Reduced myocardial blood flow resulting from dynamic changes in coronary artery stenosis

To evaluate the interaction of coronary vasomotor tone and stenosis, we studied the effects of ergonovine and adenosine on partially obstructed coronary arteries in 6 closed chest dogs. Coronary stenosis was created by partially inflating a balloon catheter with a distal lumen in the left anterior descending or circumflex coronary artery. Stenotic resistance was calculated as the mean pressure gradient across the stenosis divided by the mean blood flow measured with 15 micron radioactive microspheres. Coronary artery vasoconstriction, induced by ergonovine (0.6 mg i.v.), caused a small, but nonsignificant, increase in stenotic resistance (1.42 ± 0.25 to 2.68 ± 0.64 mm Hg/ml per min) and had no effect on myocardial blood flow. Coronary arteriolar dilation induced by adenosine increased stenotic resistance (1.52 ± 0.25 to 9.01 ± 2.49 mm Hg/ml per min, P < 0.05) and the pressure gradient across the stenosis (18.8 ± 3.0 to 41.3 ± 7.5 mm Hg, P < 0.05). Adenosine increased myocardial blood flow from 0.52 ± 0.05 ml/min per g to 1.43 ± 0.20 ml/min per g (P < 0.05) in the regions supplied by unstenosed arteries, while in the region perfused by the stenosed artery blood flow fell from 0.51 ± 0.06 to 0.29 ± 0.13 ml/min per g (P < 0.05), with the endocardium most severely affected (0.55 ± 0.04 ml/min per g to 0.26 ± 0.09 ml/min per g, P < 0.05).Thus changes in severity of stenosis produced by altered coronary pressure and flow can influence blood flow to the myocardium. Such dynamic changes in coronary artery stenosis may be important in the pathogenesis of angina and myocardial infarction.     

Changes in ischemic blood flow distribution and dynamic severity of a coronary stenosis induced by beta blockade in the canine heart

The effects of equipotent beta 1-receptor-blocking doses of propranolol, metoprolol and sotalol on distal coronary pressure, stenosis resistance and regional myocardial blood flow (endo/epi) were studied in anesthetized dogs with a severe noncircumferential stenosis of the left circumflex coronary artery. No significant differences between the three beta blockers were observed for overall hemodynamics and regional myocardial blood flow. After drug treatment, subendocardial blood flow (0.47 +/- 0.05 to 0.78 +/- 0.05 ml/min/g) and endo/epi (0.67 +/-0.04 to 1.18 +/- 0.04) increased significantly (p less than 0.05) in the ischemic region. These changes were associated with a marked increase in distal coronary perfusion pressure and a decrease in heart rate. Resistance across the stenosis decreased significantly (p less than 0.05) after beta-receptor blockade (3.2 +/- 0.3 to 1.4 +/- 0.2 units). Atrial pacing to control heart rate only partially attenuated these changes. These results suggest that a favorable redistribution of ischemic blood flow after beta blockade is the result of an increase in distal diastolic pressure-time index and an autoregulation-induced increase in distal bed vascular resistance due to a decrease in myocardial oxygen demand associated with beta blockade. The latter effect also resulted in a decrease in the dynamic severity of a proximal coronary stenosis.     

Alterations of myocardial blood flow associated with experimental canine left ventricular hypertrophy secondary to valvular aortic stenosis

Experimental renovascular hypertension or supravalvular aortic constriction results in left ventricular hypertrophy and impaired minimum coronary vascular resistance. However, these experimental models expose the coronary arteries to increased intra-arterial pressure, so that hypertensive vascular changes might be responsible for the impaired minimum coronary resistance. This study was performed to test the hypothesis that left ventricular hypertrophy in the absence of increased coronary pressure results in abnormalities of myocardial perfusion. Aortic valve stenosis was produced by plication of the noncoronary aortic cusp of 11 dogs at 6-8 weeks of age. Studies were carried out when the animals reached adulthood; mean left ventricular:body weight ratio was 7.1 +/- 0.4 as compared to 4.4 +/- 0.3 g/kg in 11 normal dogs (P less than 0.01). Under quiet resting conditions, myocardial blood flow measured with microspheres was significantly greater than normal in dogs with aortic stenosis. However, during maximum coronary vasodilation with adenosine, mean left ventricular blood flow in dogs with hypertrophy (3.29 +/- 0.39) was substantially less than in normal dogs (6.19 +/- 0.54 ml/min per g; P less than 0.01), whereas minimum coronary resistance was increased from 14.1 +/- 1.7 in normal dogs to 23.7 +/- 5.4 mmHg. min X g/ml (P less than 0.01). To examine the response of myocardial perfusion to cardiac stress, blood flow was measured during pacing at 200 and 250 beats/min. Compared with normal dogs, animals with hypertrophy had a subnormal increase in myocardial blood flow during tachycardia; this perfusion deficit was most marked in the subendocardium. These data demonstrate that left ventricular hypertrophy alone, without increased coronary artery pressure, is associated with impaired minimum coronary vascular resistance and with abnormalities of myocardial blood flow during pacing stress.     

