Cardiovascular Research, 1975, 9, 110-778.
The effects of isoprenaline on epicardial ST-segment elevation, lactate production, and myocardial blood flow following coronary artery ligation' R . M . NORRIS, H . J . SMITH, B . N . S I N G H , HEATHER NISBET, M . B . J O H N , and P . J . H U R L E Y
From the Department of Cardiology and Coronary Care, Green Lane Hospital, the Department of Medicine, Auckland University School of Medicine, and the Department of Nuclear Medicine, Auckland Hospital, Auckland, New Zealand
Recent clinical and experimental studies have suggested that infusion of isoprenaline after myocardial infarction increases the size and severity of the infarct. In patients suffering from cardiogenic shock, the drug may have a detrimental effect by increasing cardiac work and myocardial lactate production (Mueller et al, 1970; 1972), while in the experimental animal, administration of isoprenaline is associated with increased ST-segment elevation in the electrocardiogram, and accelerated loss of creatine phosphokinase activity from the infarct (Maroko et a/, 1971 ; 1972). However, the dose of isoprenaline which has been shown to be harmful in the experimental animal is 10 to 20 times greater than that which is useful in the management of bradyarrhythmia and hypotension This work was supported by the National Heart Foundation of New Zealand and the Medical Research Council of New Zealand.
1
occurring in patients after acute myocardial infarction (Shubin and Weil, 1967; Norris and Mercer, 1974), and that which has been shown to produce favourable haemodynamic changes in patients with infarction but without hypotension (Beregovich et al, 1972). The aim of the present investigation was to compare the effects of isoprenaline given at two different infusion rates in an experimental model for the study of epicardial electrocardiographic changes, myocardial blood flow, and lactate production in acute myocardial infarction (Smith et al, 1975a; 1975b). The infusion rates used were comparable with those used in clinical practice on the one hand (low dose, 0.0125 pg/ kg-min-l: Shubin and Weil, 1967; Krasnow, 1971; Norris and Mercer, 1974), and on the other with the dose which has been used previously in studies of experimental infarction
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AUTHORS' S Y N O P S I S Isoprenaline was infused at low and high rates into anaesthetized dogs after ligation of the left anterior descending coronary artery, the resultant changes in epicardial ST-segment elevation being compared with lactate production and myocardial blood flow in the infarcting myocardium. Although ST elevation was increased at both infusion rates, there was no change in the arteriallocal coronary venous difference of lactate concentration nor in myocardial blood flow at the centre of the infarct. The results suggest that the relationship between epicardial ST-segment elevation and other indices of ischaemic myocardial injury is complex and requires further evaluation.
771 Isoprenalinefor experimental myocardial infarction in dogs (high dose, 0.25 pg/kg.min-': Kuhn et al, 1967; Maroko et al, 1971; 1972; Kjekshus and Mjss, 1973; Maroko et a,, 1973; Puri, 1974; Wendt et a/, 1974). Methods Dloqonal branches
Diagram of the experimental preparation. The shaded area represents acutely ischaemic myocardium distal to the ligature around the left anterior descending coronary artery (LAD). The numbers 1-14 refer to the sites of measurement of myocardial blood flow and epicardial ST-segment elevation (see text). Alternative sites for the coronary vein catheter are shown (A and B). Ao = Aorta; PA = main pulmonary artery; R V = right ventricle; LV = left oentricle; LA =left atrium; LA press = left atrial pressure line; LCF = left circumflex coronary artery. FIG. I
