Circumflex Coronary Blood Flow Research Articles

Improvement of Postischemic, Contractile Function by the Calcium Channel Blocking Agent Nitrendipine in Conscious Dogs

The effect of the new calcium channel blocking agent, nitrendipine, on recovery of contractile function following a 10-min left anterior descending coronary artery occlusion was studied in conscious dogs instrumented with sonomicrometers in the subendocardium of ischemic and normal regions. Nitrendipine (1.0 and 2.5 micrograms/kg/min i.v.) or drug vehicle was administered 30 min prior to the onset of coronary artery occlusion and continued for 30 min following reperfusion accomplished by inflation and deflation of a vascular balloon cuff. Nitrendipine produced a dose-related reduction in arterial pressure and an increase in heart rate and left circumflex coronary blood flow velocity. At 6 h following reperfusion in control dogs (N = 8), segment shortening was significantly reduced from control levels (71 +/- 10% of control). In comparison, dogs pretreated with nitrendipine (3 micrograms/kg/min i.v.) (n = 8) had significantly greater recovery of segment shortening throughout the reperfusion period (102 +/- 10% of control at 6 h following reperfusion). The data demonstrate that pretreatment with the calcium channel blocking agent enhances the recovery of function in postischemic, reperfused, "stunned" myocardium.

Effects of aminophylline on behaviorally induced coronary blood flow increases.

It has been proposed that adenosine is a metabolic vasodilator that matches myocardial oxygen supply to demand by regulating coronary blood flow. In the present study, the adenosine antagonist aminophylline (Am) was used to evaluate the role adenosine plays in the coronary blood flow increase elicited by a controlled aversive stress, namely, classical aversive conditioning (a 30-s tone reinforced with a 1-s shock). Fifteen mongrel dogs were chronically instrumented to measure left circumflex coronary blood flow (CBF), left ventricular pressure (LVP), and heart rate. Am significantly (P greater than 0.01) attenuated the CBF response to the aversive stress without affecting the prestress levels (pre-Am control 40.9 +/- 2.4, peak 64.6 +/- 3.3 ml/min; post-Am control 41.7 +/- 2.2, peak 55.0 +/- 2.5 ml/min). The maximal CBF increase was reduced by 38.9 +/- 6.7% when compared with the control (no drug) condition. In a similar manner, neither heart rate nor LVP was affected by Am. However, Am significantly increased prestress level of first derivative of left ventricular pressure with reference to time [LV dP/dt] (pre-Am control 3,793.5 +/- 289.8 and Am 4,599.6 +/- 331.2 mmHg/s, respectively). These data suggest that adenosine contributes significantly to the regulation of CBF during a controlled emotional stress.

Diurnal changes in coronary blood flow in conscious dogs.

The purpose of the present study was to evaluate potential diurnal changes in resting coronary blood flow under conditions of comparable myocardial oxygen requirements. We studied 21 conscious, resting dogs instrumented for the measurement of coronary flow, left ventricular pressure, and regional myocardial segment length. Recordings were taken in the early morning and late afternoon. In the afternoon, left circumflex coronary blood flow was 12.8% higher than in the morning, without detectable changes in the major hemodynamic determinants of myocardial oxygen consumption, i.e., heart rate, left ventricular pressure, peak positive dP/dt, end-diastolic regional myocardial dimension, and regional myocardial stroke work. These results are consistent with a circadian variation of coronary vascular tone accompanied by compensatory alteration in myocardial oxygen extraction and may have clinical relevance, since the coronary vascular tone may change dynamically in patients with critical coronary stenosis.

Cardiovascular response to sudden strenuous exercise.

Cardiac responses to sudden strenuous exercise were studied in seven dogs instrumented to measure cardiac output (Q), stroke volume (SV), left ventricular (LV) pressure, aortic pressure and circumflex coronary blood flow (CBF). The dogs were run on a treadmill at 12.9 km/h, 20% grade for 15s without prior warm-up. During the first 10s of the run, HR and Q increased rapidly. By 2s, myocardial O2 requirements, as estimated from either the tension time index (TTI) or calculated wall tension, had increased significantly above resting values. Simultaneously, mean CBF fell 13% and stroke CBF fell 49% below resting values at the onset of sudden exercise (2s) and was associated with 17% and 21% decreases in positive and negative LV dP/dt, a 9% decrease in (dP/dt)/P and an 11% decrease in SV. After the initial decrease at 2s, these variables then increased rapidly as the run continued except for stroke CBF which never reached resting levels. HR, Q, and LV dP/dt reached near maximal values for this level of exercise by 10s after the start of exercise. In contrast, mean CBF was still increasing when the run was terminated. These data show that sudden strenuous exercise results in a transient decrease in myocardial O2 delivery at a time when myocardial O2 requirements are rapidly increasing. This imbalance between myocardial O2 supply and demand is due to a transient decrease in coronary blood flow followed by a delay in metabolic regulation of CBF.

