Mean blood flow per unit myocardial mass was similar in the two groups of dogs at a heart rate of 100 beats/min and increased regularly during pacing in both groups of animals. Increasing heart rates did not change the transmural pattern of myocardial blood flow in the normal dogs, but in the animals with left ventricular hypertrophy pacing at 250 beats/min resulted in a significant redistribution of perfusion away from the subendocardium, with the ratio of subendocardial/subepicardial blood flow falling from 1.03 +/- 0.08 at 100 beats/min to 0.83 +/0 0.06 at 250 beats/min (P < 0.01). This redistribution of blood flow away from the subendocardium was especially marked in the regions encompassing the papillary muscles and the intervening left ventricular lateral wall.

This study tested the hypothesis that in the chronically hypertrophied left ventricle pacing stress may cause abnormalities of perfusion that result in myocardial ischemia. Left ventricular hypertrophy (LVH) was produced by banding the ascending aorta of 10 dogs at 6 weeks of age, and studies were carried out after the animals had reached adulthood and when mean left ventricular/body weight ratio was 74% greater than in eight control dogs. Myocardial blood flow was measured with microspheres during pacing at 100, 200, and 250 beats/min, while aortic and coronary sinus blood samples were obtained for determination of concentrations of lactate and the adenosine metabolites inosine and hypoxanthine. In the control dogs, increasing heart rates were associated with an increase in mean myocardial blood flow while subendocardial flow was maintained at a level equal to or greater than subepicardial flow. Myocardial lactate uptake ranged from +60% to -5%, and adenosine metabolites were not detected in coronary sinus blood (less than 0.5 microM/l). In four dogs that underwent aortic banding no production of lactate or adenosine metabolites was observed at any heart rate; in these animals subendocardial flow was maintained at a level equal to or greater than subepicardial flow at all pacing rates. The remaining six dogs with LVH demonstrated net lactate production significantly greater than control during pacing at 250 beats/min; five of these six animals also produced adenosine metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of nifedipine on coronary vasodilation were studied during reactive hyperaemia after a transient coronary occlusion and during active hyperaemia associated with graded treadmill exercise. Studies were performed in 10 chronically instrumented dogs in which left circumflex coronary artery flow was measured with an electromagnetic flowmeter and myocardial oxygen extraction was determined from indwelling aortic and coronary sinus catheters. Thirty minutes after administration of nifedipine (10 micrograms.kg-1 iv), when coronary blood flow, arterial pressure, and heart rate had returned to control values, the vasodilatation following a 10 s coronary occlusion was significantly blunted, so that reactive hyperaemia blood flow debt repayment (mean(SEM)) was reduced from 387(39)% during control conditions to 270(33)% after nifedipine (p less than 0.05). In contrast, nifedipine did not alter the coronary vasodilatation that occurred in response to graded treadmill exercise so that the increase in coronary blood flow during exercise was not different from the control response. Thus, although nifedipine blunted ischaemic coronary vasodilatation during reactive hyperaemia, it did not alter coronary vasodilatation during active hyperaemia resulting from physiological increases of myocardial oxygen consumption.

This study compared the effects of two selective alpha-1 adrenergic blockers, prazosin and indoramin, on the response of coronary blood flow and myocardial oxygen consumption during treadmill exercise in chronically instrumented dogs. Left circumflex coronary artery blood flow was measured with an electromagnetic flowmeter, whereas myocardial arteriovenous oxygen difference was determined with indwelling aortic and coronary sinus catheters. During control conditions, coronary blood flow, arteriovenous oxygen extraction and myocardial oxygen consumption increased regularly with exercise. Both prazosin and indoramin decreased arterial pressure at rest and during exercise, but during heavier levels of exercise blood pressure was lower and heart rates were higher after prazosin. Prazosin did not alter myocardial oxygen consumption, whereas indoramin tended to decrease oxygen consumption; myocardial oxygen consumption was significantly less after indoramin than after prazosin during the heaviest levels of exercise. Prazosin, but not indoramin, significantly decreased coronary vascular resistance both at rest and during exercise, and blunted the decrease in coronary sinus oxygen tension which occurred during exercise. In comparison with prazosin, during heavy exercise coronary blood flow was significantly decreased, myocardial oxygen extraction significantly increased and myocardial oxygen consumption significantly decreased after indoramin.

