Biomedical subjects

R J Bache

Publications and source records attributed to R J Bache.

At least 19 recordsLinked to original sources

PubMed1992

Effect of serotonin and thromboxane A2 on blood flow through moderately well developed coronary collateral vessels.

This study was performed to determine whether thromboxane A2 (as the analogue U46619) and serotonin can cause vasoconstriction of moderately well developed coronary collateral vessels. Studies were carried out in seven adult mongrel dogs 2 to 4 months after embolic occlusion of the left anterior descending coronary artery had been performed to stimulate collateral vessel growth. At the time of study this artery was cannulated to determine interarterial collateral flow from measurements of retrograde blood flow. Radioactive microspheres were administered during retrograde flow collection to determine continuing tissue flow for evaluation of microvascular collateral communications. Serotonin (50 micrograms/min) resulted in a 48 +/- 11% decrease in retrograde flow (p less than 0.01), with a 36 +/- 10% decrease in total collateral blood flow (p less than 0.02). Infusion of U46619 (0.01 microgram/kg per min) caused a 38 +/- 13% decrease in retrograde blood flow (p less than 0.01), with a 34 +/- 13% decrease in total collateral flow (p less than 0.05). Serotonin caused a significant increase in tissue flow to the subepicardium of the collateral-dependent region, whereas U46619 caused no change in tissue blood flow. These data demonstrate that both serotonin and thromboxane A2 can cause vasoconstriction of interarterial coronary collateral vessels. The findings suggest that platelet activation in coronary arteries from which collateral vessels originate has potential for causing collateral vasoconstriction, thereby compromising blood flow to the dependent myocardium.

Animals↗

PubMed1992

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.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1992

Effect of superoxide dismutase and catalase on regional dysfunction after exercise-induced ischemia.

This study was designed to test the hypothesis that the oxygen free radical scavengers superoxide dismutase (SOD) and catalase may reduce myocardial "stunning" after exercise-induced ischemia. To test this hypothesis, 8 mongrel dogs performed treadmill exercise for 10 min in the presence of a flow-limiting coronary artery stenosis. Regional left ventricular function was measured with ultrasonic microcrystals implanted to measure regional wall thickening. Regional myocardial perfusion was measured with radioactive microspheres. The combination of SOD (5 mg/kg iv) and catalase (5 mg/kg iv) did not affect heart rate, blood pressure, coronary artery flow, or regional myocardial blood flow at rest, during exercise, or in the postexercise period. SOD and catalase had no effect on regional wall thickening at rest before exercise. During exercise in the absence of a coronary artery stenosis, thickening was slightly lower during SOD and catalase infusion (27 +/- 11.0 vs. 30.8 +/- 11.5%, SOD vs. control P = 0.05). During exercise in the presence of a coronary artery stenosis, there was no difference in thickening. Infusion of SOD and catalase affected neither the transient rebound function occurring early after exercise nor the prolonged period of stunning. These results indicate that the myocardial stunning that follows exercise-induced ischemia is unlikely to be mediated by oxygen free radicals.

Animals↗

PubMed1992

Coronary vasodilator reserve in ischemic myocardium of the exercising dog.

BACKGROUND: Previous work has reported that coronary vasodilator reserve may persist in myocardium rendered ischemic by hypoperfusion. This study investigated the presence and extent of residual coronary vasomotor tone in myocardial regions made acutely ischemic by a flow-limiting coronary stenosis during exercise. METHODS AND RESULTS: Studies were done in chronically instrumented dogs undergoing treadmill exercise in the presence of a coronary stenosis that decreased distal left circumflex coronary artery perfusion pressure to approximately 40 mm Hg. Measurements of myocardial blood flow were made with radioactive microspheres during exercise (6.5 km/hr, 6% grade) before and during intracoronary infusion of the potent coronary vasodilator adenosine (40 micrograms/kg/min). Distal coronary perfusion pressure was held equal before and during intracoronary adenosine infusion (43 +/- 5 versus 42 +/- 5 mm Hg) by adjusting the hydraulic coronary occluder. During exercise in the presence of a coronary stenosis, myocardial blood flow (milliliter per minute per gram) was significantly reduced in all layers of the ischemic posterior region compared with the nonischemic anterior region. During intracoronary adenosine infusion, with no change in coronary perfusion pressure, myocardial blood flow was significantly increased compared with preadenosine flows for both the subendocardial layer flow (1.03 +/- 0.74 versus 0.66 +/- 0.50; p less than 0.05) and mean transmural flow (1.54 +/- 0.59 versus 1.16 +/- 0.36; p less than 0.05). In the presence of a coronary stenosis, regional myocardial segment shortening in the ischemic region during exercise fell significantly to 49 +/- 8% of shortening in the absence of a coronary stenosis but improved modestly during adenosine infusion (65 +/- 7 versus 49 +/- 8%; p less than 0.05). CONCLUSIONS: These results indicate that adenosine-responsive coronary vasodilator reserve persists during exercise-induced myocardial ischemia and suggest that residual microvascular vasoconstrictor tone may affect the extent of myocardial hypoperfusion occurring consequent to a flow-limiting coronary stenosis.