Origin of atrial coving in canine phasic coronary artery blood flow.

The transient decrease in left circumflex coronary artery blood flow during atrial contraction (atrial coves) was examined in open-chest, heart-blocked dogs. Prominent atrial coves were observed in left circumflex flow during both diastole and systole as a result of the asynchrony of atrial and ventricular contractions. In eight open-chest dogs, atrial contractions decreased diastolic circumflex coronary flow by 0.016 +/- 0.002 ml and systolic flow by 0.014 +/- 0.001 ml compared with diastolic and systolic intervals during which no atrial contractions occurred. The diastolic and systolic flow reductions in this vessel were not significantly different (P greater than 0.14). In five of the eight dogs no diastolic atrial coves were observed in left anterior descending coronary flow, and only minimal diastolic coving was present in the remaining three dogs; no systolic coves were present in this vessel in any of the eight dogs. In five additional open-chest dogs, brief inflation of a balloon in the left atrium produced elevations of left ventricular diastolic pressure comparable to those produced by atrial contraction. Only minimal atrial coves were associated with these balloon inflations. These data are consistent with the hypothesis that atrial contraction limits flow through the atrial blood vessels and results in a transient decrease in flow in the atrial arteries that arise from the left circumflex coronary artery. Although increases in ventricular diastolic pressure may be partially responsible for the appearance of atrial coves in the left circumflex coronary artery, mechanical contraction of the atrial musculature appears to be of significant importance.

Effects of dipyridamole on myocardial glucose uptake in the newborn lamb

Carbohydrates are an important source of energy for the immature myocardium. Since dipyridamole (DPY) has been reported to facilitate glucose uptake in the adult heart, the present study was designed to determine whether DPY could enhance glucose uptake in the nonischemic newborn. In anesthetized, open chest lambs ( n = 8), circumflex coronary blood flow (CBF), myocardial adenine nucleotide content, and aortic and coronary sinus concentrations of glucose, lactate, and pyruvate were determined before and after a single dose of DPY (0.2 mg/kg, intravenously). Adenine nucleotides were measured by HPLC. The consumption of substrates was calculated as the product of CBF and the aortic-coronary sinus difference in substrate concentration. Coronary blood flow averaged 114 ± 6 ml/min/100 g in the untreated animals, and increased by 44% following treatment with dipyridamole ( P < 0.01). This was associated with a 32% decrease in coronary vascular resistance ( P < 0.01). Glucose uptake increased from 9 to 46 μmoles/min/100 g ( P < 0.01) following dipyridamole treatment; lactate uptake decreased by 97% ( P < 0.01). There was a net release of pyruvate from the neonatal hearts; this increased from 18 to 25 μmole/min/100 g ( P < 0.05). Myocardial ATP content averaged 4.08 μmole/g wet wt in the untreated animals, and increased 11% to 4.52 following DPY ( P < 0.01). The agent had no effect on the myocardial tissue levels of AMP or ADP. These data indicate that DPY is a coronary vasodilator in the newborn lamb and augments both glucose uptake and myocardial ATP content. These metabolic effects provide a rationale for further studies during periods of hypoxia and ischemia.

Platelet-activating factor and the release of a platelet-derived coronary artery vasodilator substance in the canine.

