Regulation of coronary blood flow during exercise

Exercise is the most important physiological stimulus for increased myocardial oxygen demand. The requirement of exercising muscle for increased blood flow necessitates an increase in cardiac output that results in increases in the three main determinants of myocardial oxygen demand: heart rate, myocardial contractility, and ventricular work. The approximately sixfold increase in oxygen demands of the left ventricle during heavy exercise is met principally by augmenting coronary blood flow (~5-fold), as hemoglobin concentration and oxygen extraction (which is already 70-80% at rest) increase only modestly in most species. In contrast, in the right ventricle, oxygen extraction is lower at rest and increases substantially during exercise, similar to skeletal muscle, suggesting fundamental differences in blood flow regulation between these two cardiac chambers. The increase in heart rate also increases the relative time spent in systole, thereby increasing the net extravascular compressive forces acting on the microvasculature within the wall of the left ventricle, in particular in its subendocardial layers. Hence, appropriate adjustment of coronary vascular resistance is critical for the cardiac response to exercise. Coronary resistance vessel tone results from the culmination of myriad vasodilator and vasoconstrictors influences, including neurohormones and endothelial and myocardial factors. Unraveling of the integrative mechanisms controlling coronary vasodilation in response to exercise has been difficult, in part due to the redundancies in coronary vasomotor control and differences between animal species. Exercise training is associated with adaptations in the coronary microvasculature including increased arteriolar densities and/or diameters, which provide a morphometric basis for the observed increase in peak coronary blood flow rates in exercise-trained animals. In larger animals trained by treadmill exercise, the formation of new capillaries maintains capillary density at a level commensurate with the degree of exercise-induced physiological myocardial hypertrophy. Nevertheless, training alters the distribution of coronary vascular resistance so that more capillaries are recruited, resulting in an increase in the permeability-surface area product without a change in capillary numerical density. Maintenance of alpha- and ss-adrenergic tone in the presence of lower circulating catecholamine levels appears to be due to increased receptor responsiveness to adrenergic stimulation. Exercise training also alters local control of coronary resistance vessels. Thus arterioles exhibit increased myogenic tone, likely due to a calcium-dependent protein kinase C signaling-mediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, training augments endothelium-dependent vasodilation throughout the coronary microcirculation. This enhanced responsiveness appears to result principally from an increased expression of nitric oxide (NO) synthase. Finally, physical conditioning decreases extravascular compressive forces at rest and at comparable levels of exercise, mainly because of a decrease in heart rate. Impedance to coronary inflow due to an epicardial coronary artery stenosis results in marked redistribution of myocardial blood flow during exercise away from the subendocardium towards the subepicardium. However, in contrast to the traditional view that myocardial ischemia causes maximal microvascular dilation, more recent studies have shown that the coronary microvessels retain some degree of vasodilator reserve during exercise-induced ischemia and remain responsive to vasoconstrictor stimuli. These observations have required reassessment of the principal sites of resistance to blood flow in the microcirculation. A significant fraction of resistance is located in small arteries that are outside the metabolic control of the myocardium but are sensitive to shear and nitrovasodilators. The coronary collateral system embodies a dynamic network of interarterial vessels that can undergo both long- and short-term adjustments that can modulate blood flow to the dependent myocardium. Long-term adjustments including recruitment and growth of collateral vessels in response to arterial occlusion are time dependent and determine the maximum blood flow rates available to the collateral-dependent vascular bed during exercise. Rapid short-term adjustments result from active vasomotor activity of the collateral vessels. Mature coronary collateral vessels are responsive to vasodilators such as nitroglycerin and atrial natriuretic peptide, and to vasoconstrictors such as vasopressin, angiotensin II, and the platelet products serotonin and thromboxane A(2). During exercise, ss-adrenergic activity and endothelium-derived NO and prostanoids exert vasodilator influences on coronary collateral vessels. Importantly, alterations in collateral vasomotor tone, e.g., by exogenous vasopressin, inhibition of endogenous NO or prostanoid production, or increasing local adenosine production can modify collateral conductance, thereby influencing the blood supply to the dependent myocardium. In addition, vasomotor activity in the resistance vessels of the collateral perfused vascular bed can influence the volume and distribution of blood flow within the collateral zone. Finally, there is evidence that vasomotor control of resistance vessels in the normally perfused regions of collateralized hearts is altered, indicating that the vascular adaptations in hearts with a flow-limiting coronary obstruction occur at a global as well as a regional level. Exercise training does not stimulate growth of coronary collateral vessels in the normal heart. However, if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence that collateral growth can be enhanced. In addition to ischemia, the pressure gradient between vascular beds, which is a determinant of the flow rate and therefore the shear stress on the collateral vessel endothelium, may also be important in stimulating growth of collateral vessels.     