Adenosine↗

PubMed1992

Effect of alpha-adrenergic blockade with prazosin on large coronary diameter during exercise.

BACKGROUND: Exercise-induced dilation of coronary resistance vessels is limited by alpha-adrenergic mechanisms. However, the effect of alpha-adrenergic mechanisms on large coronary arteries during exercise is not known. METHODS AND RESULTS: In the present study, sonomicrometry was used to measure circumflex coronary arterial diameter during treadmill exercise before and after alpha 1-adrenergic blockade with prazosin in eight instrumented dogs. Before infusion of prazosin, exercise caused a fall in coronary vascular resistance (2.1 +/- 0.4 to 1.6 +/- 0.2 units, p less than 0.05) and dilation of the circumflex coronary artery (4.66 +/- 0.37 to 4.79 +/- 0.34 mm, p less than 0.05). Intracoronary infusion of prazosin during exercise caused a further decrease in coronary vascular resistance (1.6 +/- 0.2 to 1.4 +/- 0.2 units, p less than 0.05) and a further increase in circumflex coronary arterial diameter (4.79 +/- 0.34 to 4.83 +/- 0.34 mm, p less than 0.05). Intracoronary infusion of vehicle without prazosin during exercise did not cause a further decrease in coronary vascular resistance or increase in coronary diameter. Prazosin caused no significant increase in heart rate, aortic pressure, or coronary blood flow. Therefore, both small coronary resistance vessels and large epicardial coronary arteries dilated during exercise and dilated further after alpha-adrenergic blockade. CONCLUSIONS: This finding indicates that alpha 1-adrenergic activity during exercise limits dilation of both large and small coronary arteries.

Adrenergic alpha-Antagonists↗

PubMed1992

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.

Animals↗

PubMed1992

Effect of cyclooxygenase blockade on blood flow through well-developed coronary collateral vessels.

Collateral vessels that develop after coronary artery occlusion demonstrate perivascular inflammation, subintimal hyperplasia, and endothelial proliferation. This study was performed to test the hypothesis that these abnormalities are associated with evidence for increased production of vasodilator prostaglandins. Eight dogs were studied 4-6 months after occlusion of the anterior descending coronary artery had been performed to stimulate collateral vessel growth. At the time of study, the anterior descending coronary artery was cannulated at the site of occlusion to allow measurement of retrograde blood flow as an index of interarterial collateral flow. Injection of radioactive microspheres during the retrograde flow collection allowed determination of continuing tissue flow in the collateral-dependent zone as an index of intramural microvascular collateral flow. Retrograde and tissue flows were measured before and 20 minutes after 5 mg/kg i.v. indomethacin, a dose that caused 95 +/- 3% inhibition of the coronary vasodilation in response to a 500 micrograms intracoronary bolus of arachidonic acid. Heart rate and mean aortic pressure were not significantly altered by indomethacin, and blood flow to the normally perfused myocardial region was not changed by administration of indomethacin. However, indomethacin caused a 40 +/- 7% decrease in retrograde flow (p less than 0.01), and microvascular collateral flow to the dependent myocardium decreased by 20 +/- 10% (p less than 0.05). These data indicate that, unlike the normal coronary circulation, well-developed coronary collateral vessels are under the tonic influence of vasodilator prostaglandins.

Animals↗

PubMed1991

Effects of amiodarone with and without polysorbate 80 on myocardial oxygen consumption and coronary blood flow during treadmill exercise in the dog.

