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)     

Effects of H1-receptor stimulation on coronary arterial diameter and coronary hemodynamics in humans

Effects of H1-receptor stimulation on coronary arterial diameter and coronary hemodynamics were examined in 11 patients with angiographically normal coronary arteries and without variant angina or resting angina. Selective H1-receptor stimulation was achieved by infusing histamine into the left coronary artery at a rate of 2.0 micrograms/min for 5 minutes after pretreatment with cimetidine (25 mg/kg). Plasma histamine concentration in the coronary sinus, coronary sinus blood flow, heart rate, and aortic pressure were measured before, during, and after the histamine infusion. Coronary arterial diameter was measured by cinevideodensitometric analysis of coronary arteriograms performed before and immediately after the histamine infusion. During the histamine infusion, plasma histamine concentration in the coronary sinus increased from 0.33 +/- 0.06 to 5.86 +/- 0.71 ng/ml (p less than 0.01); coronary sinus blood flow increased from 98 +/- 12 to 124 +/- 13 ml/min (p less than 0.01), and coronary vascular resistance decreased from 1,113 +/- 117 to 851 +/- 91 mm Hg.min/l (p less than 0.01). Heart rate and aortic pressure remained unchanged. The mean luminal diameters of the proximal, middle, and distal left anterior descending artery increased by 9.4 +/- 3.6% (p less than 0.05), 19.2 +/- 3.8% (p less than 0.001), and 31.5 +/- 5.6% (p less than 0.001), respectively, after the histamine infusion. The mean luminal diameters of the proximal, middle, and distal left circumflex artery increased by 15.2 +/- 3.6% (p less than 0.01), 17.5 +/- 5.2% (p less than 0.01), and 20.6 +/- 4.3% (p less than 0.001), respectively, after the histamine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of previous myocardial infarction on measurements of reactive hyperemia and the coronary vascular reserve

The measurement of coronary vascular reserve by the reactive hyperemic response to ischemia has been advocated as a practical method of assessing the physiologic significance of coronary stenoses. Because the concept of measuring coronary blood flow during maximal vasodilation assumes a normal arteriolar network and viable myocardium, the presence of previous myocardial infarction may cause a significant decrease in the coronary reserve unrelated to the severity of a coronary stenosis itself. To determine the potential importance of this effect, rest and hyperemic coronary blood flow were measured in 14 dogs in the regions subtended by the left anterior descending and left circumflex coronary arteries. One hour occlusion of the left anterior descending artery followed by reperfusion was performed in 10 dogs; the 4 remaining dogs in which no occlusion was performed served as control animals (group 3). One week later, rest and hyperemic blood flow measurements were repeated in all 14 dogs. Of the 10 dogs undergoing left anterior descending artery occlusion, 5 had a large infarct (group 1) and 5 had a small infarct (group 2). In group 1 in the 1 week study, both the coronary reserve in the left anterior descending artery zone and the ratio of the coronary reserve in this zone and the left circumflex artery zone decreased compared with values before occlusion (from 425 +/- 134 to 150 +/- 34% and from 1.56 +/- 0.40 to 0.68 +/- 0.31, respectively; both p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiologic basis for assessing critical coronary stenosis: Instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve

Quantitative hemodynamic assessment of coronary stenosis has not been previously reported. Resting coronary blood flow and its regional distribution are insensitive indexes for determining critical stenosis, but flow response to a hyperemic stimulus quantifies restrictions on maximal flow due to coronary arterial lesions. Coronary flow responses to temporary occlusion and to selective main coronary arterial injection of sodium diatrizoate (Hypaque-M 75 percent) were studied in 12 consecutive dogs with a surgically implanted electromagnetic flowmeter and separate micrometer constrictor on the left circumflex coronary artery. Selective Hypaque injection adequate for coronary cineangiography increased coronary flow to four times the resting base-line value, peaking at 6 seconds and lasting 3 minutes, a response equivalent to hyperemia after 10 seconds of circumflex arterial occlusion. With progressive micrometer constriction, resting flow measurements did not decrease until there was 85 percent stenosis. Hyperemia after intracoronary injection of Hypaque decreased when there was 30 to 45 percent stenosis and disappeared when there was 88 to 93 percent stenosis. Myocardial images obtained by gamma camera after left atrial injection of ¹³¹iodine-macroaggregated albumin demonstrated uniform regional distribution of resting flow in spite of severe constriction. However, 6 seconds after selective Hypaque injection, left atrial injection of ^99mtechnetium macroaggregates demonstrated distinct perfusion abnormalities in the region of circumflex stenosis. Thus, flow distribution with a severe lesion was normal at rest but showed marked differences due to restricted circumflex versus normal anterior descending hyperemic response after injection of Hypaque. Flow response and regional distribution during coronary hyperemia caused by Hypaque are quantitative measures for physiologically assessing critical coronary stenosis and flow reserve with potential applicability to patients.     