were readily identifiable by their relationship to epicardial blood vessels (Fig. 1). Four positions were above the arterial ligature (normal zone), four were at the level of the ligature bordering the ischaemic area (border zone), and six were over the ischaemic area (centre zone). The electrode positions corresponded to the tissue samples taken subsequently for measurement of myocardial blood flow, so that the ST-segment changes after occlusion of the left anterior descending artery could be correlated with the myocardial blood flow of each sample. Myocardial blood flow was measured on three occasions in each animal using carbonized plastic microspheres (Domenech et a / , 1969; Becker et al, 1973; Utley et al, 1974), of 1 5 + 5 p diameter, labelled with one of the gamma-emitting nuclides, 141Ce, B5Sr, or 169Yb. The microspheres were obtained commercially (Minnesota Mining and Manufacturing Company) as 1 mCi of nuclide suspended in 10 ml of 10% dextran. After vigorous shaking of the vial containing the microspheres, approximately 1 x lo6 (0.2 ml) was withdrawn into a plastic syringe and diluted to 1 .O ml with normal saline. The syringe containing the microspheres was shaken continuously to prevent aggregation ;
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Twenty-six mongrel dogs of either sex (15-32 kg) were premedicated with intramuscular trifluopromazine (Siquil, Squibb: 2.7 mg/kg) and anaesthetized with sodium pentobarbitone (25-30 mg/kg); anaesthesia was maintained with a constant infusion of the drug ( 5 mg/kg.h-') administered by a Harvard pump. Positive-pressure respiration with 30% oxygen in room air was established through a cuffed endotracheal tube, and adjustments were made before coronary ligation to keep the blood gases within the limits pH, 7.35-7.45; POz, 12.6-15.3 kPa (95-115 mm Hg); and PCOz 3.3-4.7 kPa (25-35 mm Hg). Body temperature was monitored with a rectal thermistor probe and kept between 36.5 and 383°C with external heating. Normal saline (lO(t150 ml) was infused initially to elevate the left atrial pressure to 0.67 kPa ( 5 mm Hg); the infusion was continued at 50 ml/h throughout the experiment. The heart was exposed through a left lateral thoracotomy, and a silk ligature was placed around the left anterior descending artery at approximately 2 cm from its origin, below its first major diagonal branch. Catheters were placed in the jugular vein, the femoral artery, directly into the main pulmonary artery, and into the left atrium through the left atrial appendage. A small polyethylene catheter (external diameter 1.02 mm) was placed directly in either the distal anterior interventricular vein (position A, Fig. I ) or its inferior diagonal tributary (position B). This catheter was used to sample blood from within the area of myocardium rendered ischaemic by subsequent coronary ligation. Blood pressure was measured with Statham P23Db transducers (zero reference level at mid-left ventricular cavity) and displayed on a Sanborn 350 recorder. Cardiac output was measured by the dye dilution technique, injecting indocyanine green dye (2.5 mg) into the main pulmonary artery and withdrawing blood from the femoral artery through a Gilford densitometer. Epicardial ECGs were recorded using the method of Maroko et a1 (1971), with three modifications. These were the use of a steel-ball electrode (Neutze et al, 1973), 14 predetermined epicardial positions (Smith et al, 1975b), and measurement of the STsegment at 0.06 s after the end of the S wave (Reid et al, 1971). The 14 electrode positions were situated over the anterior surface of the left ventricle, and
772 Norris, Smith, Singh, Nisbet, John, and Hurley 5 ml aliquots of each blood sample was measured in a Packard Autogamma well-type scintillation counter uisng an integral counting technique (Smith et al, 1975b). For each myocardial sample, the counts/g for each of the isotopes was computed, and the myocardial blood flow was calculated as ml/min. 100 g-1: 100 CM MBF = 3 CR
where MBF = myocardial blood flow (ml/min. 100 g-l); CM =counts/g (myocardial tissue sample); CR= counts/ml 3 min-' (reference blood sample). This equation assumes adequate mixing of microspheres in atrium and ventricle, so that their distribution to myocardium and peripheral tissues is proportional to blood flow (Domenech et a/, 1969). From the radioactivity counts, myocardial blood flow for each area, for each zone, as well as the ratios of perfusion of the endocardium to epicardium (endocardial/epicardial ratio) were computed. Variations in regional perfusion could then be correlated with the ST-segment shift over each area of the ischaemic myocardium. Blood for measurement of lactate concentration was withdrawn into 2 ml syringes and transferred immediately into pre-weighed, chilled (4°C) plastic tubes containing 10% trichloracetic acid. Lactate concentrations were measured by the method of Ellis et a1 (1963), within 4 days of the experiment and expressed as mEq/ 1.