Since amiodarone has been reported to possess antianginal activity, this study examined the effects of amiodarone on coronary blood flow and myocardial oxygen consumption during exercise. Studies were performed in 14 chronically instrumented dogs trained to run on a motor-driven treadmill. Left circumflex coronary artery blood flow was measured with an electromagnetic flowmeter while aortic and coronary sinus catheters allowed measurement of myocardial oxygen extraction. During control conditions, graded exercise resulted in progressive increases in heart rate, aortic pressure, and coronary blood flow. Two preparations of amiodarone, 5 mg/kg, one dissolved in sterile water and the other in 10% polysorbate 80, were given intravenously to separate groups of dogs. Amiodarone in sterile water caused no hemodynamic changes at rest. However, the increase in heart rate during exercise was blunted after amiodarone, so that heart rate during the heaviest level of exercise was significantly less than during control exercise. Coronary blood flow and myocardial oxygen consumption were unchanged. Amiodarone with polysorbate 80 also blunted the increase in heart rate during exercise, but in addition caused a significant decrease in aortic pressure both at rest and during exercise. Myocardial oxygen consumption and coronary blood flow were significantly decreased after administration of amiodarone with polysorbate 80 at rest and during all exercise levels. Amiodarone with or without polysorbate 80 did not change myocardial oxygen extraction. These data demonstrate that amiodarone exerts a negative chronotropic effect during exercise. However, the decreased arterial pressure and myocardial oxygen consumption were not due to amiodarone, but was seen only with the combination of amiodarone dissolved in polysorbate 80.

Amiodarone↗

PubMed1991

Adrenergic vasoconstriction limits coronary blood flow during exercise in hypertrophied left ventricle.

This study was carried out to test the hypothesis that alpha-adrenergic vasoconstriction limits coronary blood flow (CBF) during exercise in the chronically pressure overloaded, hypertrophied left ventricle. Studies were performed in dogs in which left ventricular hypertrophy had been produced by banding the ascending aorta at 9 wk of age. Left circumflex coronary artery blood flow and myocardial O2 consumption (MVO2) were examined at rest and during treadmill exercise during control conditions, after selective alpha 1-adrenergic blockade with prazosin, and after nonselective alpha-adrenergic blockade with phentolamine. All studies were performed after beta-adrenergic blockade with propranolol. During control conditions CBF and MVO2 increased progressively during exercise, while coronary sinus O2 tension decreased. Neither prazosin nor phentolamine altered CBF at rest but, in comparison with control measurements, both agents significantly increased CBF during exercise and abolished the decrease in coronary sinus O2 tension that normally occurred during exercise. Both prazosin and phentolamine caused similar significant increases of MVO2 relative to the heart rate times systolic left ventricular pressure during exercise, indicating that the increased CBF produced by these agents enhanced MVO2. Similar findings after prazosin and phentolamine indicate that adrenergic restraint of CBF during exercise resulted principally from alpha 1-adrenergic vasoconstrictions with little additional contribution from postjunctional alpha 2-adrenergic mechanisms.

Animals↗

PubMed1991

Effect of alpha 1-adrenergic blockade on myocardial blood flow during exercise after myocardial infarction.

The effect of alpha 1-adrenergic blockade with prazosin on myocardial blood flow at rest and during two levels of treadmill exercise was assessed in 16 chronically instrumented dogs 9-14 days after myocardial infarction had been produced by occlusion of the left circumflex coronary artery. During resting conditions prazosin did not alter mean myocardial blood flow or the subendocardial-to-subepicardial flow ratio in either normally perfused or collateral-dependent myocardium. However, during exercise at comparable external work loads and comparable rate-pressure products, prazosin significantly increased blood flow to normally perfused (27% increase at the second level of exercise, P less than 0.001) and collateral-dependent myocardium (35% increase at the second level of exercise, P less than 0.001) compared with control. In addition, prazosin caused a small but significant decrease in the subendocardial-to-subepicardial flow ratio in both normal (1.27 +/- 0.04 to 1.19 +/- 0.04; P less than 0.01) and collateral-dependent myocardium (0.57 +/- 0.11 to 0.52 +/- 0.11; P less than 0.01) compared with control, reflecting a disproportionally greater increase in subepicardial flow in response to alpha 1-adrenergic blockade. These data demonstrate that alpha 1-adrenergic vasoconstriction inhibits coronary vasodilation during exercise, even in areas of collateral-dependent myocardium relatively early after coronary artery occlusion.

Adrenergic alpha-Antagonists↗

PubMed1991

Response of canine coronary collateral vessels to ergonovine and alpha-adrenergic stimulation.