Effects of selectively altering collateral driving pressure on regional perfusion and function in occluded coronary bed in the dog

To determine whether selectively altering the coronary perfusion pressure in the adjacent nonoccluded vessel has any influence on the occluded bed, the effects of alterations in the perfusion pressure of the left anterior descending coronary artery on the perfusion and function of the acutely occluded left circumflex coronary (LC) arterial bed were studied in 10 anesthetized open-chest dogs. Radiolabelled microsphere-assessed regional myocardial perfusion and endocardial excursion determined by two-dimensional echocardiography were measured during control conditions prior to mid-LC occlusion with left anterior descending coronary arterial pressure (LADP) equal to aortic pressure (AoP) (Stage 0) and to 3 randomly performed postocclusion stages. At each postocclusion stage, the perfusion territory of the occluded LC bed (area at risk) was measured in vivo using myocardial contrast two-dimensional echocardiography. During Stage 1 (LADP = AoP), area at risk was 5.1 +/- 0.9 cm2 (x +/- 1 SD) and transmural blood flow to the LC arterial bed decreased from 0.96 +/- 0.50 ml/min/g (Stage 0) to 0.16 +/- 0.12 ml/min/g (p less than 0.01), while endocardial excursion decreased from 28.0 +/- 9.0% to 2.0 +/- 10.0% (p less than 0.01). During Stage 2 (LADP greater than AoP), area at risk decreased to 4.4 +/- 1.0 cm2 compared with Stage 1 (p less than 0.01), and transmural blood flow, endocardial:epicardial blood flow ratio, and endocardial excursion increased to 0.51 +/- 0.39 ml/min/g, 0.64 +/- 0.20, and 14 +/- 6%, respectively (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Dissociation of diastolic pressure-segment length and pressure-wall thickness relations during vasodilation in the conscious dog

The effects of pharmacologic vasodilation and reductions in circumflex coronary artery pressure on the ventricular diastolic pressure-segment length and pressure-wall thickness relations were studied in nine conscious dogs equipped with an inflatable cuff on the proximal circumflex artery, a micromanometer in the left ventricle and four sets of piezoelectric crystals to measure wall thickness and endocardial segment length in the left circumflex and left anterior descending artery territories. Adenosine infusion into the circumflex coronary artery increased endocardial and transmural blood flow to that territory (measured by microspheres) by 436% and 487%, respectively (both p less than 0.05), and shifted the left circumflex artery territory pressure-wall thickness curve upward (p less than 0.05) without affecting the circumflex pressure-segment length, the left anterior descending artery territory pressure-segment length or pressure-wall thickness curves significantly; papaverine also shifted the circumflex region pressure-wall thickness curve upward (p less than 0.05). Both with and without vasodilation, moderate reductions in circumflex artery perfusion pressure did not affect the position of the ventricular pressure-wall thickness or the pressure-segment length curve (although during adenosine infusion endocardial blood flow decreased from 436% to approximately 100% of control values). More severe reductions in perfusion pressure (less than 45 mm Hg under control conditions and less than 30 mm Hg during adenosine infusion) decreased coronary blood flow below control values and caused a marked downward shift of the circumflex region pressure-segment length curve without affecting the position of the pressure-wall thickness curve.(ABSTRACT TRUNCATED AT 250 WORDS)     

Parasympathetic coronary vasoconstriction induced by nicotine in conscious calves