Verapamil in two reperfusion models of myocardial infarction. Temporary protection of severely ischemic myocardium without limitation of ultimate infarct size

The ability of verapamil to protect severely ischemic myocardium was assessed in dogs using 40 minutes of temporary coronary occlusion. Reperfusion was established for 4 days after which infarcts were sized histologically. Untreated dogs developed subendocardial infarcts (the more moderately ischemic subepicardial region being salvaged by reperfusion). Pretreatment with verapamil reduced the size of these subendocardial infarcts from 34 +/- 8 to 8 +/- 3% of the ischemic circumflex vascular bed at risk (identified by postmortem perfusion of the previously occluded and unoccluded arteries with different dyes). Thus, verapamil prevented cell death in the severely ischemic subendocardial region for the 40-minute test period. In a second study to establish whether verapamil could delay cell death for a longer period of time in the less severely ischemic subepicardial region, a 3-hour period of coronary occlusion was used. This period of occlusion caused infarcts averaging 60 +/- 6% of the ischemic area at risk in untreated dogs. Dogs treated with verapamil 15 minutes postocclusion and throughout the remaining 165 minutes of the 3-hour test period had no limitation of infarct size (53 +/- 3% of the area at risk). In this 3-hour study, the effect of variation in collateral blood flow on infarct size was evaluated by plotting infarct size versus subepicardial collateral flow. Verapamil neither improved collateral flow nor altered the relationship between infarct size and baseline collateral flow. Thus, pretreatment with verapamil prevented necrosis of severely ischemic myocytes, when reperfusion was established at 40 minutes, but failed to prevent necrosis of moderately ischemic myocardium and thus failed to limit infarct size when the period of coronary occlusion was prolonged to 3 hours and treatment was started 15 minutes after the onset of ischemia.     

Myocardial performance and collateral flow after transient coronary occlusion in exercising dogs.

Fourteen dogs with prior constriction of the left circumflex (LCf) coronary artery were studied at rest and during treadmill running. Hemodynamics were measured before and after a 1-min LCf occlusion. Coronary and collateral flows were quantitated during occlusion both at rest and during exercise. Group I consisted of 4 dogs with resting collateral flow exceeding one-half (average 78%) of normal flow, and group II consisted of 10 dogs with collateral flows less than one-half (average 30%) of normal. At rest LCf occlusion caused no hemodynamic changes in group I, but stroke volume fell significantly in group II. During running, collateral flow after LCf occlusion doubled in group I, and there was only a small rise in left atrial pressure to 18 mmHg. In group II, collateral flow increased by 50% during running and actually decreased in 4 dogs. Significant cardiac failure developed as stroke volume halved, and left atrial pressure rose to an average 30 mmHg. Therefore exercise-induced depression of left ventricular function in the ischemic heart can be correlated to the amount of coronary collateral flow.     

The endothelial surface of growing coronary collateral arteries. Intimal margination and diapedesis of monocytes

Summary Slowly progressing coronary artery stenosis leading to complete occlusion within about 3 weeks was produced in dogs. Within this time collateral vessels had enlarged sufficiently to prevent myocardial infarction. Early, intermediate, and late (1 year after occlusion) stages of collateral development were studied with the scanning and transmission electron microscope. Early after coronary occlusion the number of endothelial cells per unit inner vascular surface had markedly increased and longitudinal bulges appeared in growing collaterals as opposed to the completely flat inner surface of small normal coronary arteries. The surface of many endothelial cells appeared rough and large numbers of monocytes adhered to the inner vascular surface. The endothelial cells formed three types of patterns: streams, whorls, and nonoriented mosaics suggesting different types of flow—jets, eddies, and lowshear flow, respectively. The existence of nonlaminar flow patterns could well be explained by the extremely tortuous course of collaterals and by segmental caliber changes (microstenoses) resulting from irregularities of the internal elastic lamina.Later stages showed a tendency toward normal endothelial cell density, flattening of bulges, and absence of microstenoses. A completely normal inner surface was, however, never observed in midzone segments although the observation period extended up to 1 year after coronary occlusion.Battelle Institut e.V., Frankfurt/MainThe authors are indebted to Miss Adriane Rademakers, Mr. Paul van Even, and Mrs. B. Iacurti for their skilful technical assistance.     