Nifedipine reduces reactive hyperemia following brief coronary artery occlusions. To determine whether this is related to improvement in collateral blood flow to ischemic myocardium or alterations in myocardial oxygen consumption, ten chloralose anesthetized dogs were instrumented with coronary sinus catheters, circumflex artery flowmeters, and ultrasonic microcrystals for measurement of myocardial segment shortening. Myocardial oxygen consumption and circumflex coronary artery flow were determined at rest and during incremental infusions of isoproterenol. Myocardial blood flow measured with microspheres and segmental function were assessed during and following 30- and 60-second coronary artery occlusions. Thirty minutes after the intravenous administration of nifedipine, 10 micrograms/kg iv, all measurements were repeated. Nifedipine did not alter myocardial oxygen consumption or the relationship between oxygen consumption and circumflex coronary artery flow either at rest or during isoproterenol infusion. Following 60-second coronary occlusions, nifedipine reduced peak circumflex coronary artery flow (176 +/- 99 vs. 128 +/- 68 cc/min) and reactive hyperemia debt repayment (221 +/- 84 vs. 158 +/- 66%; p less than 0.01). Nifedipine did not alter flow to ischemic segments during coronary artery occlusions (0.16 +/- 0.10 vs. 0.19 +/- 0.13 ml/min/g mean transmural flow). Furthermore, nifedipine did not affect the severity of ischemic segment dysfunction, nor the rate of recovery of ischemic segment function following release of coronary artery occlusion. We conclude that the reduction in reactive hyperemia induced by nifedipine was not related to alterations in the severity of hypoperfusion in ischemic areas, or alterations in myocardial oxygen consumption. Reductions in reactive hyperemia produced by nifedipine did not impair recovery of mechanical function in postischemic myocardium.

The hemodynamic effects of tetramethylpyrazine were examined in 27 anesthetized open chest dogs with electromagnetic flowmeter probes on the left circumflex coronary artery and ascending aorta. Tetramethylpyrazine, 2-15 mg/kg i.v., caused prominent systemic and coronary vasodilation, with a maximum reduction of mean aortic pressure from 92 +/- 5 mm Hg during control conditions to 62 +/- 7 mm Hg (p less than 0.01), a peak increase in cardiac output from 3.0 +/- 0.4 to 4.1 +/- 0.7 L/min (p less than 0.05), and a peak reduction of systemic vascular resistance from 2,450 +/- 400 to 1,210 +/- 329 dyne X s X cm-5 (p less than 0.01). Simultaneously, heart rate increased from 143 +/- 9 to 174 +/- 8 beats/min (p less than 0.01), and maximum left ventricular dP/dt increased from 2,410 +/- 120 to 4,020 +/- 60 mm Hg/s (p less than 0.01). Dose-related increases of coronary blood flow occurred from 37.3 +/- 3.7 to a maximum of 74.1 +/- 6.6 ml/min (p less than 0.01), while mean coronary vascular resistance decreased from 1,770 +/- 240 to 700 +/- 260 dyne X s X cm-3 (p less than 0.01). Myocardial oxygen consumption increased in proportion to the increase in coronary blood flow. Following beta-adrenergic blockade with propranolol (1 mg/kg, i.v.), ganglionic blockade with hexamethonium, or catecholamine depletion with reserpine (1.0 mg/kg, i.p.), the systemic and coronary vasodilator effects of tetramethylpyrazine persisted, but the increases in heart rate, maximum left ventricular dP/dt, and myocardial oxygen consumption were markedly attenuated.(ABSTRACT TRUNCATED AT 250 WORDS)