TABLE I
Haemodynamic changes after low (0.0125 p g / k g .min- l ) and high (0.25 p g / k g .min- l) doses of isoprenaline following coronary artery ligation Pre-ligalion
Control
Lo w-dose isoprenaline
High-dose isoprenaline
(I5 min)
CI (ml/min.kg-l) HR (beatslmin) MAP (kPa) (mni Hg) MLAP (kPa) (mm Hg) SWI (s-mike) SRI (units/kg) ZST (mWS
130k9 140k7 14.150.67 106+5 0.80 k 0.13 6k 1 1.2750.10 0.84 0.07
118f18' 7 146 k '
13.0+0.80* 97f 6 . 0.93f0.13 7k I 0.94k0.16' 1.08 k 0.22 59+ 14
Before (45 min)
Afier (60 min)
95k9 147f6 12.8k0.93 96k7 0.93f0.13 7+1 0.79+0.06 1.06&0.10 49k 16
101 +20
155k7t 12.6k0.93 95+7 0.93k0.13 7k1 0.79 50.10 0.98k0.08 785 17'
Before (105 min)
85512 155 f 10
13.1 f0.80 99k6 0.93f0.27 7+2 0.75k0.11 1.29k0.18 81 k22
After
(I20min)
142+36* 194+ I2t 11.0+ 1.20' 82+9* 1.30k0.27t 10+2t 0.71 f0.16 0.69fO.l It 101 k 19
* Pascular Research, I, 391400.
Beregovich, J., Reicher-Reiss, H., and Grishman, A. (1972). Haemodynamic effects of isoprenaline in acute myocardial infarction. British Heart Journal, 34, 705-710. Bernc, R. M., and Rubio, R. (1969). Acute coronary occlusion: early changes that induce coronary dilatation and development of collateral circulation. American Journal 01 Cardiology, 24, 776-78 I. Blair, E. (1960). Significance of sampling sites in the study of
myocardial metabolism in regional ischemia. Journal of Thoracic and Cardiovascular Surgery, 58, 271-278.
Buckberg, G. D., and Ross, G. (1973). Effects of isoprenaline on coronary blood flow: its distribution and myocardial performance. Cardiovascular Research, 7, 429-437. Cannon, P. J., Dell, R. B., and Dwyer, E. M. (1972). Regional myocardial perfusion rates in patients with coronary artery disease. Journal of Clinical Investigation, 51,978-994. Cohen, N. V., and Kirk, E. S. (1974). Reduction of epicardial ST-segment elevation following increased myocardial ischemia: experimental and theoretical demonstration. Clinical Research, 22, 269A.
Domenech. R. J., Hoffman, J. 1. E., Noble, M. 1. M., Saunders, K. B., Hensom, J. R., and Subijanto, S. (1969). Total and regional coronary flow measured by radioactive microspheres in conscious and anesthetized dogs. Circulation Research, 25, 58 1-596. Ellis, J. P., Cain, S. M., and Williams, E. W. (1963). Rapid accurate analysis of blood lactate. Technical documentary report, No. SAM/TDR/63/49. USAF School of Aerospace Medicine. Texas, USA. Harris, A. S. (1950). Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation, 1, 13 18- 1328.
Herman, M. V., Elliott, W. C., and Gorlin, R. (1967). An electrocardiographic, anatomic and metabolic study of zonal myocardial ischemia in coronary heart disease. Circulation, 35, 834-836.
Hood, W. B., McCarthy, B., and Lown, 9. (1967). Myocardial infarction following coronary ligation in dogs. Hemodynamic effects of isoproterenol and acetylstrophan t hidin. Circulation Research, 21, 191-1 99. Karlsson, J., Templeton, G. H., and Willerson, J. T. (1973). The relationship between epicardial ST-segment changes and myocardial metabolism during acute coronary insufficiency. Circulation Research, 32, 725-730. Kerzner, J., Wolf, M., Kosowsky, 8. D., and Lown, B. (1973). Ventricular ectopic rhythms following vagal stimulation in dogs with acute myocardial infarction. Circulation, 41, 44-50.
Kjekshus, J. K., Maroko, P. R., and Sobel, B. E. (1972). Distribution of myocardial injury and its relation t o epicardial ST-segment changes after coronary artery occlusion in the dog. Cardiovascular Research, 6, 4 9 M 9 9 . Kjekshus. J. S., and Mjm, 0. D. (1973). Effect of inhibition of lipolysis on infarct size after experimental coronary artery occlusion. Journal of Clinical Inuesligation, 53, 1770-1 718. Krasnow, N. (1971). Biochemical and physiologic response to isoproterenol in patients with left ventricular failure. American Journal of Cardiology, 21, 73-81.
Krasnow, N., Rolett, E. L., Yurchak, P. M., Hood, W. B., and Gorlin, R. (1964). lsoproterenol and cardiovascular performance. American Journal of Medicine, 31. 5 14-525. Kuhn, L. A., Kline, H.J., Goodman, P.,and Johnson, C. D. (1967). Effects of isoproterenol on hemodynamic alterations, myocardial metabolism and coronary flow in experimental acute myocardial infarction with shock. American Journal of Cardiology, 19, 137.