Myocardial infarction in the baboon: regional function and the collateral circulation.

Occlusion of the anterior descending coronary artery was produced in sedated baboons 7-15 days after implantation of a micromanometer and ultrasonic crystals for measurement of regional left ventricular dimensions in ischemic, marginal, and control segments. One minute after coronary occlusion (CO), ischemic segments exhibited a marked systolic bulge with wall thinning, and percent systolic shortening of marginal segments decreased. Over the ensuing weeks, there was a progressive increase of end-diastolic lengths in marginal and ischemic segments, whereas systolic shortening in these segments did not improve significantly. Control segments did not change. In control baboons, the coronary collateral index was 55 +/-25 (SE) compared to 560 +/- 74 in normal dogs. One month after CO, the collateral index was 543 +/- 144 in baboons compared to 6,685 +/- 716 in dogs, regions of normal tissue were seen in the infarct (14.2 +/- 2% of left ventricular mass). Minimal coronary collateral development in the baboon provides a likely explanation for differences from the dog in regional functional responses and in the character of the infarct.     

High afterload during 10 min of regional ischaemia affects diastolic creep but not systolic function in reperfused (stunned) myocardium

The effect of afterload during regional ischaemia on myocardial stunning was studied in 15 pentobarbital anaesthetized cats. 10 min occlusion of the left anterior descending artery (LAD) was followed by 60 min of reperfusion. Afterload was decreased by intravenous infusion of nitroglycerine 3–8 μg kg^-1 min^-1 in group I (n=8); left ventricular peak systolic pressure (LVSP) 84±4 mmHg (mean±SEM) during coronary artery occlusion. In group II (n=7) LVSP was increased to 188±10 mmHg by inflating an intraaortic balloon during coronary artery occlusion. Regional function in the LAD perfused region was evaluated by cross-oriented sonomicrometry. Myocardial tissue blood flow was evaluated by radio-labelled microspheres. Afterload alterations did not affect regional systolic shortening (10.8±2.0% vs. 11.0±1.5% in group I and II, respectively, after 60 min of reperfusion). However, increased end-diastolic dimensions (diastolic creep) in both the circumferential and longitudinal segments were markedly more pronounced in the high afterload group (group II). Also important, the markedly increased myocardial tissue blood flow during reperfusion in group II as compared with group I (2.30±0.18 vs.  1.34±0.08 mL min^-1 g^-1 and 2.58±0.23 vs. 1.49±0.07 mL min^-1 g^-1 in subepicardial and subendocardial layers in the LAD perfused region) suggests that increased diastolic creep increased metabolic demands. This study indicates that passive stretching of the ischaemic area during coronary artery occlusion is an important mechanism behind diastolic creep.     

The Effect of Exercise on the Development of Collateral Circulation after Experimental Occlusion of the Femoral Artery in the Cat

Flow resistance in the collateral vessels passing an occlusion of the femoral artery was determined 5 weeks after the occlusion in 24 cats kept in small cages and 21 cats trained daily on a treadmill. The collateral resistance was determined at maximal vasodilatation to reveal whether a structural outgrowth had taken place. Despite the occurrence of a pronounced “spontaneous” outgrowth of the collateral vessels, it could be shown that collateral resistance was 30 per cent less in the trained group. This difference was statistically highly significant (0.01>p>0.001). On the other hand, flow resistance in the vascular bed, distal to the occlusion, did not change after the arterial occlusion and was not affected by training.     

