Lorie R. Pelc

Intramyocardial variability in integrated backscatter: effects of coronary occlusion and reperfusion.

The present study was undertaken to characterize regional myocardial alterations of reflected ultrasound during the cardiac cycle in normal, ischemic, and postischemic reperfused myocardium. Time-averaged integrated backscatter (IB) and cardiac cycle-dependent amplitude modulation were measured from subepicardial, midmyocardial, and subendocardial regions of the left ventricular apex and the midportion of the right ventricular free wall under normal conditions (n = 5), after 1 hr of 100% acute left anterior descending (LAD) occlusion (n = 8), and after 15 min LAD occlusion plus 120 min reperfusion (n = 5) in anesthetized, ventilated open-chest dogs. A significant increase in time-averaged IB was observed in the subepicardium, the midmyocardium, and the subendocardium during ischemia and reperfusion, but there was no intramyocardial variability. Cardiac cycle-dependent amplitude modulation of IB was significantly higher in the normal subendocardium than in the subepicardium (4.3 +/- 0.6 vs 2.9 +/- 0.8 dB, p less than .01) and midmyocardium (2.8 +/- .05 dB, p less than .01). This transmural gradient in amplitude modulation was abolished during ischemia and reperfusion. We conclude that cardiac cycle-dependent amplitude modulation in IB has a transmural dependence in the normal myocardium and this is abolished during acute myocardial ischemia.

Mechanism of coronary vasodilation produced by bradykinin.

BackgroundBradykinin has been demonstrated to be an endothelium-dependent vasodilator in the cerebral circulation of the mouse, but the actions of bradykinin on regional tissue perfusion in the canine coronary circulation have not been studied. Methods and ResultsThe mechanism of coronary vasodilation by bradykinin was studied in open-chest, anesthetized dogs. The role of cyclooxygenase stimulation, bradykinin B2 receptor activation, and endothelium-derived relaxing factor in bradykinin-mediated vasodilation was studied in separate groups of dogs. Bradykinin was infused intracoronarily so as to avoid changes in systemic hemodynamics capable of altering the regional distribution of coronary blood flow (radioactive microspheres). Bradykinin produced a preferential increase in subendocardial blood flow. Pretreatment with indomethacin had no effect on bradykinin-mediated increases in total left ventricular flow or the transmural distribution of coronary blood flow. Blockade of bradykinin B2 receptors with the competitive antagonist [This58,D-Phe7]-bradykinin attenuated both the increase in total flow and redistribution of perfusion to the subendocardium produced by bradykinin. Inhibition of endothelium-derived relaxing factor with quinacrine, occlusion/reperfusion, or NG-monomethyl L-arginine attenuated the total increase in left ventricular flow and blocked the redistribution of flow to the subendocardium produced by bradykinin. ConclusionsThe present results demonstrate that intracoronary infusion of bradykinin produces a preferential increase in blood flow to the subendocardium via stimulation of B2 receptors and the release of an endothelium-dependent relaxing factor that may be nitric oxide. (Circulation 1991;83:2048—2056)

Effects of nicorandil and nifedipine on protection of ischemic myocardium.

The effects of nicorandil and nifedipine on ischemia-reperfusion-induced myocardial infarct size following a 2-h occlusion and 30-min reperfusion period of the left anterior descending coronary artery (LAD) were compared in anesthetized dogs. Myocardial blood flow was measured using the radioactive microsphere technique, and infarct size was determined using triphenyl tetrazolium chloride histochemical stain. Vehicle, nicorandil (100-μg/kg bolus followed by 25 μg/kg/min), or nifedipine (10-μg/kg bolus followed by 1 μg/kg/min) was administered intravenously 10 min after LAD occlusion and infused throughout the occlusion and reperfusion periods. Nicorandil and nifedipine reduced mean arterial blood pressure similarly (15 mm Hg) during infusion. However, neither drug altered collateral blood flow to the ischemic region during occlusion. In all three groups, left ventricular mass, area at risk mass, percentage of the left ventricle at risk, and retrograde flow during occlusion were similar. As compared with the control group, nicorandil reduced myocardial infarci size as determined by absolute mass, percentage of the area at risk infarcted, and percentage of the left ventricle infarcted. Nifedipine had no significant effect on infarct size. This beneficial effect of nicorandil was not related to an improvement in myocardial blood flow or a change in global hemodynamics.

Alteration of endothelium-dependent distribution of myocardial blood flow after coronary occlusion and reperfusion.

