Absence of functioning alpha-adrenergic receptors in mature canine coronary collaterals

To determine if mature coronary collateral vascular smooth muscle contains functioning alpha-adrenergic receptors, we studied 13 dogs, 6-10 months after circumflex ameroid occlusion. Regional myocardial blood flow was measured with radioactive microspheres in a blood-perfused heart preparation at constant aortic pressure (80 mm Hg). Normal zone resistance was calculated as aortic pressure divided by normal zone flow, and transcollateral resistance was calculated as aortic pressure minus circumflex pressure distal to the ameroid constrictor divided by coronary collateral flow. Flow and resistance were measured during adenosine vasodilation before and during graded doses of a constant infusion of the alpha-adrenergic agonist methoxamine (n = 6) or the alpha 2-adrenergic agonist clonidine (n = 7). In the hearts that received methoxamine, normal zone resistance increased from a control of 0.29 +/- 0.06 to 0.39 +/- 0.06 mm Hg X min/ml per 100 g (resistance units) during infusion of 10(-5)M methoxamine (p less than 0.05). In contrast transcollateral resistance averaged 0.24 +/- 0.02 resistance units under control conditions and did not change during methoxamine infusion. In the hearts that received clonidine, normal zone resistance averaged 0.24 +/- 0.03 resistance units and increased to 0.39 +/- 0.07 resistance units (p less than 0.05) with the highest dose of clonidine administered (10(-5) M). Transcollateral resistance averaged 0.17 +/- 0.03 resistance units during control conditions and did not change with clonidine infusion. In separate studies isometric tension development by the left anterior descending and coronary collateral vessels was examined in organ baths. The left anterior descending coronary artery demonstrated dose-dependent constriction to phenylephrine (peak response 22 +/- 5% of the response to 100 mM KCl). Clonidine produced weak constrictor responses in the left anterior descending coronary artery (5 +/- 2.5% maximal KCl response). In contrast, neither phenylephrine nor clonidine produced responses in mature collaterals. We also examined responses of mature collateral vessels to nonadrenergic agonists. In the vascular ring preparation the mature collaterals developed tension in the presence of KCl (2.3 +/- 0.9 g), prostaglandin F2 alpha (16 +/- 18% of the KCl responses), and vasopressin (90 +/- 30% of the KCl response). In adenosine-vasodilated hearts, pharmacologic doses of vasopressin caused a two-fold increase in transcollateral resistance. Thus, these studies performed on intact hearts and isolated vascular rings demonstrate that mature coronary collaterals do not contain functioning alpha-adrenergic receptors.(ABSTRACT TRUNCATED AT 400 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.     

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.     

Regional myocardial function is not affected by severe coronary depressurization provided coronary blood flow is maintained

It has been suggested that vasodilation distal to a stenosis may cause a profound decrease in perfusion pressure and adversely affect regional left ventricular function. This phenomenon could explain the clinical concept of reversal of regional dysfunction by coronary revascularization. To evaluate the hypothesis that regional myocardial function parallels regional coronary blood pressure in the absence of changes in coronary flow, dogs chronically instrumented with left circumflex coronary artery flow probes, cuff occluders, pressure catheters and segmental function sonomicrometers were studied. By decreasing regional coronary vascular resistance with selective intracoronary dipyridamole and controlling blood flow with a proximal coronary cuff occluder, the mean left circumflex artery pressure was reduced from 83 +/- 3 to 38 +/- 2 mm Hg while circumflex coronary blood flow was maintained constant. Regional contractile function as measured by circumflex sonomicrometers was unchanged at constant circumflex subendocardial blood flow as measured by radioactive microspheres. These findings suggest that regional contractile function is dependent on subendocardial blood flow and is independent of coronary perfusion pressure.     