Nicardipine augments local myocardial perfusion after coronary artery reperfusion in dogs

Nicardipine is a potent coronary and systemic vasodilator without depression of ventricular function. We investigated the changes in local myocardial perfusion (LMP) according to the nicardipine administration after coronary reperfusion in a beating canine model. A Doppler probe was placed around the left anterior descending coronary artery (LAD) and thermal diffusion microprobe was implanted in the myocardium perfused by the exposed LAD. To define the nicardipine effects, we compared the two groups (control group, n=7 vs nicardipine group, n=7). In nicardipine group, 5 microgram/kg/min nicardipine was infused continuously. After the release of the LAD occlusion, LAD blood flow were increased compared to the baseline of both groups. However, there was no difference between groups in the LAD blood flow. The LMP after LAD reperfusion did not recover to the baseline level until 30 min after LAD reperfusion in control group (74%, 52% and 70% at 10, 20 and 30 min after LAD reperfusion, respectively). In nicardipine group, however, the LMP recovered to the baseline level at 20 min (99%), and increased more than the baseline level at 30 min (141%) after LAD reperfusion. Our findings suggest that the nicardipine augments the LMP following the release of a coronary occlusion.     

Functional Development of the Coronary Collateral Circulation During Coronary Artery Occlusion in the Conscious Dog

We studied changes in the coronary collateral circulation during coronary artery occlusion in 14 conscious dogs by: a) determining simultaneous changes in peripheral coronary pressure (PCP) and retrograde flow (RF) after abrupt coronary artery occlusion; b) correlating these functional indices with quantitative anatomic indices (AI) of coronary collateral development (Menick et al: Am Heart J 82:503-510, 1971); and c) observing changes in these indices after repeated reocclusions of a coronary artery. These dogs were subjected to left circumflex coronary artery (LCCA) occlusions for 2 hours to 8 days; pressure tubes were implanted in the aorta and LCCA, the latter tube placed distal to an occlusive cuff for PCP and RF measurements. Afterwards the animals were sacrificed, their hearts injected with a modified Schlesinger's gelatin mass, and AI determined. During 2 to 24 hour LCCA occlusions (11 dogs) mean PCP rose to levels 50 to 80% of prevailing aortic pressure. During repreated 2- to 24-hour occlusions (2 dogs) in the same dog, the rate at which PCP rose increased. Retrograde flow was unchanged during 2- to 24-hour occlusions. Anatomic indices of these dogs were in the same range as those observed in unoccluded controls. When LCCA occlusion was maintained for more than 4 days (3 dogs), mean PCP rose during the first 24 hours and then remained stable; RF did not change until 4 days into occlusion and then increased. Anatomic indices of dogs occluded for more than 4 days were significantly greater (P < 0.001) than those of the 2- to 24-hour occlusion groups. Our study shows that: a) the early PCP rise after occlusion is not associated with an increase in RF, b) RF is a better index of collateral function and c) RF correlated well with the anatomic development of the collateral bed.     

Regional blood flow during reactive hyperemia in canine myocardium as determined by local washout of Xenon-133

The mechanisms regulating vascular tone in the myocardium were studied in open-chest anesthetized dogs by occlusions of the left anterior descending coronary artery (LAD) for 3 to 600 s. Cumulative excess blood flow (flow in excess of control flow), and repayment of flow debt (cumulative excess blood flow divided by blood flow deficit) were calculated using local injections of Xenon-133 for blood flow measurements. Release of vascular occlusion following 3 s of ischemia was not associated with any measurable hyperemia. Cumulative excess blood flow increased with increasing duration of ischemia from 5 to 600 s, but the increment in excess flow per unit extention of the occlusion time showed a considerable decline. Blood flow in excess exceeded blood flow debt incurred during the occlusion of 10 s duration of 161%; with prolongation of ischemia to 600 s repayment of flow debt declined markedly to about 10%. Oxygen lack in the tissue elicited by perfusion of LAD—for 10 s with constant perfusion rate—with deoxygenated blood produced a fall in peripheral coronary resistance of about 40% which closely corresponds to the fall in resistance observed after a period of LAD occlusion of similar duration. The results lead to the conclusion that ‘vasodilator’ metabolites formed in the tissue during periods of arterial occlusion are of prime importance for the fall in the tone of the vascular smooth muscle cell occurring in the post-occlusion period. The findings argue against a myogenic component in this response.     

Coronary myogenic responses to abrupt changes in aortic blood pressure in anaesthetized dogs

A transient increase in coronary transmural pressure was produced in anaesthetized dogs by occlusion of the descending thoracic aorta. Aortic blood pressure (ABP), left ventricular pressure and coronary flow were measured; coronary vascular resistance (CVR) was calculated. Results were similar in innervated and denervated hearts. Occlusion for 10 and 20 s resulted in no change in CVR for 15 s, followed by a metabolic dilatation attributable to enhanced oxygen demand; after release the fall in ABP resulted in an immediate increase in CVR, caused by vascular elastic recoil, followed by hyperaemia.     