This study examined the ability of moderately well-developed coronary collateral vasculature to undergo vasoconstriction in response to alpha-adrenergic agonists, vasopressin and angiotensin, and vasodilation in response to nitroglycerin. Studies were performed in 20 dogs 4-16 wk after left anterior descending coronary artery occlusion had been produced by an Ameroid constrictor or hollow intravascular plug. Collateral flow was estimated from retrograde flow from the cannulated left anterior descending artery. Tissue flow was measured with microspheres. Agonists were introduced into the left main coronary artery to reach collaterals arising from the left circumflex and septal arteries. Vasopressin and angiotensin II decreased retrograde flow from 22.7 +/- 5.5 to 15.5 +/- 2.7 and from 19.2 +/- 2.8 to 14.3 +/- 1.9 ml/min, respectively (each P less than 0.05). Both agents also significantly decreased tissue flow to normally perfused and collateral dependent myocardium. Neither the selective alpha 1-adrenergic agonist phenylephrine nor the alpha 2-agonist B-HT 933 decreased retrograde flow. Nitroglycerin increased retrograde flow by 63 +/- 27% (P less than 0.01). Thus, although the moderately well-developed coronary collateral circulation is capable of vasoconstriction in response to vasopressin and angiotensin II, these data fail to support a role for alpha-adrenergic mechanisms in modulating collateral flow.

Nitroglycerin and calcium antagonists are direct dilators of large coronary arteries. Their amelioration of myocardial ischemia may be in part related to their dilating action on coronary stenoses. The present study was done to determine if the effects of calcium antagonists and nitroglycerin on large coronary arterial diameter are additive. External circumflex coronary arterial diameter was measured by sonomicrometry in 16 awake, instrumented dogs. Intravenous nifedipine (mean dose 30 +/- 4 micrograms/kg) caused dilation of the circumflex coronary artery (4.01 +/- 0.13 to 4.10 +/- 0.12 mm, p less than 0.05). The addition of intravenous nitroglycerin (10 to 20 micrograms/kg) caused further coronary arterial dilation (4.10 +/- 0.12 to 4.13 +/- 0.12 mm, p less than 0.05). Intravenous verapamil (mean dose 520 +/- 77 micrograms/kg) also caused dilation of the circumflex coronary artery (4.14 +/- 0.35 to 4.26 +/- 0.35 mm, p less than 0.05). The addition of intravenous nitroglycerin caused further dilation (4.26 +/- 0.35 to 4.31 +/- 0.35 mm, p less than 0.05). Intravenous diltiazem (mean dose 640 +/- 140 micrograms/kg) caused circumflex coronary arterial dilation in four of the five dogs studied (mean change 4.14 +/- 0.36 to 4.21 +/- 0.33 mm). The addition of intravenous nitroglycerin caused further circumflex coronary dilation (4.21 +/- 0.33 to 4.26 +/- 0.33 mm, p less than 0.05). Therefore, the effects of nitroglycerin and each of these three calcium antagonists on large coronary diameter are additive, with the combination of nitroglycerin and the calcium antagonist causing more large coronary dilation than the calcium antagonist alone.

Atriopeptin II has been reported to cause profound coronary vasoconstriction in the isolated perfused guinea pig heart and in the blood perfused canine heart. Consequently, this study was carried out to examine possible mechanisms by which vasomotor effects of human atrial natriuretic peptide (ANP) occur in the canine coronary circulation. Bolus dosages of ANP were administered into the left circumflex coronary artery of in situ dog hearts perfused at constant flow rate. ANP produced dose-related coronary vasodilation with a threshold dosage of 2 ng/kg; a dosage of 2 micrograms/kg caused a 27 +/- 4% decrease in coronary vascular resistance. Coronary vasodilation produced by ANP was not altered by beta-adrenergic blockade with propranolol (1 mg/kg i.v.). In addition, neither adenosine receptor blockade with 8-phenyltheophylline (5 mg/kg i.v.) nor cyclooxygenase inhibition with indomethacin (5 mg/kg i.v.) significantly altered the response to intra-arterial ANP. These data demonstrate that in the in vitro blood perfused canine heart, ANP administered intra-arterially results in coronary vasodilation that does not utilize adenosine-dependent or prostaglandin-dependent mechanisms.