We studied the effects of intracoronary injection of nicotine and acetylcholine on coronary blood flow in nine conscious calves chronically instrumented to measure coronary blood flow, left ventricular (LV) and mean arterial pressure, LV dP/dt, and heart rate. Nicotine (5 micrograms/kg i.c.) elicited a biphasic response in coronary blood flow consisting of an initial vasoconstriction (phase 1; blood flow fell by 52 +/- 5.4% from a baseline of 66 +/- 7.5 ml/min) followed by vasodilation (phase 2, blood flow rose 119 +/- 12.7% above baseline). The change in coronary blood flow with nicotine was not associated with changes in LV systolic pressure, mean arterial pressure, or heart rate. The change in coronary blood flow was unaffected by combined alpha- and beta-adrenoceptor blockade with prazosin, rauwolscine, and propranolol but was abolished by either muscarinic blockade with atropine or ganglionic blockade with hexamethonium. Acetylcholine (0.5 microgram/kg i.c.), without affecting mean arterial pressure, elicited changes in coronary blood flow similar to those observed with nicotine, producing an initial phase of coronary vasoconstriction (blood flow fell by 71 +/- 4.9%) followed by vasodilation (blood flow rose by 228 +/- 20.7%). Both phases of the response to acetylcholine were abolished by muscarinic blockade but were unaffected by ganglionic blockade. When nicotine was injected into the left circumflex coronary artery, no change in blood flow was observed in the left anterior descending coronary artery, indicating the lack of involvement of global reflex pathways. These results suggest that nicotine locally stimulates parasympathetic nerves, which constrict the coronary circulation via a muscarinic mechanism.     

Effect of diltiazem on coronary reactive hyperemia in patients with flow-limiting coronary artery stenosis

The acute effects of diltiazem on coronary reactive hyperemia were studied in 12 patients with flow-limiting coronary stenosis. Reactive hyperemia was elicited by injection of 8 ml contrast medium into the left coronary artery, while coronary sinus blood flow and left ventricular and aortic pressures were continuously recorded. Relative magnitude of hyperemia was estimated by the ratio of coronary flow at peak hyperemia to baseline flow (hyperemic ratio). Coronary resistance was calculated as the ratio between mean aortic pressure minus left ventricular mean diastolic pressure and coronary sinus blood flow. The 12 patients studied had flow-limiting coronary stenosis since their hyperemic ratio was significantly restrained when compared to that of seven control subjects (1.45 +/- 0.17 vs 2.02 +/- 0.24, respectively; p less than 0.001). The intravenous infusion of diltiazem (0.30 mg X kg-1) reduced heart rate, mean aortic pressure, and myocardial oxygen consumption (all p less than 0.001). After diltiazem the hyperemic ratio was blunted when compared to the basal state (1.36 +/- 0.15 vs 1.45 +/- 0.17, respectively; p less than 0.05), and hyperemia volume was reduced (-33%; p less than 0.001). The decrease in coronary resistance at peak hyperemia was also reduced from -30 +/- 8% to -25 +/- 8% (p less than 0.05). We conclude that diltiazem blunts coronary reactive hyperemia in patients with demonstrated flow-limiting coronary stenosis. This reduction of coronary flow response to a hyperemic stimulus could favorably influence blood flow distribution in patients with significant coronary stenosis.     

The effect of arginine vasopressin on endothelin production in the human forearm vascular bed