Maroko, P. R., Kjekshus, J. K., Sobel, 9. E., Watanabe, T., Covell, J. W.,Ross, J., and Braunwald. E. (1971). Factors influencing infarct size following experimental coronary artery occlusions. Circulation. 43, 67-82. Maroko, P. R., Libby, P., and Braunwald, E. (1973). Effect of pharmacologic agents on the function of the ischemic heart. American Journal of Cardiolog.v, 32, 930-936. Maroko, P. R., Libby, P., Covell, J. W., Sobel, 9. E., Ross, J., and Braunwald, E. (1972). Precordial S-T segment elevation mapping: an atraumatic method for assessing alterations in the extent of myocardial ischemic injury. American Journal of Cardiology, 29, 223-230.
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Our failure to demonstrate associated changes in collateral blood flow and lactate production when ST-segment elevation was increased may not be in direct conflict with the observations of Maroko et a1 (1971), that isoproterenol increases infarct size. The data, however, suggest that a critical evaluation of the determinants of STsegment change following coronary occlusions is necessary before it can be accepted as an accurate guide to acute myocardial ischaemic injury. It is likely that vasodilatation at the centre of an infarct is already maximal due to vasoactive metabolites of ischaemia (Berne and Rubio, 1969), and anaerobic glycolysis may also be operating at a maximum level (Rovetto et al, 1973). Isoprenaline might direct available energy in these critically ischaemic zones from the maintenance of cell integrity to the production of mechanical energy, with resultant increase in STsegment elevation and accelerated cell necrosis. The effects of the drug on changes in regional myocardial contractility are thus of interest (Puri, 1974), but were not evaluated in the present experiments.
778 Norris, Smith,Singh, Nisbet, John, and Hurley
Puri, P. S. (1974). Modification of experimental myocardial infarct size by cardiac drugs. American Journal of Cardiology, 33, 521-528. Reid, D. S., Pelides, L. J., and Shillingford, J. P. (1971). Surface mapping of RS-T segment in acute myocardial infarction. British Heart Journal, 33, 370-374. Rovetto, M. J., Whitmer, J. T., and Neely, J. R. (1973). Comparison of the effects of anoxia and whole heart ischemia on carbohydrate utilization in isolated working rat hearts. Circulation Research, 32, 699-71 I. Shubin, H., and Weil, M. H. (1967).The treatment of shock complicating acute myocardial infarction. Progress in Cardiovascular Diseases, 10, 30-54. Smith, H.J., Norris, R. M., Singh, B. N., Heng, M. K.,and Harris, E. A. (1975a). Regional differences in lactate concentrations in veins draining small and large myocardial infarcts. Submitted to Australian and New Zealand Journal of Medicine. Smith, H. J., Singh, B. N., Norris, R. M., John, M. B., and Hurley, P. J. (1975b). Changes in myocardial blood flow and ST-segment elevation following coronary artery occlusion in dogs. Circulation Research, 36, 697-705 Smith, H. J., Singh, B. N., Norris, R. M., Nisbet, H., John, M. B. and Hurley, P. J. (197%). The effects of verapamil on experimental myocardial ischemia with a particular reference to regional myocardial blood flow and metabolism. European Journal of Cardiology. (In press). Utley, J., Carlson, E. L., Hoffman, J. I. E., Martinez, H. M., and Buckberg, G. D. (1974).Total and regional myocardial blood flow measurements with 25 p. I5 w , 9 IL and filtered 1-10 p diameter microspheres and antipyrine in dogs and sheep. Circuration Research, 34, 391405. Wendt, R. L., Canavan, R. C., and Michalak, R. J. (1974). Effects of various agents on regional ischemic myocardial injury: electrocardiographic analysis. American Heart Journal, 87, 468-482.