Coronary vascular and myocardial responses to carotid body stimulation in the dog.

Coronary vascular and myocardial responses to selective hypoxic and/or hypercapnic carotid chemoreceptor stimulation were investigated in constantly ventilated, pentobarbital or urethan-chloralose anesthetized dogs. Bilaterally isolated carotid chemoreceptors were perfused with autologous blood of varying O2 and CO2 tensions via an extracorporeal lung circuit. Systemic gas tensions were unchanged. Effects of carotid chemoreceptor stimulation on coronary vascular resistance, left ventricular dP/dt, and strain-gauge arch output were studied at natural coronary blood flow with the chest closed and during constant-flow perfusion of the left common coronary artery with the chest open. Carotid chemoreceptor stimulation slightly increased left ventricular dP/dt and slightly decreased the strain-gauge arch output, while markedly increasing systemic pressure. Coronary blood flow increased; however, coronary vascular resistance wa.as not affected. These studies show that local carotid body stimulation increases coronary blood flow but has little effect on the myocardium. The increase in coronary blood flow results mainly from an increase in systemic arterial pressure. Thus these data provide little evidence for increased sympathetic activity of the heart during local stimulation of the carotid chemoreceptors with hypoxic and hypercapnic blood.     

Abnormal myocardial fluid retention as an early manifestation of ischemic injury.

Fifty-seven isolated, blood perfused, continuously weighed canine hearts have been utilized to study the development of abnormal myocardial fluid retention during early myocardial ischemic injury. Inflatable balloon catheters were positioned around the left anterior descending coronary arteries (LAD) of 54 hearts or the proximal left circumflex coronary arteries of three hearts for study of the following intervals of coronary occlusion: a) 10 minutes followed by 20 minutes of reflow, b) 40 minutes followed by either no reflow or by 20 minutes of reflow, and c) 60 minutes without reflow. After 60 minutes of fixed coronary occlusion, histologic and ultrastructural examination revealed mild swelling of many ischemic cardiac muscle cells in the absence of interstitial edema, cardiac weight gain, and obvious structural defects in cell membrane integrity. After 40 minutes of coronary occlusion and 20 minutes of reflow, significant cardiac weight gain occurred in association with characteristic alterations in the ischemic region, including widespread interstitial edema and focal vascular congestion and hemorrhage and swelling of cardiac muscle cells. Focal structural defects in cell membrane integrity were also noted. The development of abnormal myocardial fluid retention after 40 minutes of LAD occlusion occurred in association with a significant reduction in sodium-potassium-ATPase activity in the ischemic area, but with no significant alteration in either creatine phosphokinase or citrate synthase activity in the same region. Despite the abnormal myocardial fluid retention in these hearts, it was possible pharmacologically to vasodilate coronary vessels with adenosine and nitroglycerin infusion to maintain a consistently high coronary flow following release of the coronary occlusion after 40 minutes and to even exceed initial hyperemic flow values following release of the occlusion when adenosine and nitroglycerin infusion was delayed until 15 minutes after reflow. Thus, the data indicate that impaired cell volume regulation and interstitial fluid accumulation and focal structural defects in cell membrane integrity are early manifestations of ischemic injury followed by reflow, but fail to establish a major role for the abnormal fluid retention in altering coronary blood flow prior to the development of extensive myocardial necrosis. In contrast, fixed coronary occlusion for 60 minutes results in mild intracellular swelling but no significant interstitial edema and no obvious structural defects in cell membrane integrity.     

Regional myocardial tissue blood flow during beta-adrenergic blockade in cat hearts with acute ischaemia

Selective beta 1- or beta 2-adrenergic blockade was achieved by practolol or IPS 339, respectively, in cats with acute ligation of a coronary artery. During blockade, heart rate was kept constant by atrial pacing and blood pressure reduction was prevented by aortic clamping. Regional myocardial blood flow was measured by the distribution of 15 micron labelled microspheres. Practolol slightly reduced epicardial blood flow in ischaemic myocardium, while blood flow in border and normally perfused myocardium remained unchanged. Following IPS 339, myocardial tissue flow increased in normally perfused myocardium, on average by 37% in the endocardium and 30% in the epicardium. No changes occurred in the other regions. The flow changes brought about by IPS 339 were unrelated to haemodynamic changes, and the coronary vascular resistance was reduced. These results are indicative of coronary vasodilation related to beta 2-adrenergic receptor blockade and was confined to well-oxygenated areas surrounding the acutely ischaemic zone.     