OBJECTIVES: To study whether arginine vasopressin (AVP) can stimulate endothelin production and/or release in vivo, in the human forearm vasculature. DESIGN: The effect of the infusion of AVP into the brachial artery on endothelin production across the human forearm vascular bed was studied in healthy male volunteers, and was compared with intra-arterial infusion of placebo. In another group the effects of AVP on endothelin production were studied after a prior infusion of L-NG-monomethyl-arginine (L-NMMA), a nitric oxide-synthase inhibitor. In a fourth group the effect of L-NMMA alone, without AVP infusion, on endothelin production was studied. METHODS: We measured the effects of AVP, placebo, L-NMMA followed by AVP and L-NMMA followed by placebo on arterial and venous endothelin concentrations in the forearm of four groups, each consisting of five healthy male volunteers. Forearm blood flow was measured by strain gauge plethysmography. The endothelin production was calculated as forearm blood flow times (venous - arterial) endothelin concentration. RESULTS: The group infused with L-NMMA followed by infusion of 8 ng AVP/min per dl forearm volume showed a significant rise in endothelin production from 1.3 (1.8) to 5.0 (2.0) pg/min/dl at 15 minutes (p<0.05, ANOVA). This rise in endothelin production was also significantly different from the endothelin production at 15 minutes in the other three groups (p<0.01, ANOVA). CONCLUSION: In healthy male volunteers intra-arterial infusion of AVP induced a rise in endothelin production in the forearm within 15 minutes, but only after prior infusion of L-NMMA. This observation suggests that the AVP-induced production of nitric oxide offsets AVP-mediated release of endothelin.     

Mechanism of remote myocardial ischaemia after coronary occlusion in open chest dogs

To determine whether or not the fall in coronary perfusion pressure after coronary occlusion is the cause of remote myocardial ischaemia, regional myocardial blood flow was measured using radiolabelled microspheres before and after left anterior descending (LAD) occlusion in the presence of a left circumflex artery stenosis in 22 anaesthetised dogs. Aortic pressure was maintained constant at the time of left anterior descending artery occlusion in 13 dogs (group 1) and proximal left circumflex artery pressure was held constant by a servocontrolled pump in nine dogs with a carotid artery-left circumflex artery shunt (group 2). Despite the maintenance of constant mean aortic pressure in group 1, remote posterior bed mean(SEM) endocardial flow fell from 0.69(0.05) to 0.43(0.07) ml.min-1.g-1 (p less than 0.05). In the dogs in which left atrial pressure rose to less than or equal to 9 mmHg after left anterior descending artery occlusion, remote bed endocardial flow did not fall significantly (0.66(0.07) to 0.56(0.11) ml.min-1.g-1; NS). In contrast, remote bed endocardial flow fell from 0.73(0.07) to 0.28(0.06) ml.min-1.g-1 (p less than 0.0001) after left anterior descending artery occlusion in the dogs in which left atrial pressure rose to greater than 9 mmHg. The fall in remote bed endocardial flow was prevented in group 2 dogs by maintaining proximal left circumflex artery pressure constant (0.95(0.08) to 0.86(0.09) ml.min-1.g-1; NS). An important mechanism for the development of remote myocardial ischaemia appears to be the fall in proximal coronary perfusion pressure at the time of coronary occlusion.     

The thromboxane A2 mimetic U46619 worsens canine myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis.

OBJECTIVE: The aim was to test the hypothesis that thromboxane A2 can cause vasoconstriction of coronary resistance vessels during exercise in hypoperfused regions of myocardium distal to an arterial stenosis. METHODS: Eight adult mongrel dogs were studied. Chronically instrumented animals with a left circumflex coronary artery Doppler flow meter, hydraulic occluder, and indwelling catheter underwent treadmill exercise at heart rates of 190-200 beats.min-1. Myocardial blood flow was measured with microspheres during unimpeded arterial inflow and in the presence of a coronary stenosis which decreased distal pressure to 42-45 mm Hg. Measurements were repeated during infusion of the thromboxane A2 analogue, U46619. RESULTS: When the occluder was partially inflated to produce a stenosis, blood flow in the region perfused by the stenotic artery was 58 (SEM 6)% of flow in the normally perfused region (p less than 0.01). U46619 (0.01 microgram.kg-1.min-1) caused a further 21 (7)% decrease in blood flow in the region perfused by the stenotic artery (p less than 0.05). The vasoconstriction produced by U46619 was uniform across the left ventricular wall from epicardium to endocardium. U46619 did not significantly decrease myocardial blood flow in the absence of a coronary stenosis. CONCLUSIONS: Even during hypoperfusion produced by a flow limiting arterial stenosis, the coronary resistance vessels remain responsive to the vasoconstrictor effect of thromboxane A2. Liberation of thromboxane A2 during platelet activation at the site of a proximal coronary stenosis may worsen myocardial hypoperfusion by causing vasoconstriction of the distal resistance vessels.     