Effect of long-term exercise on regional myocardial function and coronary collateral development after gradual coronary artery occlusion in pigs

The effect of myocardial ischemia, induced by long-term exercise, on regional myocardial function and coronary collateral development was examined in pigs after gradual occlusion of the left circumflex coronary artery (LCx) with an ameroid occluder. Thirty days after surgery, regional myocardial function and blood flow were assessed during exercise in 22 pigs separated into exercise (n = 12) and sedentary groups (n = 10). The exercise group trained on a treadmill for 25 +/- 1 days, 30-50 min/day, at heart rates of 210-220 beats/min. After 5 weeks, another exercise test was performed. In the exercise group, after training, we observed an improvement in systolic wall thickening, expressed as a percentage of rest, in the collateral-dependent LCx region from 64 +/- 8% to 87 +/- 6% (p less than 0.01) at moderate exercise levels (220 beats/min) and from 45 +/- 7% to 73 +/- 7% (p less than 0.01) at severe exercise levels (265 beats/min). Transmural myocardial blood flow in the LCx region expressed as a ratio of flow in the nonoccluded region of the left ventricle also increased significantly (p less than 0.01) during severe exercise after 5 weeks. The sedentary group showed an improvement in systolic wall thickening in the LCx region during moderate exercise compared with the initial exercise test (p less than 0.05) but no significant change in systolic wall thickening or myocardial blood flow ratios during severe exercise after 5 weeks. We conclude that long-term exercise after gradual LCx coronary artery occlusion in pigs improves myocardial function and coronary collateral reserve in collateral-dependent myocardium during exercise.     

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.     

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.     

Pressure-flow characteristics of the coronary collateral circulation during cardiopulmonary bypass. Effects of ventricualr fibrillation

Even though ventricular fibrillation is used frequently during cardiopulmonary bypass (CPB), the effects of fibrillation on myocardial regions supplied by collateral vessels have not been determined. To study these effects, nine dogs with left ventricles (ameroid model) consisting of a region of myocardium supplied by collateral vessels (CR) and a region supplied by normal coronary arteries (NR) were subjected to normothermic CPB at two perfusion pressures. In both the empty beating heart (EBH) and empty fibrillating heart (EFH) regional myocardial flow was determined by tracer microspheres. Retrograde coronary pressure was measured via cannulation of the circumflex artery distal to the ameroid induced occlusion. When perfusion pressure was maintained at 80 mm Hg, retrograde coronary pressure was similar in the EBH (46 +/- 4 mm Hg) and in the EFH (48 +/- 3 mm Hg). During fibrillation subendocardial flow in the CR was unchanged, while flow in the NR increased (P less than 0.02). In addition, the endo/epi was greater in the NR than in the CR (P less than 0.01), a difference which did not exist in the EBH. The flow response to fibrillation in the CR could be produced in the NR by reducing the perfusion pressure to 50 mm Hg. These data suggest that during CPB, fibrillation exaggerates existing subendocardial perfusion deficits in collateral regions and the impaired flow response appears to be related to a low regional intravascular pressure.     

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)     

Vasopressin and the mature coronary collateral circulation

In isolated vascular rings, we have shown that mature coronary collateral vessels are highly responsive to the vasoconstrictor effects of vasopressin. The purpose of the present study was to determine the effect of concentrations of vasopressin encountered in pathophysiologic states on the collateral circulation in vivo. We studied eight open-chest anesthetized dogs with mature coronary collateral vessels 3-6 months after placement of an ameroid constrictor on the left circumflex coronary artery. The left anterior descending coronary artery was perfused at constant pressure, and peripheral coronary pressure was monitored continuously throughout each experiment. At baseline and during intracoronary infusion of vasopressin, which resulted in concentrations ranging from 8 +/- 3 to 1,340 +/- 327 microM/ml, we measured regional myocardial perfusion with radiolabeled microspheres. At baseline, regional myocardial perfusion to the collateral-dependent myocardium and to the normally perfused myocardium was similar; however, during vasopressin infusion, collateral-dependent zone flow decreased by 49 +/- 14% whereas normal zone flow decreased by only 9 +/- 9% (p less than 0.0005, normal zone perfusion vs. collateral perfusion). Vasopressin increased transcollateral resistance by 242 +/- 95% above baseline but produced a more modest increase in normal zone resistance (15 +/- 10%). The subendocardial to subepicardial perfusion ratio increased by 28 +/- 12% in the normal zone in response to vasopressin but decreased by 18 +/- 11% in the collateral-dependent zone. These data show that mature coronary collateral vessels are responsive to the vasoconstrictor effects of vasopressin at concentrations encountered in various pathophysiologic states.(ABSTRACT TRUNCATED AT 250 WORDS)     