This study was designed to measure early sequential changes in blood flow to ischemic regions after acute coronary occlusion and to determine the relationship between blood flow and the extent of subsequent myocardial infarction. Initial studies were carried out on five dogs which verified using radioisotope-labeled microspheres, 7-10 mum in diameter, to measure changes in blood flow in small myocardial regions after acute coronary artery occlusions. Studies then were carried out on 11 awake dogs chronically prepared with dwelling catheters in the aorta and left atrium and occluders on the left circumflex coronary artery. Microspheres were injected via the left atrial catheter 45 seconds and 2, 6, and 24 hours after complete circumflex coronary occlusion. Six days later myocardial blood flow and the extent of histological infarction were determined for multiple samples from four transmural layers of the entire ischemic zone. Average blood flow to the circumflex region was 0.25 +/- 0.03 (SE), 0.39 +/- 0.05, and 0.53 +/- 0.07 ml/min per g at 45 seconds, and 2, 6, and 24 hours, respectively. When samples from each transmuarl layer were grouped according to increasing ranges of blood flow, the extent of infarction in each layer was inversely related to blood flow. When samples in the same range of blood flow were compared, the extent of infarction in endocardial samples exceeded that in epicardial samples. These data indicate that the relationship between a given measurement of regional blood flow after acute coronary occlusion and the extent of subsequent myocardial infarction varies in different transmural layers and is a function of the time after occlusion that blood flow is measured.

This study was designed to evaluate the effects of nitroglycerin and phenylephrine-induced arterial hypertension on regional myocardial blood flow in awake dogs with acute occlusion of the left circumflex coronary artery. Myocardial blood flow to four transmural layers from epicardium to endocardium was estimated with 7-9 micron radionuclide labeled microspheres in 1) the non-ischemic myocardium, 2) the central ischemic zone, and 3) the border zone separating ischemic from normally perfused myocardium. Measurements were repeated 1) during infusion of nitroglycerin, 0.015 mg/kg/min, 2) during phenylephrine administered to increase arterial pressure 60 mm Hg above the control measurements, and 3) during combined nitroglycerin and phenylephrine administration. Both nitroglycerin and phenylephrine increased myocardial blood flow to the central ischemic area; nitroglycerin significantly decreased the resistance of the collateral vascular system, while the increased flow during phenylephrine administration was accounted for entirely by the increased arterial pressure with no change in collateral vascular resistance. The increased blood flow to the central ischemic zone during nitroglycerin administration was delivered preferentially to the subendocardium, while the increased blood flow during phenylephrine administration was directed exclusively to the subepicardium. Neither nitroglycerin nor phenylephrine significantly altered computed vascular resistance of the border zone, but because of the increased driving pressure, blood flow to the border zone was significantly increased during phenylephrine administration.

In the 24 hours after coronary occlusion, some defects on thallium-201 images decrease in size. This study examined the mechanism of the decrease in defect size in dogs with experimental coronary occlusion. The left anterior descending coronary artery was permanently occluded in chronically instrumented awake dogs. Myocardial blood flow was measured with radioactive microspheres immediately before occlusion, 30 minutes, and 24 hours after occlusion. Thallium-201 was injected and imaging was performed 2 to 6 days before occlusion, 30 minutes, and 24 hours after occlusion. Two dogs, in which less than 1% of the left ventricle was infarcted, had no defects on the 30-minute postocclusion images. In four dogs the thallium-201 images did not change appreciably over 24 hours (group 1), while in three dogs the image defect size decreased (group 2). In groups 1 and 2 respectively the percent increase in blood flow to the hypoperfused area was: subendocardium 9 +/- 7% vs 31 +/- 15%; subepicardium 26 +/- 6% vs 47 +/- 2% (p less than 0.05). Therefore a decrease in the size of thallium-201 image defects occurred if a sufficient increase in collateral flow to the hypoperfused area took place in the first 24 hours after coronary occlusion. The defects appeared to decrease in size even in the absence of a detectable change in the lateral borders of the hypoperfused area.