Platelet-activating factor (acetyl-glyceryl-ether-phosphorylcholine; 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphorylcholine), which is released by stimulated neutrophils and platelets, possesses the ability to alter vascular tone and permeability and to activate various formed blood elements. We have characterized the hemodynamic effects of intracoronary injections of platelet-activating factor and the influences of pharmacological blockade and platelet depletion on its activity. Intracoronary injections of platelet-activating factor produced maximum increases in left circumflex coronary artery blood flow of 55 +/- 8, 52 +/- 8, and 52 +/- 7 ml/min at 0.5, 1.0, and 2.0 nM, respectively. Only modest changes in systemic arterial blood pressure and regional developed isometric contractile force were associated with the intracoronary artery administration of platelet-activating factor over the range of doses studied. The increase in left circumflex coronary artery blood flow in response to platelet-activating factor was attenuated (44%), but not prevented, by pretreatment with diphenhydramine, (4 mg/kg, iv), and was not affected by pretreatment with aspirin (20 mg/kg, iv) or the systemic administration of the serotonin receptor antagonist, methysergide. The coronary vasodilator response to platelet-activating factor was reduced significantly by the induction of thrombocytopenia (95 +/- 3% platelet depletion) through the administration of sheep-derived canine platelet antiserum. The intracoronary artery injection of platelet-rich plasma activated with platelet-activating factor into thrombocytopenic dogs produced a significantly greater increase in coronary artery blood flow than the injection of either non-activated platelet-rich plasma or platelet-depleted plasma to which platelet-activating factor was added. Similar changes in coronary artery blood flow could be obtained with the intracoronary artery injection of cell-free supernates from washed platelets activated with platelet-activating factor. The observed results suggest that circulating platelets, when exposed to platelet-activating factor, can release a coronary dilator substance, and that the coronary artery dilation is not prevented by pharmacological receptor antagonists for histamine, serotonin, or inhibitors of cyclooxygenase.

Prostaglandins modulate baroreflex-induced changes in blood pressure and myocardial function in anesthetized dogs.

The purpose of our study was to investigate the role of prostaglandins in the changes in myocardial function and peripheral and coronary vascular resistance which accompany a generalized increase in sympathetic tone caused by carotid baroreflex unloading in the anesthetized dog. Bilateral carotid artery occlusion (BCO) with heart rate held constant by electrical pacing (150 beats/min) resulted in increases in systolic, (33%) diastolic (40%), and mean (35%) arterial pressures, LV systolic pressure (33%) and left ventricular (LV) dP/dt (37%). After blockade of prostaglandin synthesis with indomethacin (N = 11) or meclofenamate (N = 6) the increases in systolic (41%), diastolic (45%), and mean (41%) arterial pressures, LV systolic pressure (39%), LV dP/dt (52%), and cardiac work caused by BCO were significantly greater, in spite of the initially higher baseline values (11-18%) following the administration of the drugs. In contrast, the changes in circumflex coronary blood flow and coronary vascular resistance to BCO were essentially the same before and after inhibition of prostaglandin synthesis. Systemic prostaglandin synthesis may, therefore, play a significant role in the control of systemic arterial pressure and myocardial function, most probably by modulating the release of norepinephrine from adrenergic nerve terminals, without adversely affecting coronary blood flow regulation.

Augmented catecholamine uptake by the heart during hemorrhage in the conscious dog.

Changes in arterial and coronary sinus concentrations of norepinephrine (NE) and epinephrine (E) in response to hemorrhage were examined in conscious dogs. Hemorrhage (45 +/- 3.2 ml/kg) decreased mean arterial pressure by 47 +/- 6%, left ventricular (LV) dP/dt by 38 +/- 6%, and mean left circumflex coronary blood flow by 47 +/- 6%, while heart rate increased by 44 +/- 13%. Increases in concentrations of arterial NE (5,050 +/- 1,080 from 190 +/- 20 pg/ml) and E (12,700 +/- 3,280 from 110 +/- 20 pg/ml) were far greater than increases in coronary sinus NE (1,700 +/- 780 from 270 +/- 50 pg/ml) and E (4,300 +/- 2,590 from 90 +/- 10 pg/ml). Net release of NE from the heart at rest was converted to a fractional extraction of 66 +/- 9% after hemorrhage. Fractional extraction of E increased from 16 +/- 6% at rest to 73 +/- 8% after hemorrhage. In cardiac-denervated dogs, hemorrhage (46 +/- 2.8 ml/kg) decreased mean arterial pressure by 39 +/- 15%, LV dP/dt by 36 +/- 10%, and mean left circumflex coronary blood flow by 36 +/- 13%, while heart rate increased by 24 +/- 10%. Hemorrhage increased arterial NE (1,740 +/- 150 from 210 +/- 30 pg/ml) and E (3,050 +/- 880 from 140 +/- 20 pg/ml) more than it increased coronary sinus NE (460 +/- 50 from 150 +/- 30 pg/ml) and E (660 +/- 160 from 90 +/- 20 pg/ml) but significantly less (P less than 0.05) than observed in intact dogs. These experiments indicate that hemorrhage, unlike exercise and sympathetic nerve stimulation, does not induce net overflow of NE from the heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha-receptor constriction induced by atrial fibrillation during maximal coronary dilatation.

