Effects of coronary sinus pressure elevation on coronary blood flow distribution in dogs with normal preload

Coronary sinus pressure (Pcs) elevation shifts the diastolic coronary pressure-flow relation (PFR) of the entire left ventricular myocardium to a higher pressure intercept. This finding suggests that Pcs is one determinant of zero-flow pressure (Pzf) and challenges the existence of a vascular waterfall mechanism in the coronary circulation. To determine whether coronary sinus or tissue pressure is the effective coronary back pressure in different layers of the left ventricular myocardium, the effect of increasing Pcs was studied while left ventricular preload was low. PFRs were determined experimentally by graded constriction of the circumflex coronary artery while measuring flow using a flowmeter. Transmural myocardial blood flow distribution was studied (15-micron radioactive spheres) at steady state, during maximal coronary artery vasodilatation at three points on the linear portion of the circumflex PFR both at low and high diastolic Pcs (7 +/- 3 vs. 22 +/- 5 mmHg; p less than 0.0001) (1 mmHg = 133.322 Pa). In the uninstrumented anterior wall the blood flow measurements were obtained in triplicate at the two Pcs levels. From low to high Pcs, mean aortic (98 +/- 23 mmHg) and left atrial (5 +/- 3 mmHg) pressure, percent diastolic time (49 +/- 7%), percent left ventricular wall thickening (32 +/- 4%), and percent myocardial lactate extraction (15 +/- 12%) were not significantly changed. Increasing Pcs did not alter the slope of the PFR; however, the Pzf increased in the subepicardial layer (p less than 0.0001), whereas in the subendocardial layer Pzf did not change significantly. Similar slopes and Pzf were observed for the PFR of both total myocardial mass and subepicardial region at low and high Pcs. Subendocardial:subepicardial blood flow ratios increased for each set of measurements when Pcs was elevated (p less than 0.0001), owing to a reduction of subepicardial blood flow; however, subendocardial blood flow remained unchanged, while starting in the subepicardium toward midmyocardium blood flow decreased at high Pcs. This pattern was similar for the uninstrumented anterior wall as well as in the posterior wall. Thus as Pcs increases it becomes the effective coronary back pressure with decreasing magnitude from the subepicardium toward the subendocardium of the left ventricle. Assuming that elevating Pcs results in transmural elevation in coronary venous pressure, these findings support the hypothesis of a differential intramyocardial waterfall mechanism with greater subendo- than subepi-cardial tissue pressure.     

Subendocardial and subepicardial pressure-flow relations in the rat heart in diastolic and systolic arrest

Ischemic heart disease is more apparent in the subendocardial than in subepicardial layers. We investigated coronary pressure-flow relations in layers of the isolated rat left ventricle, using 15 microm microspheres during diastolic and systolic arrest in the vasodilated coronary circulation. A special cannula allowed for selective determination of left main stem pressure-flow relations. Arterio-venous shunt flow was derived from microspheres in the venous effluent. We quantitatively investigated the pressure-flow relations in diastolic arrest (n=8), systolic arrest at normal contractility (n=8) and low contractility (n=6). In all three groups normal and large ventricular volume was studied. In diastolic arrest, at a perfusion pressure of 90 mmHg, subendocardial flow is larger than subepicardial flow, i.e., the endo/epi ratio is approximately 1.2. In systolic arrest the endo/epi ratio is approximately 0.3, and subendocardial flow and subepicardial flow are approximately 12% and approximately 55% of their values during diastolic arrest. The endo/epi ratio in diastolic arrest decreases with increasing perfusion pressure, while in systole the ratio increases. The slope of the pressure-flow relations, i.e., inverse of resistance, changes by a factor of approximately 5.3 in the subendocardium and by a factor approximately 2.2 in the subepicardium from diastole to systole. Lowering contractility affects subendocardial flow more than subepicardial flow, but both contractility and ventricular volume changes have only a limited effect on both subendocardial and subepicardial flow. The resistance (inverse of slope) of the total left main stem pressure-flow relation changes by a factor of approximately 3.4 from diastolic to systolic arrest. The zero-flow pressure increases from diastole to systole. Thus, coronary perfusion flow in diastolic arrest is larger than systolic arrest, with the largest difference in the subendocardium, as a result of layer dependent increases in vascular resistance and intercept pressure. Shunt flow is larger in diastolic than in systolic arrest, and increases with perfusion pressure. We conclude that changes in contractility and ventricular volume have a smaller effect on pressure-flow relations than diastolic-systolic differences. A synthesis of models accounting for the effect of cardiac contraction on perfusion is suggested.     