Epicardial coronary artery constriction with intravenous ethanol

Although in vitro studies have demonstrated ethanol-induced coronary artery constriction, in vivo reports suggest an ethanol-related coronary dilator effect with increases in coronary blood flow. The principal difference in these studies is the demonstration of epicardial coronary constriction with ethanol, while dilation is described only in resistance vessels. Clinical studies have noted evidence of myocardial ischemia following ethanol ingestion in patients with coronary artery disease, suggesting ethanol-related constriction of diseased epicardial coronary arteries. This study hypothesized that intravenous ethanol would constrict canine epicardial coronary arteries while producing arteriolar resistance vessel dilatation. Ten closed-chest mongrel dogs weighing 24 +/- 1 kg (mean +/- SEM) were given 8 g of ethanol intravenously over 30 min. Left anterior descending and circumflex proximal artery diameters were measured by quantitative coronary angiography; myocardial flow was measured by Xenon washout, and myocardial flow distribution was measured with radioactive microspheres. Baseline proximal left anterior descending and circumflex artery areas were 6.3 +/- 0.5 and 5.8 +/- 0.4 mm2, respectively. Up to 30% left anterior descending and circumflex proximal artery narrowing was noted at 60 and 90 min following ethanol infusion. The constriction was reversed with nitroglycerin. There was a decrease in left anterior descending artery flow but no change in circumflex artery flow at 60 min. Blood ethanol level varied from 520 micrograms/ml initially to 205 micrograms/ml 90 min after the infusion terminated (intoxication = 1500 micrograms/ml). These data suggest that ethanol has significant vasoconstrictor action in vivo on epicardial coronary arteries.     

Delayed myocardial ischemia induced by anger

The objectives of this study were to develop a reproducible behavioral model that simulates the anger state and to characterize its influence on myocardial blood flow in both the normal and compromised coronary circulations. Fourteen mongrel dogs of both sexes were studied. The animals were instrumented for the recording of electrocardiogram, arterial blood pressure, and left circumflex coronary arterial blood flow. A critical level of coronary stenosis was achieved with an adjustable occluder placed just distal to the flow probe. Anger was induced in the instrumented animals by having another dog challenge their access to food. In the absence of coronary artery stenosis, provocation of anger increased heart rate from 107 +/- 6 to 215 +/- 15 beats/min, arterial blood pressure from 95 +/- 4 to 142 +/- 5 mm Hg, and coronary blood flow from 31 +/- 5 to 72 +/- 9 ml/min. These variables returned to the preanger levels within 2 to 4 min. Induction of anger was repeated after a critical stenosis was applied to the left circumflex coronary artery. Anger increased heart rate from 112 +/- 6 to 210 +/- 16 beats/min, arterial blood pressure from 99 +/- 3 to 142 +/- 6 mm Hg, and coronary arterial flow from 23 +/- 5 to 35 +/- 7 ml/min. Within 2 to 4 min after the bout of anger, all dogs exhibited significant reductions in coronary arterial flow (35% of baseline; p less than .001), increases in coronary vascular resistance (557% of baseline; p less than .002), and ischemic ST segment changes in leads II, III, and aVF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serotonin selectively aggravates subendocardial ischemia distal to a coronary artery stenosis during exercise.