Myocardial ischaemia produced by ergonovine-induced vasoconstriction during preexisting coronary stenosis: experimental conditions for the geometric theory

Experiments were designed to determine the contribution of active vasomotor tone of a large coronary artery during a preexisting coronary stenosis to the production of myocardial ischaemia. The quantitative relations between ergonovine dose and systemic and coronary haemodynamic and electrocardiographic responses during various degrees of coronary stenosis were evaluated in 55 anaesthetised open-chest dogs. In the absence of coronary stenosis, intracoronary infusion of ergonovine (0.04 to 4 micrograms X min-1) had no systemic or coronary haemodynamic effects. In dogs with coronary stenosis created with intraluminal microballoon occluder, ergonovine produced marked decreases in coronary blood flow and distal coronary pressure followed by a decline in left ventricular dP/dt and ST-elevation in epicardial electrogram in the presence of moderate (28 +/- 1.1 mmHg in pressure gradient) and severe (41 +/- 1.4 mmHg), but not mild (15 +/- 0.9 mmHg) stenosis. These detrimental effects of ergonovine were dependent on its dose as well as the severity of preexisting coronary stenosis. Interventions such as aspirin pretreatment or endothelial denudation did not attenuate the coronary vasomotor response or ergonovine, but pretreatment with nifedipine (3 micrograms X kg-1 iv) prevented this response. Intravenous injection of ergonovine (4 to 15 micrograms X kg-1) in doses relevant to clinical usage during intraluminal obstruction resulted in similar changes in coronary haemodynamics as those of intracoronary ergonovine. In contrast, in dogs with various degrees of coronary stenosis produced with an externally applied constrictor device, ergonovine did not affect systemic and coronary haemodynamics. These experiments demonstrate that normal vasomotion superimposed on moderate and severe pliable coronary stenosis can cause transient myocardial ischaemia, which helps to clarify the conditions to produce myocardial ischaemia according to geometric theory.     

Adverse effects of circumflex coronary artery occlusion on blood flow to remote myocardium supplied by a stenosed left anterior descending coronary artery in anesthetized open-chest dogs

Left anterior descending coronary artery occlusion in open-chest dogs causes a decrease in endocardial blood flow to the remote posterior bed supplied by a stenosed left circumflex coronary artery. To determine if "remote" myocardial ischemia also occurred in the anterior bed after circumflex occlusion, myocardial blood flow (radiolabeled microspheres) and hemodynamics were measured before and after circumflex occlusion in the presence of a stenosed left anterior descending artery (gradient: 28 +/- 2 mm Hg) in 10 open-chest dogs. Aortic pressure fell from 108 +/- 3 to 100 +/- 3 mm Hg (p = 0.02) and mean distal left anterior descending coronary artery pressure fell from 81 +/- 4 to 69 +/- 5 mm Hg (p = 0.02) after circumflex occlusion. Transmural flow to normal myocardium supplied by unstenosed and unoccluded coronary arteries increased from 0.69 +/- 0.04 to 0.84 +/- 0.04 ml/min/gm (p less than 0.0001) after circumflex occlusion. Although epicardial flow to the remote anterior bed supplied by the stenosed left anterior descending coronary artery increased after left circumflex occlusion (0.61 +/- 0.03 to 0.73 +/- 0.04 ml/min/gm, p = 0.004), remote anterior bed endocardial flow did not increase, and the remote bed endocardial:epicardial blood flow ratio decreased from 0.98 +/- 0.06 to 0.78 +/- 0.10 (p less than 0.05). Therefore, in this model, remote anterior bed ischemia, relative to the normal myocardial flow response, developed when the left circumflex coronary artery was occluded in the presence of the stenosed left anterior descending coronary artery.     