Pathomorphological Manifestations of Antiocclusive Factor in Atherosclerotic Obstruction of Coronary Arteries

A total of 112 hearts with limited local dilatation zones in coronary arteries (antiocclusion factor) selected from 500 patients dead from chronic forms of coronary heart disease were studied by postmortem contrast polypositional coronarography and cardiometry. A relationship between antiocclusion factor, on the one hand, and coronary artery stenosis and degree of vascularization of the left ventricular wall, on the other, was shown. The adaptation role of antiocclusion factor in coronary blood flow disorders caused by atherosclerotic obstruction (stenosis, occlusion, thrombosis) of the major coronary arteries was demonstrated. The incidence of antiocclusion factor in individual segments of coronary arteries depending on the type of atherosclerotic involvement and index of myocardial blood supply was determined.     

Left ventricular mechanoreceptors: a haemodynamic study

1. To study the function of the left ventricular mechanoreceptors, a working left ventricle preparation was devised in dogs which permitted control of pressure and flow of the isolated perfused coronary circulation and of the flow of the isolated, separately perfused systemic circulation. The systemic circulation was perfused at a constant rate so that changes in systemic pressure reflected changes in systemic resistance.2. Increases in myocardial contractility produced by injection of catecholamines into the isolated, perfused coronary circulation produced a fall in the pressure (resistance) of the isolated, separately perfused (at a constant rate) systemic circulation.3. Completeness of isolation of the coronary and systemic circulations was shown by the marked difference in appearance times between the reflex hypotensive responses from catecholamine injections into the isolated coronary circulation and the direct hypertensive response from a similar injection when the circulations were connected as well as by the marked difference between the pressure pulses recorded simultaneously on both sides of the aortic balloon separating the two circulations.4. Myocardial beta receptor blockade produced by injection of propranolol into the isolated coronary circulation abolished or attenuated the changes in left ventricular myocardial contractility as well as the subsequent hypotensive responses following the similar injection of catecholamines.5. Electrical stimulation of a sympathetic nerve innervating the heart resulted in increases in left ventricular myocardial contractility and subsequent systemic hypotensive responses indistinguishable from those following injection of catecholamines.6. That distortion of the mechano- or stretch receptors in the left ventricular myocardium was the cause of the hypotensive responses was demonstrated by increasing left ventricular myocardial contractility by mechanically obstructing the left ventricular outflow which produced hypotensive responses similar to those following the injection of catecholamines or nerve stimulation.7. Bilateral high cervical vagotomy abolished the hypotensive responses following injection of catecholamines into the isolated coronary circulation or following left ventricular outflow obstruction in all but one instance, indicating the importance of vagal fibres to the afferent arm of the reflex.8. It is suggested that the left ventricular mechanoreceptors function normally to reduce the peripheral resistance in order to prepare the systemic circulation to receive the left ventricular output and, especially during exercise, to prepare the systemic circulation to receive the augmented cardiac output with a minimum alteration in the systemic blood pressure and to distribute this augmented output preferentially to the skeletal muscles.     

Relations between collateral flow and tissue salvage in the risk area after acute coronary occlusion in dogs: a topographical analysis.

Localization of salvaged tissue after occlusion of the left anterior descending coronary artery due to collateral blood flow within the risk area was examined in a canine model using differential autoradiography. 125I tracer microspheres were injected into the left anterior descending artery preocclusively to define the perfusion territory as a risk area. 99mTc labelled human serum albumin microspheres were injected into both the left main and right coronary arteries 48 h after ligation to determine the collateral flow area. Using a cryotome, 50 micron transverse sections of the whole heart were taken, and 125I and 99mTc autoradiograms were obtained independently. The same specimens were stained by the nitroblue-tetrazolium method to demarcate the intact and infarcted myocardium. The tracings of the infarct, risk and collateral areas were compared and measured by a plainmeter. The collateral blood flow was distributed to 86, 55 and 42% of the epi, mid- and endo-cardial portions of the risk area respectively (P less than 0.001 between the epi- and mid- or endo-cardium). Within the collateral area 88, 58 and 63% of the epi-, mid- and endo-cardial portions were free of myocardial necrosis (P less than 0.001 between the epi- and mid- or endo-cardium). There was a close linear relationship between the size of salvaged and collateral areas (r = 0.96, P less than 0.001). Thus, a topographical analysis of the tissue salvage inside the risk area demonstrated the indispensable role of collateral blood flow for maintaining tissue viability.     