Effect of angiotensin inhibition on the coronary artery lower pressure limit in anesthetized dogs

The renin-angiotensin system plays a critical role in regulating vasoconstriction and vasodilatation that can influence myocardial blood flow and its transmural distribution. We tested the hypothesis that angiotensin inhibition can induce a leftward shift of the coronary autoregulatory pressure-flow relation and preserve distribution of myocardial blood flow at lower coronary perfusion pressures. We established circumflex artery pressure-flow relations under baseline conditions and after intracoronary enalaprilat or losartan potassium. Thereafter, transmural myocardial blood flow was measured at baseline and at the lower coronary pressure limit (LPL). With enalaprilat, the LPL was shifted leftward from 48 +/- 6 mmHg at baseline to 43 +/- 3 mmHg (P = 0.026); with losartan, the LPL was shifted leftward from 48 +/- 10 mmHg at baseline to 41 +/- 5 mmHg (P = 0.027). The leftward shift occurred while cardiac hemodynamics and MVO2 were maintained at control levels. These results indicate that angiotensin inhibition extends the range of coronary autoregulation to lower LPL while preserving myocardial blood flow distribution, a physiologic effect that might explain the lower incidence of coronary events in treated patients.     

Intramyocardial pressure and coronary extravascular resistance

Intramyocardial pressure is an indicator of coronary extravascular resistance. During systole, pressure in the subendocardium exceeds left ventricular intracavitary pressure; whereas pressure in the subepicardium is lower than left ventricular intracavitary pressure. Conversely, during diastole, subepicardial pressure exceeds both subendocardial pressure and left ventricular pressure. These observations suggest that coronary flow during systole is possible only in the subepicardial layers. During diastolic, however, a greater driving pressure is available for perfusion of the subendocardial layers relative to the subepicardial layers. On this basis, measurements of intramyocardial pressure contribute to an understanding of the mechanisms of regulation of the phasic and transmural distribution of coronary blow flow.     

Effects of increased pressure inside or outside ventricles on total and regional myocardial blood flow

Increasing pressures to 30 mmHg in right (RV) and left (LV) ventricles and surrounding heart (SH) in isolated, arrested, maximally vasodilated, blood-perfused dog hearts shifted pressure-flow (PF) curves rightward and increased zero flow pressure (P(zf)) by an amount equal to the RV applied pressure, SH applied pressure, or two-thirds of the LV applied pressure. There were comparable increases in coronary venous pressures. Increasing LV or SH pressures decreased coronary blood flows, especially in the subendocardium. Decreases in driving pressure decreased flows in all layers, but even with driving pressure of 5 mmHg, a few subepicardial pieces had flow. We conclude with the following: 1) raising pressures inside or outside the heart shifts PF curves and raises P(zf) by increasing coronary venous pressure; 2) the effects are most prominent in the subendocardial muscle layer; and 3) as driving pressures are decreased, there is a range of P(zf) in the heart with the final P(zf) recorded due to the last little piece of muscle to be perfused.     