Reduction of systolic coronary blood flow in experimental left ventricular outflow tract obstruction

In aortic valvular stenosis, coronary reserve has been shown to be markedly diminished despite normal coronary arteries. To gain further insight into this phenomenon, we examined the effects of an acute subaortic valvular obstruction on coronary blood flow (CBF) in seven open-chest anesthetized dogs. Transient subaortic obstruction was produced by inflating a catheter-tip balloon in the left ventricular (LV) outflow tract. The degree of obstruction, a 26 +/- 3 mm Hg gradient across the aortic valve, was adjusted to achieve an elevation of LV pressure while maintaining a constant aortic pressure (coronary perfusion pressure). In seven dogs with intact coronary vasomotor tone, systolic left anterior descending CBF decreased from 20 +/- 9 ml/min during the control period to 13 +/- 3 ml/min during subaortic obstruction (p less than 0.001). Diastolic CBF increased from 52 +/- 9 to 58 +/- 10 ml/min (p less than 0.05), and total CBF remained unchanged. In three dogs with maximal coronary vasodilation, systolic CBF decreased during subaortic obstruction, diastolic CBF remained unchanged, and total CBF decreased. The present data suggest that elevation of LV intracavitary pressure above coronary perfusion pressure can reduce systolic CBF and lead to an autoregulatory compensation that taxes coronary flow reserve.     

Coronary alpha-adrenergic tone and contraction of ischemic myocardium in awake dog

The effect of neurogenic coronary vasomotor tone upon contraction in ischemic myocardium was investigated in awake, mongrel dogs. The animals were chronically instrumented with a hydraulic occluder around the left circumflex coronary artery; a small catheter was also implanted within the vessel. Ultra-sound crystal pairs were placed distal to the occluder in myocardium perfused by the left circumflex artery. Pacing electrodes were sutured onto the right ventricular conus. During the experiment (n = 6) the occluder was inflated to stenose the vessel; the imposition of cardiac pacing (210/min) in conjunction with this stenosis resulted in depressed contraction of the myocardium distal to the occluder as assessed by the ultra-sound crystals: Segmental shortening decreased to 45.4 +/- 5.4% of unpaced control. Phentolamine, an alpha-antagonist, was then infused into the left circumflex catheter for ten minutes (0.1 mg/min) and the experiment repeated. After the alpha-blockade the combination of coronary stenosis and heart rate pacing decreased segmental shortening to only 84.6 +/- 10.1% of control, which was significantly (P less than 0.01) improved relative to the unblocked condition. In another experiment (n = 4), a less severe stenosis was imposed upon the left circumflex vessel. During pacing, muscle shortening decreased to 94 +/- 8.5% of control. Infusion of phenylephrine, an alpha-agonist, for ten minutes (0.1 mg/min) resulted in a 56.7 +/- 5.9% decrease in shortening during pacing; this was significantly greater (P less than 0.01) than the previous decrease. These data indicate that coronary alpha-adrenergic tone can significantly compromise regional myocardial function even in ischemic muscle whose coronary blood flow reserve has been exhausted.     

The effect of coronary artery lesions on the relationship between coronary perfusion pressure and myocardial blood flow during cardiopulmonary resuscitation in pigs

In subjects without coronary disease, coronary perfusion pressure generated with closed-chest cardiopulmonary resuscitation (CPR) bears a direct relationship to myocardial blood flow. The effect of coronary lesions on this relationship was studied in an experimental porcine model not requiring thoracotomy. Coronary stenoses (a 50% reduction in coronary cross-sectional area) or total coronary occlusions were created by percutaneous, transarterial catheter placement of a Teflon cylinder in the left anterior descending artery of 21 swine (30 to 60 kg). Coronary perfusion pressure, defined as the aortic diastolic pressure minus right atrial diastolic pressure, was correlated with myocardial blood flow measured with nonradioactive, colored microspheres during external chest compression CPR. Complete occlusion of the left anterior coronary artery resulted in essentially no CPR-generated blood flow to the anterior myocardium distal to the site of occlusion. Coronary perfusion pressure showed a positive correlation with myocardial blood flow above the area of occlusion (r = 0.783; p less than 0.01) but did not correlate with myocardial blood flow below the occlusion site (r = 0.239). In the presence of a patent coronary artery stenosis, coronary perfusion pressure correlated with myocardial blood flow both above (r = 0.841; p less than 0.001) and below (r = 0.508; p less than 0.05) the stenosis. During closed-chest CPR producing coronary perfusion pressures between 30 and 60 mm Hg, anterior myocardial blood flow was 109 +/- 16 ml/min/100 gm above a patent stenosis and 66 +/- 13 ml/min/100 gm below the stenosis (p less than 0.005). Over a wide range of coronary perfusion pressures, myocardial blood flow below a coronary lesion was significantly less than that above the lesion. Coronary occlusions and stenoses can substantially affect the amount of CPR-generated coronary perfusion pressure needed to produce distal myocardial blood flow.     