BACKGROUND. The coronary circulation has been shown to remain responsive to vasodilator and vasoconstrictor stimuli during myocardial ischemia. Because serotonin possesses both vasodilator and vasoconstrictor properties, we examined its effect in the coronary circulation distal to an arterial stenosis that resulted in myocardial hypoperfusion during exercise. METHODS AND RESULTS. Seven chronically instrumented dogs were studied during treadmill exercise in the presence of a stenosis that reduced distal left circumflex coronary artery perfusion pressure to 42 +/- 1 mm Hg. Myocardial blood flow was assessed with radioactive microspheres during exercise before and during intracoronary infusion of 0.4 and 2.0 micrograms/kg-1.min-1 serotonin. The stenosis was adjusted to maintain distal coronary pressure constant during control exercise and with the two doses of serotonin. In seven dogs, the effect of serotonin (2.0 micrograms/kg-1.min-1) was also studied during exercise with normal arterial inflow. During control exercise, the stenosis decreased mean myocardial blood flow to 45% of flow in the normally perfused region. This decrease was most pronounced in the subendocardium (endocardial/epicardial ratio 0.36 +/- 0.06 versus 1.46 +/- 0.14 in the control region; p < 0.01). With no change in pressure distal to the stenosis, serotonin decreased subendocardial flow from 0.51 +/- 0.09 ml/min-1.g-1 to 0.41 +/- 0.12 (p < 0.05) and then to 0.35 +/- 0.08 ml/min-1.g-1 (p < 0.05) and tended to increase subepicardial flow from 1.47 +/- 0.17 to 1.91 +/- 0.23 and 1.85 +/- 0.21 ml/min-1.g-1 (p = 0.08) during infusions of 0.5 and 2.0 micrograms/kg-1.min-1, respectively, with no change in total arterial inflow. In contrast, in the absence of a stenosis, serotonin (2.0 micrograms/kg-1.min-1) increased subendocardial flow from 2.43 +/- 0.25 to 3.73 +/- 0.25 ml/min-1.g-1 (p < 0.01) and subepicardial flow from 1.88 +/- 0.20 to 5.29 +/- 0.38 ml/min-1.g-1 (p < 0.01). CONCLUSIONS. During normal arterial inflow, serotonin dilated coronary resistance vessels and increased flow to all myocardial layers. During hypoperfusion, a vasodilator response was still present in the subepicardium, but vasoconstriction was then observed in the subendocardium. Our data suggest that serotonin constricts the intramural penetrating arteries, thereby selectively increasing resistance to subendocardial blood flow.     

Effects of prindolol on isoproterenol-induced subendocardial ischaemia in dogs with multiple chronic coronary artery occlusion.

Multiple chronic coronary artery occlusions were produced in dogs by implantation of ameroid rings on the circumflex branches of the left and right coronary artery. Sixty-five per cent of the animals survived. Seventy-seven per cent of the remaining animals had no detectable myocardial infarction. Myocardial blood flow distribution was studied 4 weeks after operation using the tracer microsphere technique. During control conditions myocardial blood flow was homogeneously distributed within the left ventricle. In one group of dogs, regional dilatory capacity was tested by intravenous infusion of dipyridamole. Four compartments of myocardial blood flow were found. The collateral dependent subendocardium with 114 ml/min-100 g-1 was the lowest perfusion rate. In another group of dogs myocardial blood flow distribution was examined during isoproterenol infusion and after beta-blockade with prindolol during continuous isoproterenol infusion. During isoproterenol infusion, a nonhomogeneous blood flow pattern was found when the heart rate increased to 200/min together with a slight fall in diastolic perfusion pressure. Under these conditions, the flow to the collateral dependent subendocardium was severely diminished, while the flow to the areas perfused by normal coronary arteries increased, reflecting compensatory vasodilation. After beta-blockade with prindolol 0.1 mg/kg, the myocardial blood flow distribution was also nonhomogeneous but in the opposite direction: the collateral dependent subendocardium was now the best perfused compartment. The flow to the areas perfused by normal coronary arteries decreased due to the reduced oxygen requirements, while the collateral dependent subendocardium remained maximally dilated. This phenomenon was explained as a postischaemic reactive hyperaemic response to the isoproterenol-induced ischaemia in the collateral dependent subendocardium.     

Absence of coronary vascular reserve in myocardium distal to a fixed coronary stenosis