Relations between collateral flow and tissue salvage in the risk area after acute coronary occlusion in dogs: a topographical analysis

Localization of salvaged tissue after occlusion of the left anterior descending coronary artery due to collateral blood flow within the risk area was examined in a canine model using differential autoradiography. 125I tracer microspheres were injected into the left anterior descending artery preocclusively to define the perfusion territory as a risk area. 99mTc labelled human serum albumin microspheres were injected into both the left main and right coronary arteries 48 h after ligation to determine the collateral flow area. Using a cryotome, 50 micron transverse sections of the whole heart were taken, and 125I and 99mTc autoradiograms were obtained independently. The same specimens were stained by the nitroblue-tetrazolium method to demarcate the intact and infarcted myocardium. The tracings of the infarct, risk and collateral areas were compared and measured by a plainmeter. The collateral blood flow was distributed to 86, 55 and 42% of the epi, mid- and endo-cardial portions of the risk area respectively (P less than 0.001 between the epi- and mid- or endo-cardium). Within the collateral area 88, 58 and 63% of the epi-, mid- and endo-cardial portions were free of myocardial necrosis (P less than 0.001 between the epi- and mid- or endo-cardium). There was a close linear relationship between the size of salvaged and collateral areas (r = 0.96, P less than 0.001). Thus, a topographical analysis of the tissue salvage inside the risk area demonstrated the indispensable role of collateral blood flow for maintaining tissue viability.     

Effect of propranolol on the tone of collateral arteries in patients with occlusion of the superficial femoral artery

The effect of administration of 0.5 mg propranolol into the femoral artery in eight patients with lower limb ischaemia and superficial femoral artery occlusion on collateral arterial resistance was studied in supine and tilted head-up position. Mean blood pressures were recorded directly from the femoral and popliteal artery and femoral blood flow was measured by an indicator dilution technique. After beta-receptor blockade in the supine position the collateral arterial resistance increased by 7 +/- 2%, femoral blood flow decreased 10 +/- 4%, and popliteal artery pressure increased by 4 mmHg (8 +/- 3%). During head-up tilt there was no change in femoral blood flow and collateral arterial resistance after propranolol. The peripheral vasoconstrictor effect of propranolol, therefore, seems not to be harmful to patients with vascular disease.     

Pulmonary Vascular Resistance and Impedance in Isolated Mouse Lungs: Effects of Pulmonary Emboli

To study pulsatile pressure-flow rate relationships in the intact pulmonary vascular network of mice, we developed a protocol for measuring pulmonary vascular resistance and impedance in isolated, ventilated, and perfused mouse lungs. We used pulmonary emboli to validate the effect of vascular obstruction on resistance and impedance. Main pulmonary artery and left atrial pressures and pulmonary vascular flow rate were measured under steady and pulsatile conditions in the lungs of C57BL/6J mice (n = 6) before and after two infusions with 25 μm-diameter microspheres (one million per infusion). After the first and second embolizations, pulmonary artery pressures increased approximately two-fold and three and a half-fold, respectively, compared to baseline, at a steady flow rate of 1 ml/min (P < 0.05). Pulmonary vascular resistance and 0 Hz impedance also increased after the first and second embolizations for all flow rates tested (P < 0.05). Frequency-dependent features of the pulmonary vascular impedance spectrum were suggestive of shifts in the major pulmonary vascular reflection sites with embolization. Our results demonstrate that pulmonary artery pressure, resistance, and impedance magnitude measured in this isolated lung setup changed in ways consistent with in vivo studies in larger animals and humans and demonstrate the usefulness of the isolated, ventilated, and perfused mouse lung for investigating steady and pulsatile pressure-flow rate relationships.