Influence of aortic stenosis on the hemodynamic importance of coronary artery narrowing in dogs without left ventricular hypertrophy

Coronary hemodynamic effects of controlled left ventricular outflow obstruction stimulating aortic valve stenosis were studied in 20 open-chest dogs, with and without graded coronary artery diameter narrowing. Aortic stenosis was regulated so that a mean left ventricular-aortic pressure gradient of 46 +/- 20 mm Hg (mean +/- standard deviation) was created as both heart rate and stroke volume were unchanged. In addition, during aortic stenosis, mean aortic pressure (105 +/- 17 to 84 +/- 15 mm Hg, p less than 0.05) and diastolic pressure time index/systolic pressure time index ratio (1.2 +/- 0.3 to 0.6 +/- 0.2, p less than 0.05) decreased and end-diastolic left ventricular pressure (7 +/- 4 to 14 +/- 6 mm Hg, p less than 0.05) increased. With no coronary narrowing, mean coronary flow increased during aortic stenosis (53 +/- 23 to 62 +/- 23 ml/min) as the percentage of diastolic flow increased (83 +/- 6 to 89 +/- 4) and endocardial/epicardial ratio decreased (1.14 +/- 0.16 to 0.95 +/- 0.24) (all p less than 0.05). Peak reactive hyperemic flow also decreased (168 +/- 85 to 125 +/- 73 ml/min, p less than 0.05). This value with no coronary narrowing was similar to peak hyperemic flow with 60% narrowing without aortic stenosis. With 90% coronary narrowing, mean coronary flow decreased with or without aortic stenosis. Transmural flow distribution also decreased but was lower during aortic stenosis (0.86 +/- 0.19 to 0.61 +/- 0.25, respectively; p less than 0.05). These data suggest that although mean coronary flow is increased during aortic stenosis, endocardial flow may be limited, and coronary reserve exposed during reactive hyperemia appears decreased. When a coronary artery is narrowed, aortic stenosis has an even more important hemodynamic influence on the coronary circulation.     

Regional myocardial blood flow and left ventricular diastolic properties in pacing-induced ischemia

The relation between left ventricular diastolic abnormalities and myocardial blood flow during ischemia was studied in eight open chest dogs with critical stenoses of the proximal left anterior descending and circumflex coronary arteries. The heart was paced at 1.7 times the heart rate at rest for 3 min. In dogs with coronary stenoses, left ventricular end-diastolic pressure increased from 8 +/- 1 to 14 +/- 2 mm Hg during pacing tachycardia (p less than 0.01) and 16 +/- 3 mm Hg (p less than 0.01) after pacing, with increased end-diastolic and end-systolic segment lengths in the ischemic regions. Left ventricular diastolic pressure-segment length relations for ischemic regions shifted upward during and after pacing tachycardia in dogs with coronary stenoses, indicating decreased regional diastolic distensibility. In dogs without coronary stenoses, the left ventricular diastolic pressure-segment length relation was unaltered. Pacing tachycardia without coronary stenoses induced an increase in anterograde coronary blood flow (assessed by flow meter) in both the left anterior descending and circumflex coronary arteries, and a decrease in regional vascular resistance. In dogs with coronary stenoses, regional vascular resistance before pacing was decreased by 18%; myocardial blood flow (assessed by microspheres) was unchanged in both the left anterior descending and circumflex coronary artery territories. During pacing tachycardia with coronary stenoses, regional coronary vascular resistance did not decrease further; subendocardial myocardial blood flow distal to the left anterior descending coronary artery stenosis decreased (from 1.03 +/- 0.07 to 0.67 +/- 0.12 ml/min per g, p less than 0.01), as did subendocardial to subepicardial blood flow ratio (from 1.04 +/- 0.09 to 0.42 +/- 0.08, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary microcirculatory vasoconstriction during ischemia in patients with unstable angina