The mechanism of coronary vasoconstriction induced by atrial fibrillation during maximal coronary dilatation was studied in 19 chloralose-urethane anesthetized dogs. Maximal coronary dilatation was achieved by carbochromene (5 mg/kg i.v.) or dipyridamole (0.2 mg/kg i.v.). Left circumflex coronary blood flow was measured with an electromagnetic flowmeter. Atrial fibrillation was compared with rhythmic atrial pacing at similar heart rates (207 +/- 12 vs. 204 +/- 12 beats/min). During maximal coronary dilatation, coronary resistance was 0.38 +/- 0.05 mm Hg X min X 100 g/ml (RU) at sinus rhythm, 0.41 +/- 0.06 RU at atrial pacing, and 0.52 +/- 0.07 RU at atrial fibrillation, that was significantly (p less than 0.005) higher than during sinus rhythm and atrial pacing. Accordingly, coronary oxygen extraction was 14 +/- 1% at sinus rhythm, 17 +/- 1% at atrial pacing (p less than 0.005 vs. sinus rhythm) and 27 +/- 2% at atrial fibrillation (p less than 0.001 vs sinus rhythm and atrial pacing). Beta-adrenoceptor blockade with propranolol (1 mg/kg i.v.) did not prevent this coronary vasoconstrictive effect. Following alpha-blockade with phenoxybenzamine (10 mg/kg i.v.), however, coronary resistance was 0.52 +/- 0.08 RU during sinus rhythm, 0.54 +/- 0.10 RU during atrial pacing and 0.57 +/- 0.09 RU during atrial fibrillation. The data suggest coronary vasoconstriction induced by atrial fibrillation mediated by an alpha-adrenoceptor mechanism.

Deterioration of metabolic coronary regulation in hemorrhagic shock. Role of hypoxia and the renin-angiotensin system.

The effect of hypoxia and the renin-angiotensin system on metabolic coronary regulation in hemorrhagic shock was studied in 22 anesthetized open-chest dogs. Left circumflex coronary blood flow was measured with an electromagnetic flowmeter. Dogs were ventilated with room air (n = 8) or 100% oxygen (n = 7). A third group of dogs was ventilated with room air and bilaterally nephrectomized 5 h prior to starting the experimental protocol (n = 7). After control data had been obtained, dogs were bled from the femoral arteries into a pressurized reservoir which maintained blood pressure at 45 +/- 1 mmHg. The angiotensin II receptor blocker, saralasin, was then infused i.v. (0.1, 1.0, 10.0 micrograms/kg per min). Coronary blood flow was reduced by hemorrhage, and no significant difference existed in coronary flow during hemorrhage among the three groups. Coronary sinus oxygen saturation was diminished in control animals during hemorrhage from 26% +/- 1% to 17% +/- 1% (P less than 0.05) but normal in 100% oxygen ventilated animals (30% +/- 3%) and in nephrectomized dogs (34% +/- 4%). Coronary oxygen extraction was reduced by saralasin in intact but not in nephrectomized dogs. In six additional experiments, in which blood pressure was not artificially held constant during saralasin infusion, saralasin still significantly improved coronary sinus oxygen saturation and thus reduced coronary oxygen extraction. The data suggest that both hypoxia and the renin-angiotensin system participate in the restriction of metabolic coronary regulation in hemorrhagic shock.