We have previously demonstrated that intracoronary infusion of the endothelium-dependent vasodilators acetylcholine, ATP, or arachidonic acid produces a preferential increase in subendocardial blood flow in anesthetized dogs. This study was performed to assess the effects of coronary artery occlusion and reperfusion on the distribution of myocardial blood flow produced by endothelium-dependent and endothelium-independent vasodilators. The endothelium was damaged by occlusion of the left anterior descending coronary artery for 45 minutes followed by 60 minutes of reperfusion in pentobarbital-anesthetized dogs. Intracoronary infusions of the endothelium-dependent vasodilators acetylcholine, bradykinin and thiazolylethylamine or the endothelium-independent vasodilator sodium nitroprusside were performed, and regional myocardial blood flow (by radioactive microspheres) was measured before and after occlusion and reperfusion. There were no changes in systemic hemodynamics during intracoronary infusion of vasodilators before or after coronary occlusion and reperfusion. All vasodilators produced similar increases in transmural blood flow before occlusion; however, only the endothelium-dependent vasodilators produced a significant increase in the subendocardial-to-subepicardial blood flow ratio. Increases in transmural flow as well as the preferential increase in subendocardial blood flow produced by acetylcholine, bradykinin, and thiazolylethylamine were attenuated after coronary occlusion and reperfusion. In contrast, increases in transmural blood flow produced by sodium nitroprusside were unchanged. These results suggest that the preferential increase in subendocardial perfusion produced by acetylcholine, bradykinin, and thiazolylethylamine is endothelium-dependent and may be selectively modified by ischemic insult.

Alterations of Alpha1 and Alpha2 Adrenoceptor-mediated Pressor Responses by Halothane and Isoflurane Anesthesia

The mechanism by which halothane and isoflurane interfere with catecholamine-mediated vasoconstriction was investigated, utilizing selective agonists of postjunctional alpha1 and alpha2 adrenoceptors in chronically instrumented dogs. After ganglionic, cholinergic, and beta adrenergic blockade, dose responses to phenylephrine (0.3-1.2 micrograms/kg, iv), a selective alpha1 adrenoceptor agonist, and azepexole [B-HT 933] (5-20 micrograms/kg, iv), a selective alpha2 adrenoceptor agonist, were obtained in conscious dogs. Each dog was subsequently anesthetized with either halothane (1.7%) or isoflurane (2%) in oxygen in equihypotensive concentrations. After a 1 h equilibration period, the dose response curves were repeated. Twenty experiments in ten chronically instrumented dogs were completed. Halothane and isoflurane produced significant (P less than 0.05) attenuation of both the increase in systolic and diastolic arterial pressure after bolus administration of all doses of phenylephrine and azepexole. No specific selectivity of either volatile anesthetic for alpha1 or alpha2 mediated pressor responses was found. Therefore, in chronically instrumented dogs, alpha1- and alpha2-mediated pressor responses were similarly influenced by halothane and isoflurane. The present results suggest that both halothane and isoflurane act as functional antagonists to alpha adrenergic mediated vasoconstriction.

Nitrous Oxide Impairs Functional Recovery of Stunned Myocardium in Barbiturate-anesthetized, Acutely Instrumented Dogs

The purpose of this investigation was to characterize the effects of nitrous oxide or nitrogen (70%) on systemic and regional hemodynamics and myocardial tissue perfusion after a brief coronary artery occlusion (15 min) and reperfusion (3 h). Two groups of experiments (14 experiments total) were completed with 24 open-chest, barbiturate-anesthetized dogs. Coronary collateral blood flow was diverted from the ischemic zone during coronary artery occlusion to eliminate a source of variability in degree of ischemia produced by differences in degrees of collateral blood flow among animals. Seven of 16 dogs treated with nitrous oxide and 7 of 8 dogs treated with nitrogen survived coronary occlusion and reperfusion (P < 0.05). coronary artery occlusion produced paradoxical systolic bulging in the ischemic zone in both groups of experiments. after reperfusion, segment shortening gradually returned toward control levels but remained depressed from the preocclusion state after 3 h in the nitrogen-treated control group. similar results were observed after reperfusion in the nitrous oxide group; however, segment function in the ischemic region was significantly (p < 0.05) depressed throughout the 3-h reperfusion period compared with the control group. transmural coronary collateral blood flow during occlusion was not significantly different (p > 0.05) between groups, indicating that differences in recovery of contractile function observed between groups could not be attributed to differences in myocardial oxygen supply. In addition, the similarity in systemic hemodynamics between the nitrous oxide and control groups indirectly suggests that differences in recovery of function could not be attributed to differences in myocardial oxygen demand. The results indicate that 70% nitrous oxide produces greater mortality after coronary artery occlusion and reperfusion and reduces functional recovery of postishemic, reperfused myocardium compared with 70% nitrogen in open-chest, acutely instrumented dogs.

Preferential increase in subendocardial perfusion produced by endothelium-dependent vasodilators.

The transmural distribution of myocardial blood flow across the left ventricles of anesthetized dogs was measured with radioactive microspheres during intracoronary infusion of the endothelium-dependent vasodilators acetylcholine (10 micrograms/min), adenosine triphosphate (ATP; 20 micrograms/min), and arachidonic acid (600 micrograms/min) and the endothelium-independent vasodilator nifedipine (5 micrograms/min). These compounds were administered before and after a 30 min intracoronary infusion of the phospholipase A2 inhibitor quinacrine (300 micrograms/min). Acetylcholine, ATP, and arachidonic acid produced significant (p less than .05) increases in transmural blood flow and in the ratio of subendocardial to subepicardial blood flow (endo/epi) when compared with control. Infusion of quinacrine did not affect this ratio and did not block the increase in transmural blood flow produced by each agent; however, it did block the redistribution of flow to the subendocardium. In contrast, there was no change in endo/epi during intracoronary infusion of nifedipine before and after quinacrine. These results suggest that endothelium-dependent vasodilators produce a preferential increase in subendocardial perfusion via a product of unsaturated fatty acid metabolism.