OBJECTIVE: To verify the behavior of coronary microvascular tone during spontaneous ischemia in patients with unstable angina (UA). BACKGROUND: In UA, the pathogenetic role of vasoconstriction is classically confined at the stenotic coronary segment. However, microcirculatory vasoconstriction has been also suggested by previous experimental and clinical studies. METHODS: The study included 10 patients with UA (recent worsening of anginal threshold and appearance of angina at rest) and single-vessel CAD. Blood flow velocity was monitored by a Doppler catheter in the diseased artery. Transstenotic pressure gradient was monitored by aortic and distal coronary pressure monitoring. Stenosis resistance was calculated as the ratio between pressure gradient and blood flow, microvascular resistance as the ratio between distal pressure and blood flow. Measurements were obtained at baseline, following intracoronary adenosine (2 mg) and during transient ischemia. Aortic and distal coronary pressures were also measured during balloon coronary occlusion. RESULTS: Adenosine did not affect stenosis resistance, while it decreased (p < 0.05) microvascular resistance to 52 +/- 22% of baseline. Angina and ischemic ST segment shift were associated with transient angiographic coronary occlusion in 7 of 10 patients; however, in no case was ischemia associated with interruption of flow. Despite markedly different flow values, distal coronary pressure was similar during adenosine and during spontaneous ischemia (48 +/- 15 vs. 46 +/- 20 mm Hg, respectively, NS). During ischemia, a marked increase in the resistance of both coronary stenosis and coronary microcirculation was observed (to 1,233% +/- 1,298% and 671% +/- 652% of baseline, respectively, p < 0.05). Distal coronary pressure was markedly reduced during balloon coronary occlusion (14 +/- 7 mm Hg, p < 0.05 vs. both adenosine and ischemia), suggesting the absence of significant collateral circulation. CONCLUSIONS: In patients with UA, transient myocardial ischemia is associated with vasoconstriction of both stenotic arterial segment and downstream microcirculation.     

Subepicardial vasodilator reserve in the presence of critical coronary stenosis in dogs

Critical coronary stenosis is the term used to describe obstruction that eliminates reactive hyperemia presumably because downstream arterioles have dilated maximally to compensate for a proximal stenosis. However, evidence of distal vasomotor capacity exists despite the presence of severe constriction. Coronary blood flow in the left circumflex artery and blood pressure in the aorta and distal circumflex artery were studied in six open chest, anesthetized dogs. The circumflex artery was obstructed sufficiently to eliminate 95 to 98 percent of reactive hyperemia, but resting coronary blood flow was not reduced. The regional distribution of myocardial blood flow was studied with tracer microspheres (diameter 15 μm) before and after intracoronary injection of adenosine (5 μmoles) and after the release of a 15 to 20 second occlusion. The subendocardial to subepicardial ratio of flow in the obstructed bed was not changed by the stenosis (ratio 1.23 ± 0.10 [mean ± standard error of the mean] versus 1.28 ± 0.07, difference not significant). Administration of adenosine decreased subendocardial flow from 0.95 ± 0.07 to 0.73 ± 0.08 ml/min per g (p < 0.001) and increased subepicardial flow from 0.76 ± 0.04 to 1.31 ± 0.08 ml/min per g (p < 0.001); the subendocardial to subepicardial blood flow ratio decreased to 0.58 ± 0.06 (p < 0.001). After the release of the temporary occlusion, subendocardial flow decreased and subepicardial flow increased a comparable amount and the subendocardial to subepicardial ratio decreased to 0.55 ± 0.07 (p < 0.001). Circumflex coronary blood flow measured simultaneously with use of an electromagnetic flowmeter increased from 29 ± 2 to approximately 35 ml/min (p < 0.01). Thus, arteriolar vasodilator reserve persists in the presence of proximal critical stenosis, but the vasomotor capacity is limited primarily to the outer layers of the myocardium.     

The effect of an increase in heart rate on remote myocardial blood flow in a two vessel coronary stenosis-occlusion model

The effect of a moderate increase in heart rate on regional blood flow (8-10 mu radiolabeled microspheres) to myocardium supplied by a stenosed left circumflex coronary artery with (n = 11) or without (n = 7) concomitant left anterior descending coronary artery occlusion was investigated in anesthetized mongrel dogs. In the presence of a left circumflex coronary artery stenosis (gradient 32 +/- 5 mmHg [x +/- SEM]) and an unstenosed left anterior descending coronary artery a pacing-induced rise in heart rate (22 +/- 1 beats/min) increased epicardial flow to the posterior wall supplied by the left circumflex coronary artery (+0.21 +/- 0.08 mL/min/g, p = 0.03). Posterior bed endocardial flow was unchanged (-0.03 +/- 0.08 mL/min/g, p = 0.76). In dogs with a left circumflex coronary artery stenosis of similar severity (gradient 34 +/- 4 mmHg), left anterior descending coronary occlusion did not significantly alter posterior bed endocardial or epicardial flow. Atrial pacing increased heart rate by 22 +/- 1 beats per minute and caused remote posterior bed endocardial flow to fall (-0.08 +/- 0.03 mL/min/g, p = 0.03). Epicardial flow to that region rose (+0.09 +/- 0.02 mL/min/g, p less than 0.0002). Thus, a moderately severe coronary stenosis prevents the expected increase in endocardial flow normally seen after an increase in heart rate. Remote bed endocardial flow actually falls when heart rate is increased in the presence of an occlusion in a second major coronary artery.     