In a study to test the hypothesis that vascular reserve is exhausted in the setting of a resting blood flow deficit, the left anterior descending or circumflex artery was cannulated and perfused from the left carotid artery. After reactive hyperaemia had been assessed a stenosis was produced with a screw clamp. In the first experiment a moderate stenosis (diastolic perfusion pressure 40 mmHg) was produced in the left anterior descending artery (three dogs) or left circumflex artery (three dogs). Blood pressure was held constant with aortic constriction during intracoronary adenosine infusion (6 mumol.min-1). The stenosis was then adjusted to the preadenosine perfusion pressure. In the second experiment the anterior interventricular coronary vein was also isolated and segment length crystals were placed in the ischaemic and non-ischaemic zones. Severe stenosis (flow reduction of at least 50% and evidence of decreased segmental shortening) was produced in the cannulated left anterior descending artery (eight dogs). Intracoronary adenosine was given with aortic pressure held constant by transfusion and coronary venous drainage. In the first experiment resting coronary flow (ml.min-1) decreased from 41(3) to 29(6) (p less than 0.05) with stenosis. Coronary flow increased from 29(6) to 34(7) (p less than 0.05) with adenosine and to 50(10) (p less than 0.05) with stenosis adjustment. Subendocardial flow (ml.g-1.min-1) decreased from 0.89(0.26) to 0.78(0.23) (p less than 0.05) with adenosine and then increased from 0.94(0.49) with perfusion pressure adjustment. Subepicardial flow tended to increase with adenosine, and increased further with stenosis adjustment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transmural distribution of myocardial blood flow during systole in the awake dog.

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

Downstream resistance effects of intracoronary thrombosis in the stenosed canine coronary artery.

OBJECTIVE: The presence is well established in unstable angina of intracoronary thrombosis in a stenosed epicardial coronary artery. The effects of the thrombus formation on the distal microcirculation are however still unclear. METHODS: We adapted the Folts canine model of left circumflex coronary arterial stenosis and intracoronary thrombosis by the insertion of a pressure catheter distal to the stenosis and by the use of 15 microns radioactive microspheres for measurement of regional myocardial blood flow. This permitted measurement during circumflex artery occlusion of collateral flow, downstream vascular resistance and collateral resistance. RESULTS: Distal circumflex resistance, obtained by dividing the distal circumflex coronary pressure gradient by the collateral flow, significantly increased with thrombosis (94.47 +/- 35.72 to 120.06 +/- 34.47; p = 0.0018) mmHg/ml/min/g. Changes in collateral flow and resistance in the presence of thrombosis, during maximum ischaemic vasodilatation, were inconsistent. CONCLUSION: Thrombosis causes increased vascular resistance in the microcirculation distal to the site of injury. This may be of clinical relevance in unstable angina, characterised by episodes of thrombus growth and embolization, in which ischaemic episodes may be worsened by generalised downstream vascular changes.     

Effects of dobutamine and arbutamine on regional myocardial function in a porcine model of myocardial ischemia

Objectives. The present study was performed to determine the mechanisms for catecholamine-induced wall motion abnormalities and to compare the diagnostic efficacy of two catecholamines: arbutamine and dobutamine.Background. Catecholamine stress echocardiography is used to induce regional wall motion abnormalities for the detection of coronary artery disease, but the mechanism by which these abnormalities occur is unknown.Methods. Ten pigs were instrumented with left circumflex coronary artery ameroid constrictors, sonomicrometers to measure transmural wall thickening in the left circumflex (ischemic) and left anterior descending (control) coronary artery beds and a pressure gauge to measure left ventricular pressure and its first derivative (dP/dt). Myocardial blood flow was measured by microspheres.Results. At 38 ± 6 days (mean ± SEM) after surgery, percent wall thickening was normal at rest in both beds but abnormal in the left circumflex coronary artery bed during atrial pacing. These findings were associated with reduced myocardial blood flow in the ischemic bed during atrial pacing. Dobutamine infusion increased percent wall thickening, with no differences between the two beds (p = 0.63). In contrast, arbutamine infusion increased percent wall thickening only in the nonischemic bed, with no effect on percent wall thickening in the ischemic bed (p s 0.03). Although the endocardial/epicardial blood flow ratio tended to be reduced in the left circumflex artery bed during catecholamine infusion (p = 0.07), both agents were similar in this effect. Despite differences in function between the beds, there was no difference in transmural myocardial blood flow between the two beds during catecholamine infusion. When examined at matched metabolic demands, arbutamine elicited greater differences in percent wall thickening than dobutamine between the two beds (p < 0.01).Conclusions. Arbutamine was able to provoke regional differences in fonction in a manner superior to dobutamine. This occurred independently of altered transmural myocardial blood flow or differences in hemodynamic effects between the agents. Differences in their inotropic properties may be important in explaining their different effects on ischemic myocardium.