Platelet glycoprotein IIb/IIIa receptor inhibitor preserves coronary flow reserve during progressive coronary arteriostenosis in swine

Thrombosis resulting from blood platelet aggregation via glycoprotein (GP) IIb/IIIa receptor activation triggers the local release of vasoactive substances. Therefore, inhibition of these receptors could affect coronary vasoactive function during thrombotic coronary arteriostenosis. Twenty pigs were instrumented with an aortic catheter and with hydraulic occluders and flow probes on both the left anterior descending (LAD) and the left circumflex (LCx) coronary arteries. One of these 2 coronary arteries was repeatedly injured by external clamping for 15-second periods at 30-minute intervals while the pigs were given either a GP IIb/IIIa receptor inhibitor (L-739,758) (n=5), heparin (n=5), aspirin (n=3), or saline (n=7). There were no baseline differences between the 4 groups in mean arterial pressure, resting coronary blood flow (CBF), or reactive hyperemic response (RHR), which was induced by brief coronary artery occlusion and expressed as flow debt repayment. After multiple injuries, resting CBF had decreased by 95+/-2% (ie, nearly complete coronary artery occlusion) at 15+/-4 minutes in the control group, whereas in the heparin-, aspirin-, and GP IIb/IIIa inhibitor-treated groups, resting CBF had decreased by only 21+/-7% at 18+/-3 minutes, 15+/-3% at 18+/-5 minutes, and 15+/-7% at 21+/-4 minutes, respectively, suggesting that heparin, aspirin, and the GP IIb/IIIa inhibitor each prevented injury-induced coronary artery occlusion. After the initial injury, the RHR was progressively reduced in the control and heparin- and aspirin-treated groups but not in the GP IIb/IIIa inhibitor-treated group. At a comparable level of resting CBF ( approximately 15% below baseline), the RHR was reduced more in the control (-56+/-9%), heparin-treated (-49+/-9%), and aspirin-treated (-61+/-12) groups (P:<0.05) than in the GP IIb/IIIa inhibitor-treated group (-26+/-6%). When the resting CBF had decreased by approximately 35%, the RHR still was reduced significantly more (P<0.01) in the heparin-treated group (-64+/-9%) than in the GP IIb/IIIa inhibitor-treated group (-21+/-6%). In a separate group of control pigs (n=4) subjected to 2 injuries, coronary perfusion pressure distal to the injury site was reduced by 14+/-1 mm Hg from the arterial pressure, and the RHR was 20+/-6%. When the distal coronary perfusion pressure was reduced similarly (-14+/-1 mm Hg) in a separate group of GP IIb/IIIa inhibitor-treated pigs (n=4) by 2 injuries and the use of a hydraulic occluder, the RHR was 130+/-16% (P<0.01 versus control). Our data demonstrate for the first time that a platelet GP IIb/IIIa receptor inhibitor can preserve the distal coronary vasodilatory response during progressive coronary arteriostenosis.     

Electromechanical characterization of myocardial hibernation in a pig model.