Collateral conductance changes during a brief coronary occlusion in awake dogs

Function of the coronary collateral circulation during the course of a single abrupt coronary occlusion was evaluated in awake dogs instrumented over the long term. Studies were performed approximately 2 weeks after collateral development had been stimulated in the dogs by partial stenosis of the proximal left circumflex coronary artery. The pressure drop from the central aorta to the distal circumflex coronary artery was measured continuously. Under control conditions and at 30 sec and 4 min of a single abrupt complete circumflex occlusion, myocardial blood flow was determined by a radioactive microsphere technique. Coronary collateral conductance was calculated as mean collateral blood flow divided by the mean drop in pressure. The following was noted in dogs that developed collateral vessels: during the coronary occlusion, mean distal circumflex coronary pressure increased from 42 +/- 9 to 49 +/- 10 mm Hg (p less than or equal to .01); mean collateral flow increased from 0.78 +/- 0.30 to 0.84 +/- 0.33 ml/min/g (p less than or equal to .05); the endocardial/epicardial flow ratio increased from 0.77 +/- 0.36 to 1.04 +/- 0.25 (p less than or equal to .01); and the coronary collateral conductance increased significantly from 0.017 +/- 0.017 to 0.021 +/- 0.021 (ml/min/g)/mm Hg (p less than or equal to .005). These data suggest that during a brief occlusion of a major coronary artery, immature coronary collateral channels do not reach maximal function immediately after the occlusion. Rather, coronary collateral conductance increases with time and may be associated with improved transmural perfusion of the myocardium.     

Effects of acute coronary occlusion on hemodynamics in an adjacent coronary artery in dogs

The effects of acute occlusion of 1 coronary artery on flow responses in another were studied in 24 open-chest dogs. Left circumflex (LC) flow was measured with and without LC stenoses before and during reactive hyperemia. In 19 dogs the left anterior descending artery (LAD) was occluded and measurements were repeated after 1 hour (group 1). Four dogs had measurements before and after 1 hour without LAD occlusion (group 2). In group 2 no systemic, left ventricular (LV) or coronary hemodynamic changes were observed after 1 hour. In group 1, an hour after LAD occlusion, heart rate and aortic pressure had not changed but stroke volume decreased slightly (-8 +/- 7%, mean +/- SD, p = not significant) and LV end-diastolic pressure had increased (2 +/- 3 mm Hg, p less than 0.05). Basal LC flow was not changed by less than 90% LC stenosis. Ninety percent LC stenosis decreased LC flow both before and after LAD occlusion. During reactive hyperemia without LC stenosis, LC flow decreased after LAD occlusion in 15 of 19 dogs (from 154 +/- 80 to 141 +/- 75 ml/min, p less than 0.05). With 60 and 80% LC stenoses, LC flow during reactive hyperemia decreased before LAD occlusion (110 +/- 62 and 74 +/- 40 ml/min, respectively), but decreased further (both p less than 0.05) after LAD occlusion (98 +/- 54 and 63 +/- 43 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of adenosine in the maintenance of coronary vasodilation distal to a severe coronary artery stenosis. Observations in conscious domestic swine