Estimation of myocardial infarct size with ultrasonic tissue characterization.

BackgroundUltrasonic tissue characterization (UTC) can distinguish normal from infarcted myocardium. Infarcted myocardium shows an increase in integrated backscatter and loss of cardiac cycle-dependent variation in backscatter. The cyclic variation of backscatter is closely related to regional myocardial contractile function; the latter is a marker of myocardial ischemia. The present study was designed to test the hypothesis that intramural cyclic variation of backscatter can map and estimate infarct size. Methods and ResultsTransmural myocardial infarction was produced in 12 anesthetized, open-chest dogs by total occlusion of the left anterior descending coronary artery for 4 hours. A real-time ultrasonic tissue characterization instrument, which graphically displays integrated backscatter Rayleigh 5, cardiac cycle-dependent variation, and patterns of cyclic variation in backscatter, was used to map infarct size and area at risk of infarction. Staining with 2,3,4-triphenyltetrazolium chloride (TTC) and Patent Blue Dye was used to estimate infarct size and the area at risk, respectively. The ratio of infarct size to area at risk of infarction determined with UTC correlated well with that determined with TTC (r = 0.862, y=23.7±0.792x). Correlation coefficients for infarct size and area at risk were also good (r = 0.736, y=12.3 ± 737x for infarct size and r = 0.714, y = 5.80 ± 1.012x for area at risk). However, UTC underestimated both infarct size and area at risk. ConclusionsUltrasonic tissue characterization may provide a reliable, noninvasive method to estimate myocardial infarct size.

Role of ultrasonic tissue characterization to distinguish reversible from irreversible myocardial injury.

Tissue characterization reflects structural and functional integrity of tissues. Inasmuch as reversible ischemia causes no structural damage and irreversible ischemia results in persistent structural myocardial damage, we postulated that ultrasonic tissue characterization can distinguish the two types of injuries. Anesthetized open chest dogs underwent 15 minutes (group 1, n = 5) and 90 minutes (group 2, n = 8) of acute total occlusion of the left anterior descending coronary artery, followed by 3 hours of reperfusion. Myocardial ischemia-infarction was confirmed with segment shortening, electronmicroscopic examination, and triphenyl tetrazolium chloride staining. Integrated backscatter Rayleigh 5 (IBR5), a measure of ultrasonic backscatter, and Fourier coefficient of amplitude modulation (FAM), an index of cardiac cycle dependent variation in backscatter, were measured at baseline, during ischemia, and after reperfusion. Group 1 (reversible ischemia) showed an increase in IBR5 from -48 +/- 1.2 dB at control to -45 +/- 1.0 dB (p less than 0.01) during ischemia, which returned to baseline after reperfusion (-47 +/- 1.3 dB). FAM was blunted during ischemia (6.2 +/- 1.0 dB during control versus 1.2 +/- 1.0 dB during ischemia, p less than 0.01) and recovered completely during reperfusion. Segment shortening was abolished during ischemia (18% +/- 3% during control versus -12% +/- 5% during ischemia, p less than 0.01) and recovered partially during reperfusion (4% +/- 5%). The group 2 animals with irreversible myocardial injury showed an increase in IBR5, from -49 +/- 1.2 dB during control to -44 +/- 1.0 dB during ischemia (p less than 0.01) and paradoxical bulging of the ischemic region (17% +/- 3% to -7% +/- 3%, p less than 0.01) during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Muscarinic receptor subtypes mediating myocardial blood flow redistribution.

Selective M1 and M2 muscarinic receptor antagonists pirenzepine and AF-DX 116, respectively, were administered to open-chest, pentobarbital-anesthetized dogs to determine the muscarinic receptor subtype responsible for the preferential vasodilation of subendocardial blood vessels during intracoronary methacholine infusion. There were no changes in systemic hemodynamics responsible for the myocardial blood flow redistribution produced by methacholine. Selective M1 receptor blockade with pirenzepine attenuated increases in transmural perfusion and prevented the redistribution of blood flow favoring the subendocardium during methacholine infusion. M2 receptor blockade with AF-DX 116 also attenuated the increase in transmural perfusion produced by methacholine but did not selectively block increases in subendocardial blood flow. These results support the hypothesis that M1 muscarinic coronary receptors are responsible for the redistribution of blood flow to the subendocardium (increased endo/epi) during cholinergic coronary vasodilation, whereas M2 receptors mediate an increase in total coronary blood flow. In additional experiments in isolated rabbit aorta, AF-DX 116 was 0.38 times less potent than pirenzepine with respect to endothelium-dependent muscarinic vasodilation but 1.47 times more potent with respect to endothelium-independent muscarinic vasoconstriction. This suggests that differences exist in the receptors found on the vascular smooth muscle and endothelium and that the preferential distribution of blood flow to the subendocardium may be due to stimulation of M1 receptors located on the vascular endothelium.