Xue-Zheng Dai

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

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

Oxygen consumption and coronary reactivity in postischemic myocardium.

Coronary vascular responses in regions of reversible postischemic myocardial contractile dysfunction (stunned myocardium) were examined in chronically instrumented, awake dogs. Left anterior descending coronary artery blood flow and oxygen extraction, aortic and left ventricular pressures, and regional myocardial segment shortening were determined. Regional myocardial blood flow was measured with microspheres. Coronary reactive hyperemia and vasodilator reserve, and regional myocardial oxygen consumption were determined. Three sequential 10-minute left anterior descending coronary artery occlusions separated by 30-minute reperfusion periods resulted in progressive postischemic dysfunction so that 1 hour after the final coronary artery occlusion, myocardial segment shortening was reduced to 37% of baseline. Despite this decrease in contractile function, left anterior descending artery flow (19.6±2.6 vs. 18.4±3.0 ml/min), myocardial blood flow and the transmural distribution of flow measured with microspheres, and regional myocardial oxygen consumption were unchanged. Although the coronary vasodilator reserve hi response to adenosine was unaltered (63±9 vs. 70±15 ml/min), the reactive hyperemia response to a 10-second coronary occlusion was decreased in intensity (debt repayment ratio=474±78% vs. 322±74%; p<0.05) and duration (57±9.1 vs. 35±4.5 seconds; p<0.05), while the peak flow response was unchanged (57±6.8 vs. 60±7.1 ml/min). Thus, in the intact awake animal postischemic myocardial contractile dysfunction was not associated with decreased myocardial oxygen consumption and did not impair the normal relation between coronary blood flow and myocardial oxygen utilization. Although coronary vessels showed a normal ability to vasodilate in response to adenosine, coronary reactive hyperemia was reduced.

Role of adenosine in coronary vasodilation during exercise.

This study examined the hypothesis that increases in myocardial blood flow during exercise are mediated by adenosine-induced coronary vasodilation. Active hyperemia associated with graded treadmill exercise and coronary reactive hyperemia were examined in chronically instrumented awake dogs during control conditions, after intracoronary infusion of adenosine deaminase (5 units/kg/min for 10 minutes), and after adenosine receptor blockade with 8-phenyltheophylline. Both adenosine deaminase and 8-phenyltheophylline caused a rightward shift of the dose-response curve to intracoronary adenosine; 8-phenyltheophylline was significantly more potent than adenosine deaminase. Adenosine deaminase caused a 33 ± 7 to 39 ± 3% decrease in reactive hyperemia blood flow following coronary occlusions of 5–20 seconds duration, respectively, while 8-phenyltheophylline produced a 40 ± 6 to 62 ± 8% decrease in reactive hyperemia. Increasing myocardial oxygen consumption during treadmill exercise was associated with progressive increases of coronary blood flow. Neither adenosine deaminase nor 8-phenyltheophylline attenuated the increase in coronary blood flow or the decrease of coronary vascular resistance during exercise. Neither agent altered the relation between myocardial oxygen consumption and coronary blood flow. Thus, although both adenosine deaminase and 8-phenyltheophylline antagonized coronary vasodilation in response to exogenous adenosine and blunted coronary reactive hyperemia, neither agent impaired coronary vasodilation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support a substantial role for adenosine in mediating coronary vasodilation during exercise.

The role of alpha 1- and alpha 2-adrenergic receptors in mediation of coronary vasoconstriction in hypoperfused ischemic myocardium during exercise.

This study was carried out to test the hypothesis that adrenergic coronary vasoconstriction limits blood flow to hypoperfused regions of myocardium during exercise. The vasoconstrictor influence of alpha-adrenergic receptor subtypes was assessed by use of selective adrenergic blocking agents. Dogs chronically instrumented with a circumflex coronary artery hydraulic occluder and an intra-arterial catheter underwent treadmill exercise in the presence of a coronary stenosis that decreased distal perfusion pressure to 40 mm Hg. Myocardial blood flow was measured with radioactive microspheres (15 microns) before and during selective alpha 1- or alpha 2-adrenergic receptor blockade produced by intracoronary infusion of prazosin (1 microgram/kg/min x 10 min) or idazoxan (1 microgram/kg/min x 10 min), respectively. Coronary perfusion pressure was held equal before and during receptor blockade with the hydraulic occluder. Compared with control exercise, subendocardial blood flow increased during alpha 1-receptor blockade with prazosin from 0.60 +/- 0.14 to 1.12 +/- 0.17 ml/min/g (p less than 0.05), and mean transmural flow increased from 1.07 +/- 0.19 to 1.60 +/- 0.22 ml/min/g (p less than 0.05). In contrast, subendocardial and mean transmural blood flow were not different from control during selective alpha 2-adrenergic receptor blockade with idazoxan (0.48 +/- 0.10 vs. 0.67 +/- 0.14 ml/min/g, p = 0.33, and 0.82 +/- 0.15 vs. 1.02 +/- 0.20 ml/min/g, p = 0.45, respectively). These data indicate that even in the presence of a coronary stenosis that causes substantial myocardial underperfusion during exercise, residual coronary vasoconstrictor tone is present in ischemic myocardium, and this vasoconstriction is mediated predominantly by the alpha 1-adrenergic receptor.