Mechanisms of oxygen demand/supply balance in the right ventricle

Few studies have investigated factors responsible for the O2 demand/supply balance in the right ventricle. Resting right coronary blood flow is lower than left coronary blood flow, which is consistent with the lesser work of the right ventricle. Because right and left coronary artery perfusion pressures are identical, right coronary conductance is less than left coronary conductance, but the signal relating this conductance to the lower right ventricular O2 demand has not been defined. At rest, the left ventricle extracts approximately 75% of the O2 delivered by coronary blood flow, whereas right ventricular O2 extraction is only ~50%. As a result, resting right coronary venous PO2 is approximately 30 mm Hg, whereas left coronary venous PO2 is approximately 20 mm Hg. Right coronary conductance does not sufficiently restrict flow to force the right ventricle to extract the same percentage of O2 as the left ventricle. Endogenous nitric oxide impacts the right ventricular O2 demand/supply balance by increasing the right coronary blood flow at rest and during acute pulmonary hypertension, systemic hypoxia, norepinephrine infusion, and coronary hypoperfusion. The substantial right ventricular O2 extraction reserve is used preferentially during exercise-induced increases in right ventricular myocardial O2 consumption. An augmented, sympathetic-mediated vasoconstrictor tone blunts metabolically mediated dilator mechanisms during exercise and forces the right ventricle to mobilize its O2 extraction reserve, but this tone does not limit resting right coronary flow. During exercise, right coronary vasodilation does not occur until right coronary venous PO2 decreases to approximately 20 mm Hg. The mechanism responsible for right coronary vasodilation at low PO2 has not been delineated. In the poorly autoregulating right coronary circulation, reduced coronary pressure unloads the coronary hydraulic skeleton and reduces right ventricular systolic stiffness. Thus, normal right ventricular external work and O2 demand/supply balance can be maintained during moderate coronary hypoperfusion.     

Myocardial tissue pressure and blood flow during coronary sinus pressure modulation in anesthetized dogs.

To determine whether coronary sinus outflow pressure (Pcs) or intramyocardial tissue pressure (IMP) is the effective back pressure in the different layers of the left ventricular (LV) myocardium, we increased Pcs in 14 open-chest dogs under maximal coronary artery vasodilation. Circumflex arterial (flowmeter), LV total, and subendocardial and subepicardial (15-microns radioactive spheres) pressure-flow relationships (PFR) and IMP (needle-tip pressure transducers) were recorded during graded constriction of the artery at two diastolic Pcs levels (7 +/- 3 vs. 23 +/- 4 mmHg). At high Pcs, LV, aortic and diastolic circumflex arterial pressure, heart rate, myocardial oxygen consumption, and lactate extraction were unchanged; IMP in the subendocardium did not change (130/19 mmHg), whereas IMP in the subepicardium increased by 17 mmHg during systole and 10 mmHg during diastole (P < or = 0.001), independently of circumflex arterial pressure. Increasing Pcs did not change the slope of the PFR; however, coronary pressure at zero flow increased in the subepicardium (P < or = 0.008), whereas in the subendocardium it remained unchanged at 24 +/- 3 mmHg. Thus Pcs can regulate IMP independently of circumflex arterial pressure and consequently influence myocardial perfusion, especially in the subepicardial tissue layer of the LV.     

Redistribution in left ventricular regional flow following acute right ventricular pressure overload

The left ventricular dysfunction following acute pulmowary hypertension remains unexplained. We wondered if acute pulmonary hypertension could alter the transmural flow distribution within the left ventricular myocardium, independent of coronary flow and perfusion pressure. We used a canine preparation in which the left coronary system was perfused at constant flow and induced a two- to three-fold increase in pulmonary artery pressure by banding the pulmonary artery. Regional myocardial blood flow of the left coronary system was measured using radioactive microspheres, injected into the left coronary system before and after 10-30 min of banding of the pulmonary artery. The left ventricular subendocardial:epicardial ratio fell by 12 and 31% (p less than 0.05) of control value, 10 and 30 min, respectively, after banding of the pulmonary artery, the total flow to the left coronary system being kept constant. Left atrial mean pressure increased from 2.9 +/- 2.4 to 3.6 +/- 1.9 and 6.0 +/- 2.1 (p less than 0.05) following banding. The mechanism of the redistribution of coronary flow may relate to inappropriate vasodilation of the right septal myocardium with consequent relative left ventricular subendocardial hypoperfusion which might aggravate left ventricular ischemia in the presence of hypotension and hypoxia.     