The ability of moderately well-developed coronary collateral vessels to undergo vasoconstriction in response to alpha-adrenergic stimulation and to ergonovine was studied. Studies were performed in 15 dogs 4-16 wk after embolic occlusion of the left anterior descending coronary artery had been performed to stimulate collateral vessel growth. Interarterial collateral flow was measured as retrograde flow from the cannulated left anterior descending coronary artery, while microvascular collateral flow was measured as continuing tissue flow determined with radioactive microspheres administered during the retrograde flow collection. Studies were performed after beta-adrenergic blockade with propranolol. Neither cardiac sympathetic nerve stimulation nor alpha 1-adrenergic stimulation with phenylephrine caused significant change in retrograde blood flow or myocardial tissue flow. The selective alpha 2-adrenergic agonist, B-HT 933, decreased tissue flow in the collateral-dependent region but did not significantly alter retrograde flow. Although these data indicate that intramural microvascular collateral communications are capable of vasoconstriction in response to alpha 2-adrenergic stimulation, the larger interarterial collaterals are unresponsive to alpha-adrenergic influences. However, under the conditions of the experiment, adrenergic activity did not appear to influence collateral function, since neither alpha 1-adrenergic blockade with prazosin nor alpha 2-adrenergic blockade with rauwolscine altered collateral flow. Ergonovine, 0.2-0.8 microgram.kg-1.min-1, caused a 22 +/- 4% decrease in retrograde flow (P less than 0.01) but did not alter microvascular collateral flow. Thus, of the agents tested, only ergonovine caused vasoconstriction of the large interarterial coronary collateral vessels.

Adrenergic alpha-Agonists↗

PubMed1991

Vasoconstriction of canine coronary collateral vessels with vasopressin limits blood flow to collateral-dependent myocardium during exercise.

This study was performed to test the hypothesis that active constriction of coronary collateral vessels can worsen hypoperfusion of collateral-dependent myocardium during exercise. Studies were performed in seven adult mongrel dogs in which intermittent followed by permanent occlusion of the left circumflex coronary artery produced an area of collateral-dependent myocardium without gross evidence of infarct. Myocardial blood flow was determined with microspheres while measurement of aortic and distal coronary pressures allowed calculation of collateral and small vessel resistance at rest and during treadmill exercise. The ability of collateral vessel constriction to limit blood flow was assessed by infusion of vasopressin during exercise. During control conditions, blood flow in the collateral zone underwent a subnormal increase during exercise in comparison with the normal zone (1.74 +/- 0.27 versus 2.50 +/- 0.40 ml/min/g, respectively, p less than 0.05). Infusion of vasopressin in a dose that caused no change in normal zone flow (0.01 microgram/kg/min i.v.) produced a 30 +/- 5% further decrease in flow to the collateral zone (p less than 0.01). This decrease in collateral zone flow resulted from a 48 +/- 14% increase in transcollateral resistance in response to vasopressin infusion (p less than 0.01), as well as a 40 +/- 9% increase in small vessel resistance in the collateral zone (p less than 0.01). These data demonstrate that active constriction of both collateral vessels and coronary resistance vessels can contribute to hypoperfusion of collateral-dependent myocardium during exercise.

Animals↗

PubMed1990

Transmural high energy phosphate distribution and response to alterations in workload in the normal canine myocardium as studied with spatially localized 31P NMR spectroscopy.

Spatially localized phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy has been applied to the study of the normal canine myocardium to measure the relative content of high energy phosphates across the left ventricular wall. Transmural NMR data were acquired in five voxels spanning the wall of the left ventricle using the FLAX-ISIS technique. The validity of the FLAX-ISIS approach in acquiring localized spectra for transmural studies and in providing quantitative information from the localized spectra was examined rigorously by studies involving phantoms, intact rats, and the canine myocardium in vivo. The results indicated that (1) this technique yields spatially resolved spectra with partial overlap between adjacent voxels and virtually no overlap between every other voxel; (2) in the canine heart, signals from subepicardium, midwall, and subendocardium can be detected separately without cross contamination; and (3) relative metabolite contents within a voxel and among voxels can be quantitated. Transmural 31P NMR spectra were acquired with cardiac gating on 29 separate animals either at early systole or late diastole, and at three different workloads with the heart rate peak systolic pressure product (RPP) increasing from 6000 mmHg/min to 35,000 mmHg/min. The data revealed that in the normal canine myocardium, the creatine phosphate (CP) content and the CP/ATP ratio was significantly lower in the subendocardium than in the subepicardium. ATP levels were transmurally constant. Both the CP content and the CP/ATP ratio measured for each voxel remained unaltered in relation to either the phase of the cardiac cycle or approximately fourfold increase in workload. Free ADP levels calculated for each voxel showed that ADP was relatively higher in the subendocardium than the subepicardium, and in all transmural layers was higher than its apparent Km for oxidative phosphorylation. In this domain changes in ADP content with workload and MVO2 are not expected and were not observed.