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Marshall, R. J., Parratt, J. R., and Ledingham, I. M. (1974). Changes in blood flow and oxygen consumption in normal and ischaemic regions of the myocardium following acute coronary artcry ligation. Cardiovascular Research, 8, 204715. Mueller, H., Ayres, S. M., Giannelli, S., Conklin, E. F., Mazzara, J. T., and Grace, W. J. (1972).Effect of isoproterenol, I-norepinephrine and intraaortic counterpulsation on hemodynamics and myocardial metabolism in shock following acute myocardial infarction. Circulation, 45, 335-350. Mueller, H., Ayres, S. M., Gregory, J. J., Giannelli, S.,and Grace, W. J. (1970). Hemodynamics, coronary blood flow and myocardial metabolism in coronary shock: response to I-norepinephrine and isoproterenol. Journal of Clinical Inoestigntion, 49, 1885-1902. Neutze, J. M.,Kerr, A. R., and Whitlock, R. M. L. (1973). Epicardial mapping in a variantofType A Wolff-ParkinsonWhite syndrome. Circulation, 48, 662-666. Norris, R. M., and Mercer, C. J. (1974). Significance of idioventricular rhythms in acute myocardial infarction. Progress in Cardiocascular Diseases, 16, 455-468. Owen, P., Thomas, M.,Young, V., and Opie, L. (1970). Comparison between metabolic changes in local venous and coronary sinus blood after acuteexperimental coronary arterial occlusion. American Journal of Cardiology, 24, 562-570. Parratt, J. R., Ledingham, I. M., and McArdle, C. S. (1973). The effect of a coronary vasodilator drug (carbochromen) on blood flow and oxygen extraction in acute myocardial infarction. Cardiovascular Research, 7,401-407. Phibbs, R. H., Wyler, F., and Neutze, J. M. (1967). Rheology of microspheres injected into circulation of rabbits. Nature (London), 216, 1339-1340.
!
The effects of isoprenaline on epicardial ST-segment elevation, lactate production, and myocardial blood flow following coronary artery ligation' R . M . NORRIS, H . J . SMITH, B . N . S I N G H , HEATHER NISBET, M . B . J O H N , and P . J . H U R L E Y
From the Department of Cardiology and Coronary Care, Green Lane Hospital, the Department of Medicine, Auckland University School of Medicine, and the Department of Nuclear Medicine, Auckland Hospital, Auckland, New Zealand
Recent clinical and experimental studies have suggested that infusion of isoprenaline after myocardial infarction increases the size and severity of the infarct. In patients suffering from cardiogenic shock, the drug may have a detrimental effect by increasing cardiac work and myocardial lactate production (Mueller et al, 1970; 1972), while in the experimental animal, administration of isoprenaline is associated with increased ST-segment elevation in the electrocardiogram, and accelerated loss of creatine phosphokinase activity from the infarct (Maroko et a/, 1971 ; 1972). However, the dose of isoprenaline which has been shown to be harmful in the experimental animal is 10 to 20 times greater than that which is useful in the management of bradyarrhythmia and hypotension This work was supported by the National Heart Foundation of New Zealand and the Medical Research Council of New Zealand.
1
occurring in patients after acute myocardial infarction (Shubin and Weil, 1967; Norris and Mercer, 1974), and that which has been shown to produce favourable haemodynamic changes in patients with infarction but without hypotension (Beregovich et al, 1972). The aim of the present investigation was to compare the effects of isoprenaline given at two different infusion rates in an experimental model for the study of epicardial electrocardiographic changes, myocardial blood flow, and lactate production in acute myocardial infarction (Smith et al, 1975a; 1975b). The infusion rates used were comparable with those used in clinical practice on the one hand (low dose, 0.0125 pg/ kg-min-l: Shubin and Weil, 1967; Krasnow, 1971; Norris and Mercer, 1974), and on the other with the dose which has been used previously in studies of experimental infarction
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AUTHORS' S Y N O P S I S Isoprenaline was infused at low and high rates into anaesthetized dogs after ligation of the left anterior descending coronary artery, the resultant changes in epicardial ST-segment elevation being compared with lactate production and myocardial blood flow in the infarcting myocardium. Although ST elevation was increased at both infusion rates, there was no change in the arteriallocal coronary venous difference of lactate concentration nor in myocardial blood flow at the centre of the infarct. The results suggest that the relationship between epicardial ST-segment elevation and other indices of ischaemic myocardial injury is complex and requires further evaluation.