Transmural difference in coronary arteriolar dilation to adenosine: effect of luminal pressure and K(ATP) channels

Coronary blood flow in the subendocardium is preferentially increased by adenosine but is redistributed to the subepicardium during ischemia in association with coronary pressure reduction. The mechanism for this flow redistribution remains unclear. Since adenosine is released during ischemia, it is possible that the coronary microcirculation exhibits a transmural difference in vasomotor responsiveness to adenosine at various intraluminal pressures. Although the ATP-sensitive K(+) (K(ATP)) channel has been shown to be involved in coronary arteriolar dilation to adenosine, its role in the transmural adenosine response remains elusive. To address these issues, pig subepicardial and subendocardial arterioles (60-120 micrometer) were isolated, cannulated, and pressurized to 20, 40, 60, or 80 cmH(2)O without flow for in vitro study. At each of these pressures, vessels developed basal tone and dilated concentration dependently to adenosine and the K(ATP) channel opener pinacidil. Subepicardial and subendocardial arterioles dilated equally to adenosine and pinacidil at 60 and 80 cmH(2)O luminal pressure. At lower luminal pressures (i.e., 20 and 40 cmH(2)O), vasodilation in both vessel types was enhanced. Enhanced vasodilatory responses were not affected by removal of endothelium but were abolished by the K(ATP) channel inhibitor glibenclamide. In a manner similar to reducing pressure, a subthreshold dose of pinacidil potentiated vasodilation to adenosine. In contrast to adenosine, dilation of coronary arterioles to sodium nitroprusside was independent of pressure changes. These results indicate that coronary microvascular dilation to adenosine is enhanced at lower intraluminal pressures by selective activation of smooth muscle K(ATP) channels. Since microvascular pressure has been shown to be consistently lower in the subendocardium than in the subepicardium, it is likely that the inherent pressure gradient in the coronary microcirculation across the ventricular wall may be an important determinant of transmural flow in vivo during resting conditions or under metabolic stress with adenosine release.     

Haemodynamics in the first seconds after coronary artery occlusion.

The changes in cardiac and in total haemodynamics, occurring during the first seconds of occlusion and the subsequent desocclusion of coronary arteries were studied on 28 dogs. The most intensive changes were observed after the trunk occlusion of the left coronary artery. Simultaneously with decreasing blood inflow into the myocardium its contractility and the systolic pressure in the left ventricle and the outflow from the coronary sinus began to fall rapidly. The systolic pressure in the left ventricle decreased within the first 10 s from 24 to 13-15 kPa (180 to 100-110 mm Hg), which means that the systolic pressure fell about 1 kPa (7-8 mm Hg) per second, or 0.5-0.6 kPa (4-5 mm Hg) per systole. At the same time the end-diastolic pressure in the left ventricle also increased from zero to 3-4 kPa (25-30 mm Hg). After the trunk desocclusion of the left coronary artery the systolic pressure in the left ventricle proceeded to fall by about 2-3 kPa (15-22 mm Hg). Only then, 20-25 s after the desocclusion, blood flow in the left coronary artery began to rise intensively and 4-6 s later the myocardial contractility and the systolic pressure in the left ventricle also increased. After unclamping (50-60 s), there was an overshoot of haemodynamic values above preocclusive values and then followed the compensatory phase. This phase lasted 80-90 s and on its peak the pressure and flow parameters increased by about 50-60% above preocclusive values. During the occlusion of ramus interventricularis anterior or ramus circumflexus for 30-60 s the haemodynamic parameters changed only slightly. The same was observed during trunk occlusion of the right coronary artery (30-60 s), but in that case many extrasystoles occurred.     

Dynamics of flow velocities in endocardial and epicardial coronary arterioles

The subendocardium is the most vulnerable area of the left ventricle to the effects of hypoperfusion and ischemia. Despite this well-acknowledged observation, the mechanisms underlying this susceptibility are not elucidated, although numerous explanations including differences in transmural distribution of hemodynamics, metabolism, and wall stresses have been proposed. Our goal was to make dynamic measurements of endocardial and epicardial flow velocities, which reflect hemodynamic and wall stresses, to approach this problem. We measured blood flow velocities in subendocardial and subepicardial coronary arterioles of in vivo beating canine hearts using a high-speed, charge-coupled device, intravital videomicroscope with a rod-probe lens. Subendocardial flow was characterized by remarkable systolic flow-velocity reversal (systolic slosh ratio, 84%; measurable velocity of retrograde flow, faster than -40 mm/s), which contrasted to predominant forward-flow velocity during systole in the subepicardial arterioles (systolic slosh ratio, 25%; maximum velocity, approximately -20 mm/s; P < 0.0005 and 0.05 vs. subendocardial arterioles, respectively). We speculate that this retrograde flow is "wasteful," because this volume must be refilled during the subsequent diastole, which thereby detracts from the net perfusion as well as the time for perfusion. Accordingly, we also believe that the retrograde systolic blood flow contributes to the vulnerability of the subendocardium to ischemia.     