Postsynaptic α1- and α2-Adrenergic Mechanisms in Coronary Vasoconstriction

Summary: This study examined the relative importance of postsynaptic α1- and α2-adrenoceptors in mediating coronary vasoconstriction in open chest dogs in which the left circumflex coronary artery was cannulated and perfused at a constant rate. The cervical vagus nerves and central connections of the stellate ganglia were transsected, and β-adrenergic blockade was produced with propranolol. Coronary vasoconstriction occurred in response to intraarterial administration of both the α1-agonist phenylephrine and the α2-agonist BHT 933. The response to phenylephrine was partially blocked with prazosin and nearly completely eliminated by yohimbine. The response to BHT 933 was resistant to prazosin, but almost completely blocked by yohimbine. Coronary vasoconstriction produced by norepinephrine was resistant to prazosin, but was blunted by α2-adrenergic blockade with yohimbine or idazoxan. Prazosin produced some blunting of coronary vasoconstriction in response to small doses of epinephrine, while yohimbine markedly attenuated epinephrine-induced vasoconstriction at all doses used. Measurements of regional myocardial blood flow with radioactive microspheres demonstrated no transmural redistribution of perfusion during vasoconstriction produced by either α1- or α2 stimulation. Thus, although stimulation of both α1- and α2-adrenoceptors is capable of causing coronary vasoconstriction, vasoconstriction in response to norepinephrine and epinephrine is mediated principally by postsynaptic α2-adrenoceptors.

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.

Effect of serotonin and thromboxane A2on 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.

Myocardial blood flow during exercise in dogs with left ventricular hypertrophy produced by aortic banding and perinephritic hypertension.

This study tested the hypothesis that for similar degrees of left ventricular hypertrophy, subendocardial blood flow would be facilitated by the increased diastolic coronary perfusion pressure associated with arterial hypertension, as compared with hypertrophy produced by banding the ascending aorta. Left ventricular hypertrophy was produced with perinephritic hypertension in seven adult dogs and by banding the ascending aorta in nine adult dogs. Left ventricular/body weight ratios were 6.15 +/- 0.59 g/kg in the hypertensive animals and 6.87 +/- 0.47 g/kg in dogs with aortic banding, as compared with 4.23 +/- 0.23 g/kg in seven normal dogs (p less than .01). Studies were performed at rest and during two stages of treadmill exercise to achieve heart rates of 195 and 260 beats/min. Diastolic aortic pressure was increased in animals with hypertension but not in dogs with aortic banding. Systolic ejection period was prolonged in dogs with aortic banding but not in hypertensive dogs. Mean blood flow per gram of myocardium measured with microspheres was similar at rest and during light exercise in all three groups of animals, whereas during heavy exercise blood flow was significantly greater than normal in both groups with hypertrophy. In normal dogs subendocardial/subepicardial (endo/epi) flow ratios did not change significantly during exercise. In both groups with hypertrophy, endo/epi ratios were normal at rest but decreased significantly during exercise. During heavy exercise the endo/epi ratio decreased to 0.73 +/- 0.08 in dogs with aortic banding as compared with 1.07 +/- 0.12 in hypertensive dogs (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary vasodilator reserve in ischemic myocardium of the exercising dog.

BackgroundPrevious 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 ResultsStudies 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,μg/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 < 0.05) and mean transmural flow (1.54±0.59 versus 1.16±0.36; p < 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 < 0.05) ConclusionsThese 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.

α-Adrenergic Effects of Dopamine and Dobutamine on the Coronary Circulation

After β-adrenergic blockade, dopamine causes coronary vasoconstriction that is blocked by nonselective α-adrenergic antagonists. This study was carried out to determine the relative importance of α1- and α2-adrenoceptors in mediating coronary vasoconstriction in response to dopamine. Because dobutamine has been reported to cause α-adrenergic stimulation, the response to dobutamine was also examined. The circumflex coronary artery was cannulated and perfused at a constant blood flow rate in 14 dogs; coronary vasomotor responses were assessed from changes in perfusion pressure. Central effects were eliminated by vagotomy and stellate ganglionectomy; propranolol (1 mg/kg i.v.) was administered to block β-adrenergic effects. The coronary responses to intracoronary bolus doses of dopamine and dobutamine were determined; the effects of selective α1-blockade with prazosin (600μ.g/kg i.v.) and selective α2-blockade with idazoxan or rauwolscine (1–5 μ.g/kg per min intracoronary for 10 min) were examined. Dopamine produced dose-related coronary vasoconstriction; this response was not significantly altered by α1-blockade with prazosin, but was abolished by the addition of α2-adrenergic blockade with idazoxan or rauwolscine. Dobutamine did not produce coronary vasoconstriction at any dose tested. These data demonstrate that coronary vasoconstriction produced by dopamine is mediated through postjunctional α2-adrenergic receptors.