771 Isoprenalinefor experimental myocardial infarction in dogs (high dose, 0.25 pg/kg.min-': Kuhn et al, 1967; Maroko et al, 1971; 1972; Kjekshus and Mjss, 1973; Maroko et a,, 1973; Puri, 1974; Wendt et a/, 1974). Methods Dloqonal branches
Diagram of the experimental preparation. The shaded area represents acutely ischaemic myocardium distal to the ligature around the left anterior descending coronary artery (LAD). The numbers 1-14 refer to the sites of measurement of myocardial blood flow and epicardial ST-segment elevation (see text). Alternative sites for the coronary vein catheter are shown (A and B). Ao = Aorta; PA = main pulmonary artery; R V = right ventricle; LV = left oentricle; LA =left atrium; LA press = left atrial pressure line; LCF = left circumflex coronary artery. FIG. I
were readily identifiable by their relationship to epicardial blood vessels (Fig. 1). Four positions were above the arterial ligature (normal zone), four were at the level of the ligature bordering the ischaemic area (border zone), and six were over the ischaemic area (centre zone). The electrode positions corresponded to the tissue samples taken subsequently for measurement of myocardial blood flow, so that the ST-segment changes after occlusion of the left anterior descending artery could be correlated with the myocardial blood flow of each sample. Myocardial blood flow was measured on three occasions in each animal using carbonized plastic microspheres (Domenech et a / , 1969; Becker et al, 1973; Utley et al, 1974), of 1 5 + 5 p diameter, labelled with one of the gamma-emitting nuclides, 141Ce, B5Sr, or 169Yb. The microspheres were obtained commercially (Minnesota Mining and Manufacturing Company) as 1 mCi of nuclide suspended in 10 ml of 10% dextran. After vigorous shaking of the vial containing the microspheres, approximately 1 x lo6 (0.2 ml) was withdrawn into a plastic syringe and diluted to 1 .O ml with normal saline. The syringe containing the microspheres was shaken continuously to prevent aggregation ;
Downloaded from by guest on June 7, 2016
Twenty-six mongrel dogs of either sex (15-32 kg) were premedicated with intramuscular trifluopromazine (Siquil, Squibb: 2.7 mg/kg) and anaesthetized with sodium pentobarbitone (25-30 mg/kg); anaesthesia was maintained with a constant infusion of the drug ( 5 mg/kg.h-') administered by a Harvard pump. Positive-pressure respiration with 30% oxygen in room air was established through a cuffed endotracheal tube, and adjustments were made before coronary ligation to keep the blood gases within the limits pH, 7.35-7.45; POz, 12.6-15.3 kPa (95-115 mm Hg); and PCOz 3.3-4.7 kPa (25-35 mm Hg). Body temperature was monitored with a rectal thermistor probe and kept between 36.5 and 383°C with external heating. Normal saline (lO(t150 ml) was infused initially to elevate the left atrial pressure to 0.67 kPa ( 5 mm Hg); the infusion was continued at 50 ml/h throughout the experiment. The heart was exposed through a left lateral thoracotomy, and a silk ligature was placed around the left anterior descending artery at approximately 2 cm from its origin, below its first major diagonal branch. Catheters were placed in the jugular vein, the femoral artery, directly into the main pulmonary artery, and into the left atrium through the left atrial appendage. A small polyethylene catheter (external diameter 1.02 mm) was placed directly in either the distal anterior interventricular vein (position A, Fig. I ) or its inferior diagonal tributary (position B). This catheter was used to sample blood from within the area of myocardium rendered ischaemic by subsequent coronary ligation. Blood pressure was measured with Statham P23Db transducers (zero reference level at mid-left ventricular cavity) and displayed on a Sanborn 350 recorder. Cardiac output was measured by the dye dilution technique, injecting indocyanine green dye (2.5 mg) into the main pulmonary artery and withdrawing blood from the femoral artery through a Gilford densitometer. Epicardial ECGs were recorded using the method of Maroko et a1 (1971), with three modifications. These were the use of a steel-ball electrode (Neutze et al, 1973), 14 predetermined epicardial positions (Smith et al, 1975b), and measurement of the STsegment at 0.06 s after the end of the S wave (Reid et al, 1971). The 14 electrode positions were situated over the anterior surface of the left ventricle, and
772 Norris, Smith, Singh, Nisbet, John, and Hurley 5 ml aliquots of each blood sample was measured in a Packard Autogamma well-type scintillation counter uisng an integral counting technique (Smith et al, 1975b). For each myocardial sample, the counts/g for each of the isotopes was computed, and the myocardial blood flow was calculated as ml/min. 100 g-1: 100 CM MBF = 3 CR
where MBF = myocardial blood flow (ml/min. 100 g-l); CM =counts/g (myocardial tissue sample); CR= counts/ml 3 min-' (reference blood sample). This equation assumes adequate mixing of microspheres in atrium and ventricle, so that their distribution to myocardium and peripheral tissues is proportional to blood flow (Domenech et a/, 1969). From the radioactivity counts, myocardial blood flow for each area, for each zone, as well as the ratios of perfusion of the endocardium to epicardium (endocardial/epicardial ratio) were computed. Variations in regional perfusion could then be correlated with the ST-segment shift over each area of the ischaemic myocardium. Blood for measurement of lactate concentration was withdrawn into 2 ml syringes and transferred immediately into pre-weighed, chilled (4°C) plastic tubes containing 10% trichloracetic acid. Lactate concentrations were measured by the method of Ellis et a1 (1963), within 4 days of the experiment and expressed as mEq/ 1.