The purpose of this study was to test the hypothesis that adenosine is required to maintain arteriolar vasodilation distal to a severe coronary stenosis. Eight closed-chest conscious pigs were prepared by placing a 7.5-mm long stenosis (82% lumenal diameter reduction) in the proximal left anterior descending coronary artery. Regional myocardial blood flow (microsphere technique) was measured at control 1, after 10 minutes of intracoronary infusion of adenosine deaminase (7-10 U/kg per min) distal to the stenosis, and 20-30 minutes after stopping adenosine deaminase infusion. Studies with 125I-labeled adenosine deaminase were conducted in six additional pigs to document the extent to which infused adenosine deaminase penetrated the interstitial space. 125I-labeled adenosine deaminase was infused for 10 minutes (10-11 U/kg per min) into the left anterior descending coronary artery. Calculated interstitial fluid concentrations of adenosine deaminase ranged between 71 and 272 U/ml and were at least one order of magnitude greater than that required to deaminate all the adenosine which would be released into the interstitium in response to 15-30 seconds of coronary occlusion. In the primary group of animals (n = 8), endocardial flow (ml/min per g) distal to stenosis at control 1 (1.15 +/- 0.33) was reduced vs. endocardial flow in the nonobstructed circumflex zone (1.59 +/- 0.38, P less than 0.05). Flows in epicardial layers were comparable at control 1 (distal zone = 1.40 +/- 0.36 vs. circumflex zone = 1.45 +/- 0.41). Distal zone endocardial and epicardial flows did not change vs. control 1 in response to infusion of adenosine deaminase. However, the distal: circumflex epicardial flow ratio declined vs. control 1 (0.98 +/- 0.14) during adenosine deaminase infusion (0.87 +/- 0.17, P less than 0.05). The distal:circumflex endocardial flow ratio during adenosine deaminase (0.72 +/- 0.20) was unchanged vs. control 1 (0.76 +/- 0.22) but was less than control 2 (0.80 +/- 0.18, P less than 0.05). Thus, destruction of all or most interstitial adenosine caused only slight relative reduction in regional myocardial blood flow distal to a severe coronary artery stenosis. Accordingly, adenosine contributes only modestly to maintenance of arteriolar vasodilation in this setting or else its absence is almost fully compensated for by another mechanism(s).     

Effect of beta-adrenergic suppression by propranolol on coronary collateral development in response to chronic coronary ischemia in dogs.

Acute left circumflex coronary artery (LC) occlusion in conscious dogs caused marked ischemia in the myocardium supplied by the occluded artery, as judged by the radioactive microsphere technique for determining blood flow distribution. With the chest open, LC pressure distal to the occlusion fell to 21 +/- 1.9% of aortic pressure. By 8 weeks after gradual LC occlusion with an ameroid constrictor, collateral development had restored coronary blood flow distribution to near-normal under basal conditions and during pacing, at a heart rate of 200 beats/min. The only evidence for ischemia was in the subepicardium within the distribution of the unoccluded left anterior descending artery, which provided the extra collateral blood flow. Distal LC pressure was 70 +/- 1.7% of aortic pressure. Propranolol 160 mg orally every 6 hours for 8 weeks had no detectable effect on coronary collateral development, as judged by blood flow distribution or distal LC pressure. The only significant difference for the propranolol dogs was a slight transmural shift away from the subendocardium in the left anterior descending region.     

Effects of nitroglycerin-induced hypotension on myocardial blood flow in a two vessel occlusion-stenosis anesthetized canine model

The effects of acute occlusion of the left anterior descending coronary artery on regional blood flow (microspheres) to the remote bed supplied by either an unstenosed or a stenosed circumflex coronary artery were assessed during the infusion of intravenous nitroglycerin in 11 open chest barbiturate-anesthetized mongrel dogs. Left anterior descending coronary artery occlusion in the presence of an unstenosed left circumflex artery during nitroglycerin infusion caused systolic aortic and distal circumflex pressure to decrease significantly from 98 +/- 4 to 91 +/- 3 and from 99 +/- 4 to 92 +/- 3 mm Hg, respectively. Remote circumflex bed flow was unchanged. The infusion of intravenous nitroglycerin in the presence of a left circumflex stenosis (gradient 31 +/- 3 mm Hg) reduced systolic aortic and distal circumflex pressure to 98 +/- 2 (p = 0.001) and 71 +/- 4 mm Hg (p = 0.001), respectively, and lowered remote circumflex bed endocardial flow from 1.00 +/- 0.08 to 0.79 +/- 0.07 ml/min per g (p = 0.001). When the left anterior descending coronary artery was occluded under these conditions, systolic aortic and distal left circumflex pressure decreased to 89 +/- 3 (p = 0.005) and 62 +/- 4 mm Hg (p = 0.08), respectively. Remote circumflex artery bed endocardial and transmural flow were significantly reduced to 0.58 +/- 0.07 (p = 0.01) and 0.65 +/- 0.07 ml/min per g (p = 0.03), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relationships of high energy phosphates, tissue pH, and regional blood flow to diastolic distensibility in the ischemic dog myocardium