Effect of magnesium sulfate administration on subendocardial and subepicardial perfusion

The objective of this study was to determine the effect of systemic MgSO₄ infusion on subendocardial and subepicardial perfusion. Seventeen spontaneously breathing piglets were examined. Myocardial perfusion was measured using radiolabeled microspheres at baseline, 30 and 60 min after either MgSO₄ (80 mg/kg) or saline infusion. Blood pressure, heart rate, and cardiac output were also measured at these time intervals. Comparison of the magnesiuminduced changes in systemic blood pressure and on subendocardial and subepicardial perfusion at 30 and 60 min with values obtained with saline solution at 30 and 60 min, yielded no statistically significant difference (Tables 1–3). The ratio of subendocardial/subepicardial blood flow and subendocardial and subepicardial coronary vascular resistance at 30 and 60 min revealed no statistically significant differences between the magnesium and the control group (Table 3). There were no statistically significant difference in cardiac output and heart rate during any of the measured periods (Table 2). Our results suggest that the administration of MgSO₄ does not alter the ratio of subendocardial/subepicardial blood flow and the ratio of subendocardial/subepicardial coronary vascular resistance.     

Why is the subendocardium more vulnerable to ischemia? A new paradigm

Myocardial ischemia is transmurally heterogeneous where the subendocardium is at higher risk. Stenosis induces reduced perfusion pressure, blood flow redistribution away from the subendocardium, and consequent subendocardial vulnerability. We propose that the flow redistribution stems from the higher compliance of the subendocardial vasculature. This new paradigm was tested using network flow simulation based on measured coronary anatomy, vessel flow and mechanics, and myocardium-vessel interactions. Flow redistribution was quantified by the relative change in the subendocardial-to-subepicardial perfusion ratio under a 60-mmHg perfusion pressure reduction. Myocardial contraction was found to induce the following: 1) more compressive loading and subsequent lower transvascular pressure in deeper vessels, 2) consequent higher compliance of the subendocardial vasculature, and 3) substantial flow redistribution, i.e., a 20% drop in the subendocardial-to-subepicardial flow ratio under the prescribed reduction in perfusion pressure. This flow redistribution was found to occur primarily because the vessel compliance is nonlinear (pressure dependent). The observed thinner subendocardial vessel walls were predicted to induce a higher compliance of the subendocardial vasculature and greater flow redistribution. Subendocardial perfusion was predicted to improve with a reduction of either heart rate or left ventricular pressure under low perfusion pressure. In conclusion, subendocardial vulnerability to a acute reduction in perfusion pressure stems primarily from differences in vascular compliance induced by transmural differences in both extravascular loading and vessel wall thickness. Subendocardial ischemia can be improved by a reduction of heart rate and left ventricular pressure.     

Ischemia-induced changes in sarcolemmal (Na+, K+)-ATPase, K+-pNPPase, sialic acid, and phospholipid in the dog and effects of the nisoldipine and chlorpromazine treatment