BACKGROUND: This study attempted to assess in-vivo electromechanical changes following gradual coronary artery occlusion in a pig ameroid constrictor model using a novel three-dimensional left ventricular mapping system. METHODS AND RESULTS: We measured unipolar and bipolar voltage potentials and local endocardial shortening in the ischemic lateral and non-ischemic anterior zones in animals at rest (n = 9) 5 weeks after the implantation of ameroid constrictors around the left circumflex artery. Echocardiography was used to assess regional contractility (percentage myocardial thickening), and an echo-contrast perfusion study was performed using acoustic densitometry methods. The ischemic lateral zone showed reduced myocardial perfusion at rest (peak intensity; 3.4 +/- 1.7 versus 20.7 +/- 14.8, P = 0.005), impaired mechanical function (percentage wall thickening 22 +/- 19% versus 40 +/- 11%, P = 0.03; local endocardial shortening 2.9 +/- 5.5% versus 11.7 +/- 2.1%, P = 0.002), and preserved electrical activity (unipolar voltage 12.4 +/- 4.7 versus 14.4 +/- 1.9 mV, P = 0.25; bipolar voltage 4.1 +/- 1.1 versus 3.8 +/- 1.5 mV, P = 0.62), compared with the anterior region. CONCLUSIONS: Gradual coronary artery occlusion resulting in regional reduced perfusion and function at rest (i.e. hibernating myocardium) is characterized by preserved electrical activity. An electromechanical left ventricular mapping procedure such as the one described here may be of diagnostic value for identifying the hibernating myocardium.     

Changes in isovolumic segment shortening following acute coronary occlusion: disproportionate effects of anterior versus posterior ischemia

We evaluated the changes in left ventricular pressure and isovolumic segment shortening in both the ischemic and nonischemic areas following acute coronary occlusion in 12 conscious dogs instrumented for the measurement of subendocardial segment lengths perfused by the left circumflex coronary artery and left anterior descending coronary artery, and left ventricular pressure. An externally inflatable pneumatic occluder was placed around the left circumflex coronary artery. In 6 dogs, another occluder was installed around the proximal left anterior descending coronary artery. Under the resting conditions, the isovolumic segment shortening in the areas supplied by the left anterior descending coronary artery and the left circumflex coronary artery were 2.1 +/- 0.5% (SE) and -0.1 +/- 0.5% (P less than 0.01; versus values in the area of the left anterior descending coronary artery), respectively. During a 1-min occlusion of the left circumflex coronary artery, the isovolumic shortening in the anterior segment increased to 3.8 +/- 0.5% (P less than 0.001; versus values in the basal state), while the posterior segment produced isovolumic elongation (-2.2 +/- 0.5%, P less than 0.001; versus values in the basal state). By contrast, during a 1-min occlusion of the left anterior descending coronary artery, the extent of isovolumic bulge in the anterior segment and the augmentation in the isovolumic shortening in the posterior segment was less prominent compared with the occlusion of the left circumflex coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Distinction between metabolic and myogenic mechanisms of coronary hyperemic response to brief diastolic occlusion

We monitored an index of coronary vascular resistance (mean aortic pressure/mean coronary flow) in 19 heart-blocked conscious dogs paced at 60 beats/min and instrumented with an aortic pressure catheter, left circumflex artery electromagnetic flow probe, and a coronary occluder. Cessation of pacing for a single beat resulted in a long diastole control (LDC) intervention beat of 2-second duration characterized by a progressive rise in diastolic coronary vascular resistance index. A 400-msec coronary artery occlusion early in a long diastole (LD4) dramatically inhibited the rate of rise in resistance index during the first 600 msec (phase 1) after occlusion. Partial recovery of the resistance index rise rate was evident during the remaining 400 msec (phase 2) of the long diastole. In nine dogs, LDC and LD4 intervention beats were instituted during two conditions of myocardial metabolic activity in which the myogenic stimuli associated with coronary occlusion would be similar: 1) paired pacing and 2) normal pacing plus intravenous adenosine and phenylephrine infusions (AP) to maintain mean aortic pressure and coronary flow at paired pacing levels. During paired pacing, the LD4-LDC differences in phase 1 and 2 resistance index rise rates (-69 +/- 18 and -48 +/- 31 mmHg/ml/sec2, respectively) were greater than during normal pacing plus AP (-32 +/- 14 and -1 +/- 32 mm Hg/ml/sec2, phase 1 and 2, respectively) (p less than 0.05). These differences are consistent with operation of a metabolic mechanism in response to occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

Transmural differences in sympathetic coronary constriction during exercise in the presence of coronary stenosis