Myocardial ischemia due to increased oxygen demand (pacing tachycardia plus critical coronary stenoses) alters diastolic distensibility and relaxation more than ischemia of comparable duration due to coronary occlusion. To investigate the relationship between myocardial diastolic function and metabolism, we compared myocardial high energy phosphate content, tissue pH, and regional blood flow for these two types of ischemia in anesthetized open-chest dogs. Myocardial biopsies were done with a high-speed air-turbine biopsy drill, permitting rapid (less than 1-second) freezing of tissue samples from both nonischemic and ischemic areas, while myocardial pH was measured with a hydrogen ion-selective polymer membrane implanted in the subendocardium. After 3 minutes of pacing tachycardia in dogs with critical coronary stenoses (demand-type ischemia, n = 14), regional systolic function (% segment shortening by ultrasonic crystals) was mildly depressed (from 19 +/- 2% control to 13 +/- 2% post-pacing, P less than 0.01), while left ventricular diastolic pressure-segment length relations shifted upward, indicating decreased distensibility of the ischemic myocardial segment. Associated with these changes in function, subendocardial adenosine triphosphate decreased (from 31.3 +/- 1.5 to 27.9 +/- 1.0 nmol/mg protein, P less than 0.01), as did creatine phosphate (53.8 +/- 2.1 to 39.6 +/- 2.5 nmol/mg protein, P less than 0.01), while myocardial pH declined slightly (delta pH = -0.14 +/- 0.02, P less than 0.01). In contrast, at 3 minutes of coronary artery occlusion (primary ischemia, n = 14), regional segment shortening was replaced by systolic bulging (% shortening decreased from 17 +/- 2% to -2 +/- 1% during occlusion, P less than 0.01), while left ventricular pressure-segment length relations were not shifted upward, and there was no decrease in diastolic distensibility of the ischemic segment. With coronary artery occlusion, subendocardial adenosine triphosphate declined slightly (33.2 +/- 0.5 to 29.2 +/- 2.0 nmol/mg, P less than 0.05), while creatine phosphate decreased substantially (51.1 +/- 2.3 to 7.8 +/- 1.4 nmol/mg protein, P less than 0.01). Myocardial pH fell strikingly (delta pH = -0.33 +/- 0.03, P less than 0.01), and the decline was 236% of that seen with demand-type ischemia. Regional myocardial blood flow (microsphere technique) showed a decreased endocardial:epicardial (endo:epi) ratio (1.04 +/- 0.04 control vs. 0.40 +/- 0.05 during pacing, P less than 0.01) and absolute subendocardial flow (1.02 +/- 0.47 to 0.47 +/- 0.05 ml/min per g, P less than 0.01) with demand-type ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)     

Acute coronary occlusion: prolonged increase in collateral flow following brief administration of nitroglycerin and methoxamine.

Regional coronary blood flow was determined with the radioactive microsphere technique 10 an 70 minutes and 2 1/2 and 5 hours after abrupt occlusion of the left anterior descending coronary artery in 12 closed chest sedated dogs. In six dogs, nitroglycerin, 200 to 400 microng/min, was infused intravenously 10 to 70 minutes after occlusion. Methoxamine was administered to return blood pressure and heart rate to prenitroglycerin levels. Ten minutes after occlusion (before treatment) collateral flow values and ischemic zone endocardial/epicardial flow ratios were equivalent in untreated (0.11+/-0.03 ml/min per g; 0.31+/-0.05) and treated dogs (0.14+/-0.02 ml/min per g; 0.29+/-0.03). In untreated dogs, collateral flow did not change over 5 hours; the endocardial/epicardial flow ratio was decreased at 5 hours (0.21+/-0.05, P less than 0.05). In contrast, in treated dogs, collateral flow and the endocardial/epicardial flow ratio were increased at 70 minutes (0.27+/-0.04 ml/min per g, P less than 0.05; 0.53+/-0.10, P less than 0.05). Most importantly, collateral flow remained elevated 5 hours after occlusion (0.26+/-0.03 ml/min per g, P less than 0.05) although treatment was discontinued 70 minutes after occlusion. Hence, collateral flow was unchanged over 5 hours of occlusion in untreated dogs, but short-term treatment with nitroglycerin and methoxamine resulted in a sustained increase in collateral flow. These findings may be a result of stimulation by nitroglycerin and methoxamine of the spontaneous rate at which intrinsic collateral function increases after ischemia. Alternatively, nitroglycerin and methoxamine may maintain cell viability until collateral vessels develop spontaneously.