This work was undertaken to study functional and structural changes of the cardiac sarcolemmal membrane which was isolated from the ischemic lesion in the dog. The sarcolemmal fraction was prepared, by adopting the method devised by Reeves and Sutko , from the right ventricle and the subendocardial and subepicardial layers of the left ventricle. Ischemic lesion was produced by occlusion of a branch of the left anterior descending coronary artery for a period of 1.5 hr in the thoracotomized dog, followed by release of the occlusion for 3 hr. Nisoldipine, 5 micrograms/kg, was given twice intravenously, and chlorpromazine was infused at a rate of 10 micrograms/kg X min, in addition to the administration of twice bolus doses of 400 micrograms/kg each. Nisoldipine significantly decreased the incidence of premature ventricular contractions and microvascular hemorrhage. Sarcolemmal purity was monitored by using enzyme and chemical markers; the results indicated that the membrane preparation was tenfold purified over the homogenate. Although the activities of ouabain-sensitive (Na+, K+)-ATPase and ouabain-sensitive K+-p-nitrophenylphosphatase ( pNPPase ) of the sarcolemmal preparation isolated from the subendocardial layer were similar to those from the subepicardial layer in the nonischemic left ventricle, a significant decrease in these activities was observed only when the sarcolemmal fraction isolated from the subendocardial layer of ischemic area was compared with that from the subendocardial layer of nonischemic area. In contrast, the sialic acid content of the sarcolemma from the ischemic subendocardial layer was significantly increased compared to that of the nonischemic subendocardial layer. No such changes occurred in sarcolemma prepared from the ischemic subepicardial layer. The total phospholipid content as well as phosphatidylcholine and -ethanolamine contents of the sarcolemmal membrane prepared from the subendocardial layer of ischemic area were significantly decreased compared to nonischemic area. Nisoldipine prevented the ischemia-induced alterations in sarcolemmal (Na+, K+)-ATPase, pNPPase , sialic acid and phospholipids of the subendocardial layer. Chlorpromazine showed a less consistent effect than did Nisoldipine under our experimental conditions. Our study thus demonstrates that the lipid component and function of cardiac sarcolemmal membrane are altered in the early ischemic lesion and that these alterations are nonuniform in distribution and are alleviated by some pharmacological intervention.     

Intramyocardial pressure measurements in the stage 18 embryonic chick heart

Intramyocardial pressure (IMP) and ventricular pressure (VP) were measured in the trabeculating heart of the stage 18 chick embryo (3 days of incubation). Pressure was measured at several locations across the ventricle using a fluid-filled servo-null system. Maximum systolic and minimum diastolic IMP tended to be greater in the dorsal wall than in the ventral wall, but transmural distributions of peak active (maximum minus minimum) IMP were similar in both walls. Peak active IMP near midwall was similar to peak active VP, but peak active IMP in the subepicardial and subendocardial layers was four to five times larger. These results suggest that the passive stiffness of the dorsal wall is greater than that of the ventral wall and that during contraction the inner and outer layers of both walls generate more contractile force and/or become less permeable to flow than the middle part of the wall. Measured pressures likely correspond to regional variations in wall stress that may influence morphogenesis and function in the embryonic heart.     

Left ventricular myocardal activation under ventricular paced beats in chickens Gallus gallus domesticus

The aim of the study was to advance our knowledge regarding the activation process of the ventricular myocardium in birds in which Purkinje fibres penetrate into the ventricular wall to reach the epicardium. A depolarization pattern of the left ventricular free wall was studied in chickens (Gallus gallus) during ventricular paced beats. Duration of the activation process of the left ventricular free wall is significantly increased during ventricular ectopic excitation as compared with sinus rhythm. Its lowest increase occurs during subendocardial pacing of the middle part of the left ventricle, but its greatest increase is observed during subepicardial pacing of the left ventricular base. Multifocality and mosaicity of depolarization of the left ventricular free wall myocardium in chicken are expressed in a considerably less degree during ventricular paced beats in comparison with sinus rhythm. During ventricular paced beats, excitation of the left ventricular free wall is mostly due to the successive spreading of the depolarization wave from pacing sites.     