Antagonism of Vasopressin-Induced Coronary Artery Constriction by the Vasopressin Antagonist d(CH2)5Tyr(Me)-AVP

d(CH2)5Tyr(Me)-AVP is a potent inhibitor of the systemic vasoconstrictor action of vasopressin (AVP). In order to examine the effectiveness of this agent in blocking AVP-induced coronary vasoconstriction, 11 pentobarbital-anesthetized mongrel dogs were instrumented for the measurement of left circumflex (LCX) coronary blood flow, systemic arterial blood pressure, heart rate, lead II electrocardiogram, left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular +/- dP/dt. Direct injection of AVP (0.01-1 microgram) into the LCX produced a dose-dependent decrease in coronary artery blood flow (maximum reduction: 60.5 +/- 8.1% after 1 microgram), - dP/dt (maximum reduction: 41.8 +/- 5.3% after 1 microgram), and +dP/dt (maximum reduction: 14.6 +/- 5.3%), whereas a dose-dependent increase in left ventricular end-diastolic pressure was observed (maximum increase: 62.6 +/- 20.2%). No significant changes occurred in heart rate, mean blood pressure, or left ventricular developed pressure. Intravenous administration of d(CH2)5Tyr(Me)-AVP reduced (1 microgram/kg) or abolished (5 micrograms/kg) the effects of AVP on coronary blood flow +/-dP/dt and left ventricular end-diastolic pressure. In addition, doses of 1,2, and 5 micrograms/kg of d(CH2)5Tyr(Me)-AVP alone produced increases of LCX blood flow of 5.1 +/- 1.5, 2.0 +/- 0.7, and 6.8 +/- 1.7 ml/min, respectively (p less than 0.05). We conclude that d(CH2)5Tyr(Me)-AVP is effective in preventing the coronary artery constriction and hemodynamic sequelae of intracoronary administered AVP.

Effect of vasopressin on phasic coronary blood flow.

The effects of vasopressin on the coronary circulation have been studied with regard to its general hemodynamic effects. Aortic blood pressure (BP), left ventricular pressure (LVP), aortic blood flow (AoBF), and circumflex blood flow (CBF), were measured in 12 open-chest dogs, under control conditions and during vasopressin infusion (25 mU/kg/min). During vasopressin infusion, the mean aortic blood pressure (MBP) was increased from 104 +/- 23 mm Hg to 161 +/- 23 mm diastolic blood pressure (DBP) was more increased (+55%) than the systolic blood pressure (SBP) (+40%). AoBF was decreased from 2.169 +/- 0.408 l/min to 1.118 +/- 0.303 l/min; and the heart rate was decreased by 18%. The total combined left ventricular power did not change significantly. The increase in total peripheral resistance (TPR) (+200%) was the main change in impedance spectrum. The mean circumflex coronary blood flow (MCBF) was decreased from 48 +/- 8.6 ml/min to 33.4 +/- 9.7 ml/min. This decrease was more important in the diastolic circumflex blood flow (DCBF) (-33%) than in the systolic one (-0.8%). The diastolic pressure time index (DPTI) was more increased than the systolic pressure time index (SPTI). The DPTI/SPTI ratio was increased from 0.91 to 1.3. Long diastoles, induced by vagus nerve stimulation, have permitted to characterise the relationship between pressure and coronary blood flow during diastole. This relationship was linear under basal condition, and during vasopressin perfusion. This made it possible to determine the critical closing pressure (Pf0), and the coronary conductance (the slope of the regression curve). Vasopressin induced an increase in Pf0, from 33.7 +/- 95 to 77.4 +/- 16.07 mm Hg (p less than 0.001), and a decrease in coronary conductance, from 0.8 +/- 0.32 to 0.5 +/- 0.1 ml/min/mm Hg. The effect of an acute change in perfusion pressure on the coronary flow, under control conditions and during vasopressin infusion was studied by opening a large arteriovenous fistula. Unclamping of the fistula, under control conditions, allowed to realize an acute fall in DBP from 82.5 +/- 6.36 to 35.5 +/- 9.19 mm Hg, and in DCBF, from 58.5 +/- 9.2 to 20 +/- 9.8 ml/min. During vasopressin infusion, a similar fall in perfusion pressure lead to a zero diastolic circumflex blood flow, for a diastolic aortic blood pressure of 56 +/- 12 mm Hg. However, vasopressin did not affect the delayed active coronary vasodilatation.

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.