Adenosine Diphosphate↗

PubMed1990

Myocardial oxygen consumption during exercise in the presence of left ventricular hypertrophy secondary to supravalvular aortic stenosis.

The hypothesis that abnormally increased myocardial oxygen demands may contribute to increased vulnerability to ischemia during exercise in the chronically pressure-overloaded hypertrophied left ventricle was tested. Myocardial oxygen consumption was measured during a five stage graded treadmill exercise protocol in eight normal dogs and nine adult dogs in which a 90% increase in left ventricular mass was produced by banding the ascending aorta at 8 weeks of age. Heart rate increased progressively during exercise in both groups of dogs, but was significantly faster than normal in the group with aortic banding. Coronary blood flow increased progressively with exercise in both groups, but was significantly greater than normal in dogs with aortic banding during each exercise stage. Coronary sinus oxygen tension decreased significantly and similarly during exercise in normal and hypertrophied hearts. In dogs with hypertrophy, oxygen consumption per gram of myocardium averaged 52% greater than normal during exercise. This excess myocardial oxygen consumption in dogs with aortic banding resulted from an abnormally large increase in oxygen consumption per beat during exercise and from the faster heart rate in this group of dogs. Measurements of myocardial blood flow with microspheres demonstrated a lower subendocardial/subepicardial blood flow ratio in dogs with hypertrophy; this ratio decreased significantly during exercise in dogs with hypertrophy, but not in normal dogs. These data are consistent with the hypothesis that increased vulnerability to ischemia in the pressure-overloaded hypertrophied left ventricle is the result of both increased myocardial oxygen demands during exercise and abnormalities of myocardial perfusion.

Animals↗

PubMed1990

Effect of stenosis on exercise-induced dilation of large coronary arteries.

The effects of a flow-limiting stenosis on external circumflex coronary arterial diameter during treadmill exercise were studied in 10 instrumented dogs. Coronary arterial diameter was measured by sonomicrometry proximal to the stenosis-producing hydraulic occluder so that the effects of a post-stenotic pressure drop were excluded. With no stenosis, heart rate increased (116 +/- 7 to 183 +/- 10 beats/min, p less than 0.001), aortic pressure increased (97 +/- 3 to 105 +/- 5 mm Hg. p less than 0.005), circumflex coronary blood flow increased (48 +/- 8 to 72 +/- 8 ml/min, p less than 0.001), and circumflex coronary diameter increased (3.82 +/- 0.29 to 3.93 +/- 0.27 mm, p less than 0.01). In the presence of a flow-limiting stenosis, heart rate increased (120 +/- 6 to 176 +/- 9 beats/min, p less than 0.001), aortic pressure did not change significantly (95 +/- 4 to 92 +/- 4 mm Hg), circumflex coronary blood flow increased slightly (39 +/- 8 to 46 +/- 9 ml/min, p less than 0.005), and circumflex coronary arterial diameter did not change significantly (3.78 +/- 0.29 to 3.80 +/- 0.28 mm). The stenosis prevented the increase in aortic pressure, blunted the increase in circumflex coronary blood flow (24 +/- 4 versus 7 +/- 2 ml/min, p less than 0.005), and prevented the increase in circumflex coronary arterial diameter. Therefore normal coronary arteries dilated during exercise and a flow-limiting stenosis prevented exercise-induced coronary dilation proximal to the stenosis, possibly due to both the failure of aortic pressure to increase and less flow-induced endothelium-dependent dilation.

Animals↗

PubMed1990

Coronary arteriolar vasoconstriction in myocardial ischaemia: coronary vasodilator reserve during ischaemia.