An anatomic basis for fetal right ventricular dominance and arterial pressure sensitivity

Fetal right ventricular dominance of flow and arterial pressure sensitivity were recently recognized but controversial findings. We investigated ventricular volumes, weights and dimensions in order to understand if there were anatomic differences between the ventricles which might explain these differential functional findings in the fetal sheep. Forty-four near term lambs and their hearts were weighed. Right and left ventricular free wall weights were not different. Volumes were measured by generating in vitro pressure-volume relations and by casting the two ventricles after fixation at equal, physiologic pressures. Right ventricular volume was greater than left ventricular volume by both techniques. Ventricular interaction and a restraining effect of the pericardium were present. Measurements of the fixed ventricles and their casts revealed the following: left ventricular wall thickness was slightly greater than right ventricular wall thickness; lateral ventricular diameters were not different but anteroposterior ventricular diameters were much greater in the right than left ventricle. Because of these findings, the right ventricular circumferential radii of curvature were greater than for the left ventricle as was the radius to wall thickness ratio. Greater right ventricular volume and radius to wall thickness ratio may be important factors in right ventricular flow dominance and greater sensitivity to arterial pressure.     

Stenosis differentially affects subendocardial and subepicardial arterioles in vivo

The presence of a coronary stenosis results primarily in subendocardial ischemia. Apart from the decrease in coronary perfusion pressure, a stenosis also decreases coronary flow pulsations. Applying a coronary perfusion system, we compared the autoregulatory response of subendocardial (n = 10) and subepicardial (n = 12) arterioles (<120 microm) after stepwise decreases in coronary arterial pressure from 100 to 70, 50, and 30 mmHg in vivo in dogs (n = 9). Pressure steps were performed with and without stenosis on the perfusion line. Maximal arteriolar diameter during the cardiac cycle was determined and normalized to its value at 100 mmHg. The initial decrease in diameter during reductions in pressure was significantly larger at the subendocardium. Diameters of subendocardial and subepicardial arterioles were similar 10--15 s after the decrease in pressure without stenosis. However, stenosis decreased the dilatory response of the subendocardial arterioles significantly. This decreased dilatory response was also evidenced by a lower coronary inflow at similar average pressure in the presence of a stenosis. Inhibition of nitric oxide production with N(G)-monomethyl-L-arginine abrogated the effect of the stenosis on flow. We conclude that the decrease in pressure caused by a stenosis in vivo results in a larger decrease in diameter of the subendocardial arterioles than in the subepicardial arterioles, and furthermore stenosis selectively decreases the dilatory response of subendocardial arterioles. These two findings expand our understanding of subendocardial vulnerability to ischemia.     

Modifications by ischemia of carbohydrate and lipid metabolism of the dog heart in situ from circulating and endogenous substrates

The uptake of circulating substrates, lactate, glucose and free fatty acids (FFA) has been investigated concurrently with the tissular contents of these principles and the glycogen and triglyceride stores in the dog heart in situ submitted to incomplete obstruction of left coronary bed. Transmural samples necessary for the repeated determination of tissular substrates were taken from left ventricular wall by means of a total cardiopulmonary by-pass system, then divided to allow the analysis separately in subendocardial and subepicardial layer. A 40 to 70% reduction in coronary blood flow gave rise to decrease or suppression of uptake of all the substrates or even to conversion of uptake into output. The modifications of uptake are chiefly related to the deficiency of breakdown by oxidation, though lessened in the case of FFA by incorporation into triglycerides and enhanced in the case of glucose by glycogenolysis. Glycogenolysis and consequent anaerobic glycolysis appear to be the main process available against the energy cellular defect linked with oxygen lack which affects notably more subendocardial than subepicardial layer.     

Changes of regional myocardial blood flow during and after acute focal experimental ischaemia.

The regional blood flow through the myocardium of the left ventricle was measured in 11 dogs after ligation of the left anterior descending coronary artery, by means of a local injection of 133Xe depot and precordial detection of its washout 2 hours after ligation. Immediately after ligation the blood flow in the ischaemic area declined considerably but at the same time there was a significant increase of blood flow in the non-ischaemic left ventricular myocardium. The regional flow in the ischaemic and non-ischaemic area increased insignificantly for 2 hrs. These changes were not due to alterations in coronary artery pressure, as the mean arterial pressure declined significantly during the first hour. After temporary ischaemia by ligation of the left anterior descending coronary artery for 2--4 minutes, an intensive reactive hyperaemia developed in the ischaemic region (the blood flow reached 221% of control values on the average) which was the more intensive, the greater the drop of blood flow in the ischaemic area after ligation.