Streptokinase thrombolysis in experimental coronary artery thrombosis: pattern of reflow and effect of a stenosis

We studied recanalization of an obstructed left circumflex coronary artery by streptokinase in open-chest anesthetized dogs. Thrombotic occlusion was induced by a 100 μA anodal current selectively delivered to the intimal surface of the vessel. Intracoronary streptokinase (50,000 U) or saline was infused over a 50-min period beginning at either 30 min or 90 min after occlusion. Continous recordings were made of antegrade circumflex flow and regional myocardial function, which was quantitated using sonomicrometer crystals in the regions of the left anterior descending and circumflex coronary arteries. In some experiments a fixed stenosis, having no effect on mean circumflex coronary artery blood flow, was placed at the site of subsequent thrombus formation. The presence of a stenosis decreased the weight of occlusive thrombi obtained from nonreperfused saline controls by 40% and increased the proportion of animals successfully reperfused by streptokinase from 13 to 76%. Streptokinase reduced thrombus mass by 44% in animals recanalized in the presence of the stenosis. On the average, reflow was established after 26 min of streptokinase infusion, was less in magnitude than pre-occlusion flow, and was unstable and intermittent, being marked by frequent reocclusions. Initiating treatment at 30 min or 90 min post-occlusion did not influence characteristics of the reflow. Return of myocardial contractility in the ischemic bed was not detected during the immediate reperfusion period in the majority of these experiments.

Effects of nifedipine and diltiazem on coronary reactive hyperaemia.

The effects of nifedipine and diltiazem on the reactive hyperaemic response which followed 10 s occlusions of the left circumflex coronary artery was studied in 18 chronically instrumented awake dogs. Nifedipine (0.010 mg X kg-1, iv) and diltiazem (0.30 mg X kg-1, iv) were administered to produce 2 1/2 to 3-fold peak increases in left circumflex coronary blood flow. Coronary flow returned to the control value within 30 min after drug administration, and reactive hyperaemia was examined from 30 min to 2 h after drug administration, when resting coronary blood flow, heart rate, arterial pressure and left ventricular end-diastolic pressure were not different from pretreatment values. Both nifedipine and diltiazem caused blunting of the reactive hyperaemic response following 10 s coronary occlusions with reduction of excess blood flow during reactive hyperaemia from 20.5 +/- 2.65 ml during control conditions to 11.4 +/- 3.2 ml 30 min after nifedipine (P less than 0.001), and from 21.0 +/- 3.74 ml to 13.8 +/- 3.2 ml 30 min after diltiazem (P less than 0.001). Coronary reactive hyperaemia remained depressed for 60 min after nifedipine and throughout the entire 2 h observation period after diltiazem. Measurements of myocardial blood flow with radioactive microspheres demonstrated that neither nifedipine nor diltiazem increased collateral flow during coronary occlusion. Thus, blunting of the reactive hyperaemic response could not be attributed to relief of ischaemia by enhanced collateral blood flow.

The repetitive extrasystole as an index of vulnerability to ventricular fibrillation during myocardial ischemia in the canine heart

The repetitive extrasystole threshold (RET) is a reliable measure of vulnerability to ventricular fibrillation (VF) during diverse interventions in the normal heart. Whether this relationship also holds during varying degrees of myocardial ischemia has not been adequately explored. In 15 chloralose-anesthetized dogs, circumflex coronary blood flow (CBF) was decreased progressively with the use of an externally applied balloon occluder. There was a statistically significant correlation between the RET and ventricular fibrillation threshold (VFT) until left circumflex coronary artery flow was reduced by 90% of control values ( r = 0.92). During reductions of CBF of 90% or greater, the VFT fell more than the RET and the RET/VFT ratio was disrupted. Total coronary occlusion, whether performed abruptly or gradually (5 minutes), likewise resulted in a disproportionate decline in VFT. During sustained total coronary occlusion, the VFT recovered to control values within 15 minutes, and the relationship between the RE and VF thresholds was restored. We conclude that the vulnerable period threshold for provoking repetitive extrasystole is a reliable index of vulnerability to VF during myocardial ischemia and remains so until nearly total occlusion of a major coronary vessel.

Dipyridamole dilates large coronary arteries in conscious dogs.