This study was performed to determine whether vasomotor tone of the coronary resistance vessels limits blood flow to ischaemic myocardium perfused by a stenotic coronary artery during exercise. Studies were performed on dogs in which a hydraulic occluder, in place for greater than or equal to 14 days, allowed production of a coronary stenosis, while distal coronary pressure was monitored with a miniature intra-arterial catheter. Treadmill exercise at 6.5 km h-1 with a 6% grade resulted in a mean heart rate of 209 +/- 4 beats min-1, with mean myocardial blood flow in the normally perfused left ventricular region of 2.90 +/- 0.37 ml min-1 g-1. An arterial stenosis that decreased coronary pressure to 40-42 mmHg resulted in a decrease of myocardial blood flow to 1.07 +/- 0.19 ml min-1 g-1 (P less than 0.01), hypoperfusion being most severe in the subendocardium. Intracoronary administration of the selective alpha 1-adrenergic antagonist, prazosin, resulted in a 50 +/- 14% increase in blood flow with no change in perfusion pressure. This increase in flow in response to prazosin was uniform across the left ventricular wall, from epicardium to endocardium. After administration of the selective alpha 2-adrenergic antagonist, idazoxan, there was a trend toward higher blood flow in the region of myocardium perfused by the stenotic coronary artery, but this change did not achieve statistical significance. These data indicate that residual vasomotor tone may limit blood flow to ischaemic areas of myocardium perfused by a stenotic coronary artery, and that this vasoconstriction is mediated, at least in part, by alpha 1-adrenergic mechanisms.

Adrenergic alpha-Antagonists↗

PubMed1990

Effect of pinacidil on myocardial blood flow in the presence of a coronary artery stenosis.

This study examined the effect of pinacidil on transmural distribution of myocardial blood flow during normal conditions and in the presence of a coronary artery stenosis. Studies were performed in 11 awake dogs; blood flow was measured with radioactive microspheres. Two doses of pinacidil were administered to decrease mean arterial pressure (MAP) by approximately 10 mm Hg (low dose, 0.18 +/- 0.02 mg/kg) and 20 mm Hg (high dose, 0.32 +/- 0.03 mg/kg). Measurements were performed during unimpeded arterial inflow and with two levels of coronary stenosis that limited blood flow to approximately 60% above (moderate stenosis) and approximately 30% above basal flow (severe stenosis). With no stenosis, coronary flow increased 227 +/- 17% after low-dose and 321 +/- 31% after high-dose pinacidil (each p less than 0.01). During control conditions, subendocardial (endo) flow exceeded subepicardial (epi) flow (endo/epi ratio = 1.33). This ratio was not changed by low-dose pinacidil but decreased to 0.93 after high-dose pinacidil (p less than 0.05). During high-dose pinacidil, a coronary stenosis caused uniform reduction of blood flow across the left ventricular wall, with no further significant change in the ratio of endo/epi flow. With low-dose pinacidil, both moderate and severe degrees of stenosis caused redistribution of flow away from the subendocardium similar to that observed with high-dose pinacidil. Although a stenosis that limited the increase in mean coronary flow after pinacidil administration to 162% of the predrug control value had a 95% probability of not causing a decrease in absolute subendocardial flow, the data suggest that pinacidil could have potential for aggravating subendocardial ischemia in severe occlusive coronary artery disease.

Animals↗

PubMed1990

Effect of pinacidil on myocardial blood flow in the chronically pressure overloaded hypertrophied left ventricle.

This study examined the effect of pinacidil on the transmural distribution of myocardial blood flow in the chronically pressure overloaded hypertrophied left ventricle. Studies were performed in six dogs in which banding of the ascending aorta had resulted in an 88% increase in left ventricular mass, as well as in six normal control animals. Two doses of pinacidil were administered to decrease mean arterial pressure by approximately 10 mm Hg (low dose) and 20 mm Hg (high dose). Animals with hypertrophy required significantly smaller drug doses to achieve the desired reductions in arterial pressure. During control conditions mean myocardial blood flow was significantly higher in animals with hypertrophy (1.90 +/- 0.21 ml/min/g) than in normal animals (1.12 +/- 0.08 ml/min/g; p less than 0.05). Subendocardial flow (endo) exceeded subepicardial flow (epi) in normal dogs during control conditions (endo/epi = 1.41 +/- 0.13), but not in animals with hypertrophy (endo/epi = 1.06 +/- 0.06; p less than 0.05). Pinacidil caused coronary vasodilation with similar relative increases in blood flow in both normal and hypertrophied hearts, so that after pinacidil, absolute blood flow rates remained higher than normal in animals with hypertrophy. Pinacidil caused a redistribution of blood flow away from the subendocardium in normal hearts (endo/epi = 0.90 +/- 0.11 during high-dose pinacidil) and in hearts with hypertrophy (endo/epi = 0.81 +/- 0.13 during high-dose pinacidil). The endo/epi ratios during high-dose pinacidil were not significantly different between the two groups. This study demonstrates that pinacidil is a potent coronary vasodilator in both normal and hypertrophied hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