This study compares the effects of piroximone (MDL 19,205), a new inotropic agent, with dobutamine in dogs with congestive heart failure. With dobutamine, (15 micrograms/kg/min) left ventricular (LV) dp/dt increased from 2220 +/- 215 (mean +/- S.E.M.) to 2815 +/- 280 mm Hg/sec and cardiac index increased from 2.9 +/- 0.2 to 3.7 +/- 0.4 liters/min/m2, whereas LV filling pressure was essentially unchanged (18.7 +/- 2.6-16.3 +/- 2.4 mm Hg). The hemodynamic effects of piroximone (50 micrograms/kg/min) were more pronounced. LV dp/dt increased from 2615 +/- 260 to 3760 +/- 410 mm Hg/sec and cardiac index from 3.0 +/- 0.1 to 4.4 +/- 0.6 liters/min/m2, whereas LV filling pressure decreased from 15.6 +/- 2.4 to 6.4 +/- 1.8 mm Hg (all P less than .05). Systemic vascular resistance index decreased from 2730 +/- 225 to 1905 +/- 256 dynes sec cm-5 m-2. Regional blood flow to the myocardium increased 48% with dobutamine and 24% with piroximone, whereas skeletal muscle flow increased 59% with dobutamine and 36% with piroximone. Renal blood flow remained unchanged with either drug. We conclude that piroximone is an inotropic agent with vasodilator properties that has an interesting hemodynamic profile somewhat similar to that of dobutamine but with the advantage of being orally active; therefore piroximone could be useful in the treatment of heart failure.

This study was carried out to test the hypothesis that adrenergic coronary vasoconstriction limits blood flow to hypoperfused regions of myocardium during exercise. The vasoconstrictor influence of alpha-adrenergic receptor subtypes was assessed by use of selective adrenergic blocking agents. Dogs chronically instrumented with a circumflex coronary artery hydraulic occluder and an intra-arterial catheter underwent treadmill exercise in the presence of a coronary stenosis that decreased distal perfusion pressure to 40 mm Hg. Myocardial blood flow was measured with radioactive microspheres (15 microns) before and during selective alpha 1- or alpha 2-adrenergic receptor blockade produced by intracoronary infusion of prazosin (1 microgram/kg/min x 10 min) or idazoxan (1 microgram/kg/min x 10 min), respectively. Coronary perfusion pressure was held equal before and during receptor blockade with the hydraulic occluder. Compared with control exercise, subendocardial blood flow increased during alpha 1-receptor blockade with prazosin from 0.60 +/- 0.14 to 1.12 +/- 0.17 ml/min/g (p less than 0.05), and mean transmural flow increased from 1.07 +/- 0.19 to 1.60 +/- 0.22 ml/min/g (p less than 0.05). In contrast, subendocardial and mean transmural blood flow were not different from control during selective alpha 2-adrenergic receptor blockade with idazoxan (0.48 +/- 0.10 vs. 0.67 +/- 0.14 ml/min/g, p = 0.33, and 0.82 +/- 0.15 vs. 1.02 +/- 0.20 ml/min/g, p = 0.45, respectively). These data indicate that even in the presence of a coronary stenosis that causes substantial myocardial underperfusion during exercise, residual coronary vasoconstrictor tone is present in ischemic myocardium, and this vasoconstriction is mediated predominantly by the alpha 1-adrenergic receptor.

This study examined the relative importance of postsynaptic alpha 1- and alpha 2-adrenoceptors in mediating coronary vasoconstriction in open chest dogs in which the left circumflex coronary artery was cannulated and perfused at a constant rate. The cervical vagus nerves and central connections of the stellate ganglia were transected, and beta-adrenergic blockade was produced with propranolol. Coronary vasoconstriction occurred in response to intraarterial administration of both the alpha 1-agonist phenylephrine and the alpha 2-agonist BHT 933. The response to phenylephrine was partially blocked with prazosin and nearly completely eliminated by yohimbine. The response to BHT 933 was resistant to prazosin, but almost completely blocked by yohimbine. Coronary vasoconstriction produced by norepinephrine was resistant to prazosin, but was blunted by alpha 2-adrenergic blockade with yohimbine or idazoxan. Prazosin produced some blunting of coronary vasoconstriction in response to small doses of epinephrine, while yohimbine markedly attenuated epinephrine-induced vasoconstriction at all doses used. Measurements of regional myocardial blood flow with radioactive microspheres demonstrated no transmural redistribution of perfusion during vasoconstriction produced by either alpha 1- or alpha 2 stimulation. Thus, although stimulation of both alpha 1- and alpha 2-adrenoceptors is capable of causing coronary vasoconstriction, vasoconstriction in response to norepinephrine and epinephrine is mediated principally by postsynaptic alpha 2-adrenoceptors.