The effects of 0.25 mg/kg dipyridamole on left ventricular (LV) pressures, LV dP/dt, heart rate, aortic pressures, left circumflex coronary blood flow, and left circumflex coronary arterial diameters and on calculations of late diastolic coronary resistance and large coronary cross-sectional area were studied in 15 conscious dogs. Injection of dipyridamole, a drug that has a mechanism of action dependent on myocardial adenosine production, caused sustained increases in mean coronary blood flow (244 +/- 28%), large coronary arterial cross-sectional area (28 +/- 3.2%), heart rate (32 +/- 3.6%), and LV dP/dt (23 +/- 3.0%) and reductions in late diastolic coronary resistance (73 +/- 2.4%) and mean arterial pressure (14 +/- 1.9%). Neither beta-adrenergic-receptor blockade alone nor in conjunction with constant heart rate affected the dilation of large coronary arteries to dipyridamole significantly. Ganglionic blockade with hexamethonium also had little effect on the response of large and small coronary vessels to dipyridamole. Surprisingly neither beta-adrenergic-receptor nor ganglionic blockade abolished the rise in LV dP/dt observed after dipyridamole. Aminophylline, however, effectively eliminated the dilation of large coronary arteries and resistance coronary vessels in response to dipyridamole. In summary, as long as dipyridamole does not induce severe sustained hypotension it exerts potent effects on both coronary arterial resistance and large coronary arteries in the conscious dog. The coronary dilation is independent of reflex adrenergic activation, but appears dependent on myocardial adenosine production.

Ventricular fibrillation in a conscious canine model - Its prevention by UM-272

The antifibrillatory properties of UM-272 (dimethylpropranolol; Pranolium) were evaluated in a conscious canine model of sudden coronary death. The initial preparation of the animal model was carried out under surgical anesthesia and involved the intraluminal implantation of a Teflon-coated silver wire into the circumflex coronary artery so that 3 mm of the bared electrode was in contact with the endothelial surface. The left anterior descending coronary artery then was occluded for a period of 90 min and reperfused in the presence of a critical stenosis. Three days after myocardial infarction, they were randomized into two groups. One group (n = 10) served as controls and received saline. The second group (n = 10) received UM-272 in a dose of 5 mg/kg every 6 h. On day 4, a 150 μA current was applied to the intimal surface of the left circumflex coronary artery, resulting in transient or permanent alterations in circumflex coronary blood flow accompanied by electrocardiographic evidence of regional myocardial ischemia. The time to onset of ST-segment changes in the saline control group was 99 ± 34 min and was followed by the appearance of premature ventricular complexes (111 ± 34 min) and subsequent ventricular tachycardia (131 ± 37 min) which terminated in ventricular fibrillation in each of the 10 dogs. Animals treated with UM-272 likewise developed ST-segment changes (156 ± 28 min) and premature ventricular complexes (168 ± 29 min), but 4 of 10 animals failed to develop ventricular fibrillation (P < 0.05 vs. saline). These results demonstrate that UM-272, the dimethyl quaternary analog of propranolol, is effective in reducing the incidence of ventricular fibrillation in a conscious canine model in which the superimposition of a transient ischemic event upon an already jeopardized heart leads to the development of sudden death.

Coronary vasodilator reserve impairment distal to systolic coronary artery compression in dogs.

To investigate the mechanism by which muscular coronary overbridging can cause myocardial ischaemia, we studied the effect of systolic compression (SC) of the proximal left circumflex coronary artery in ten anaesthetised dogs, with both intact autoregulation and maximally dilated coronary arteries. Systolic compression was produced by a mechanical device adjusted to interrupt circumflex coronary flow only during the aortic ejection period and we measured left ventricular, aortic and distal circumflex coronary pressures, phasic coronary blood flow, regional myocardial blood flow (RMBF), myocardial oxygen consumption (MVO2), and myocardial lactate extraction (MLE). During both autoregulation and maximal coronary vasodilatation, there was a diastolic time lag after SC to restart phasic circumflex coronary blood flow (34 +/- 3 vs 31 +/- 3 ms) and to increase distal circumflex coronary pressure (69 +/- 4 vs 79 +/- 6 ms). With autoregulation, SC reduced the diastolic circumflex coronary: systolic left ventricular pressure time ratio (DPTIc:SPTI) and there were no changes in the other measured variables. During maximal coronary vasodilatation and SC, the coronary vasodilator reserve, the DPTIc:SPTI ratio and the inner:outer myocardial blood flow distribution were decreased in the territory of the left circumflex coronary artery; a linear relationship was observed between the DPTIc:SPTI and the inner:outer myocardial blood flow ratio. Systolic compression during vasodilatation also produced a reduction in myocardial oxygen consumption of the whole heart and a production of lactate in the coronary sinus. These results suggest that myocardial ischaemia with a myocardial bridge is due to the combined effects of a diastolic time lag to repressurise the coronary vascular bed, of tachycardia and of coronary vasodilatation.