The goal of this study was to determine the effect of sympathetic neural activation on the transmural distribution of myocardial perfusion distal to a flow-limiting coronary artery stenosis. Treadmill exercise in conscious dogs was used as a physiological stimulus to activate the sympathetic nervous system. In the experimental model, the anterior region of the circumflex artery was innervated, but the posterior circumflex region was treated with phenol to produce regional sympathectomy within the stenotic territory. Myocardial perfusion to innervated and sympathectomized left ventricular regions was measured before and after inflation of the occluder to reduce distal coronary pressure to 45 mm Hg. Measurements were obtained during control conditions with the animal standing on the treadmill, during inflation of the occluder with the animal standing, during exercise alone, during exercise with beta-adrenergic blockade, and during exercise with combined alpha- and beta-adrenergic blockade. Exercise (6 km/hr) resulted in a marked increase in heart rate from 128 +/- 9 (standing) to 218 +/- 7 beats/min. beta-Adrenergic blockade blunted the tachycardia during exercise (146 +/- 6 beats/min). Under control conditions (while standing), there were no differences in myocardial perfusion between the innervated and sympathectomized regions, 187 +/- 26 and 181 +/- 24 ml.min-1.100 g-1, respectively. During exercise or in combination with beta-adrenergic blockade, subepicardial perfusion was significantly less (18-25%) in the innervated stenotic region than that in the sympathectomized stenotic region. In contrast, subendocardial perfusion was significantly greater in the innervated stenotic region (17-26%) than that in the sympathectomized stenotic region. The subendocardial-to-subepicardial blood flow ratio during exercise was 0.60 +/- 0.08 in the innervated stenotic region and 0.42 +/- 0.07 in the sympathectomized stenotic region (p less than 0.05). During exercise with beta-adrenergic blockade, the endocardial-to-epicardial blood flow ratios in the innervated and sympathectomized stenotic regions were 0.47 +/- 0.09 and 0.37 +/- 0.07, respectively (p less than 0.05). These differences were abolished during alpha- and beta-adrenergic blockade. These data indicate that alpha-adrenergic coronary constriction distal to a flow-limiting stenosis facilitates redistribution of blood flow toward the subendocardium. This redistribution was produced by alpha-adrenergic constriction in the outer layers of the left ventricle.     

Mechanisms of remote myocardial dysfunction during coronary artery occlusion in the presence of multivessel disease

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

Functional consequences and intracoronary localization of alpha-adrenergic stimulation of the canine coronary circulation

Although alpha-adrenergic stimulation can increase coronary vascular resistance, it remains unknown whether the vasoconstriction can override intrinsic coronary regulatory influences to produce ischemia. Methoxamine, 2 to 4 mg, was infused into the circumflex coronary artery of 23 chloralose-anesthetized open chest dogs, and resulted in a 68% increase in coronary vascular resistance. The functional consequence of this increased coronary vascular resistance was assessed by gated radionuclide ventriculography and ST-T wave changes on the electrocardiogram. In six dogs (Group I), aortic pressure changed trivially (less than 5 mm Hg) to allow distinction between direct effects of the flow reduction and indirect effects of increased aortic pressure. In this group, coronary blood flow decreased 33% from a control value of 44 +/- 10 ml/min (p less than 0.001) and left ventricular ejection fraction decreased from 0.54 +/- 0.12 to 0.46 +/- 0.10 (p less than 0.025). In eight dogs (Group II) in which aortic pressure increased by more than 5 mm Hg, left ventricular ejection fraction decreased from 0.46 +/- 0.07 to 0.39 +/- 0.09 (p less than 0.002). Pressure gradients were measured between the aorta and a distal coronary artery branch to calculate small and large vessel resistances separately in four other dogs (Group III). The resistance of small coronary arteries accounted for 92% of the total increase in coronary vascular resistance produced by methoxamine. In five other dogs (Group IV), intracoronary methoxamine, 2 mg, produced ST-T wave changes suggestive of ischemia as it increased coronary vascular resistance by 33%.(ABSTRACT TRUNCATED AT 250 WORDS)