TABLE I
Haemodynamic changes after low (0.0125 p g / k g .min- l ) and high (0.25 p g / k g .min- l) doses of isoprenaline following coronary artery ligation Pre-ligalion
Control
Lo w-dose isoprenaline
High-dose isoprenaline
(I5 min)
CI (ml/min.kg-l) HR (beatslmin) MAP (kPa) (mni Hg) MLAP (kPa) (mm Hg) SWI (s-mike) SRI (units/kg) ZST (mWS
130k9 140k7 14.150.67 106+5 0.80 k 0.13 6k 1 1.2750.10 0.84 0.07
118f18' 7 146 k '
13.0+0.80* 97f 6 . 0.93f0.13 7k I 0.94k0.16' 1.08 k 0.22 59+ 14
Before (45 min)
Afier (60 min)
95k9 147f6 12.8k0.93 96k7 0.93f0.13 7+1 0.79+0.06 1.06&0.10 49k 16
101 +20
155k7t 12.6k0.93 95+7 0.93k0.13 7k1 0.79 50.10 0.98k0.08 785 17'
Before (105 min)
85512 155 f 10
13.1 f0.80 99k6 0.93f0.27 7+2 0.75k0.11 1.29k0.18 81 k22
After
(I20min)
142+36* 194+ I2t 11.0+ 1.20' 82+9* 1.30k0.27t 10+2t 0.71 f0.16 0.69fO.l It 101 k 19
* Pascular Research, I, 391400.
Beregovich, J., Reicher-Reiss, H., and Grishman, A. (1972). Haemodynamic effects of isoprenaline in acute myocardial infarction. British Heart Journal, 34, 705-710. Bernc, R. M., and Rubio, R. (1969). Acute coronary occlusion: early changes that induce coronary dilatation and development of collateral circulation. American Journal 01 Cardiology, 24, 776-78 I. Blair, E. (1960). Significance of sampling sites in the study of
myocardial metabolism in regional ischemia. Journal of Thoracic and Cardiovascular Surgery, 58, 271-278.
Buckberg, G. D., and Ross, G. (1973). Effects of isoprenaline on coronary blood flow: its distribution and myocardial performance. Cardiovascular Research, 7, 429-437. Cannon, P. J., Dell, R. B., and Dwyer, E. M. (1972). Regional myocardial perfusion rates in patients with coronary artery disease. Journal of Clinical Investigation, 51,978-994. Cohen, N. V., and Kirk, E. S. (1974). Reduction of epicardial ST-segment elevation following increased myocardial ischemia: experimental and theoretical demonstration. Clinical Research, 22, 269A.
Domenech. R. J., Hoffman, J. 1. E., Noble, M. 1. M., Saunders, K. B., Hensom, J. R., and Subijanto, S. (1969). Total and regional coronary flow measured by radioactive microspheres in conscious and anesthetized dogs. Circulation Research, 25, 58 1-596. Ellis, J. P., Cain, S. M., and Williams, E. W. (1963). Rapid accurate analysis of blood lactate. Technical documentary report, No. SAM/TDR/63/49. USAF School of Aerospace Medicine. Texas, USA. Harris, A. S. (1950). Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation, 1, 13 18- 1328.
Herman, M. V., Elliott, W. C., and Gorlin, R. (1967). An electrocardiographic, anatomic and metabolic study of zonal myocardial ischemia in coronary heart disease. Circulation, 35, 834-836.
Hood, W. B., McCarthy, B., and Lown, 9. (1967). Myocardial infarction following coronary ligation in dogs. Hemodynamic effects of isoproterenol and acetylstrophan t hidin. Circulation Research, 21, 191-1 99. Karlsson, J., Templeton, G. H., and Willerson, J. T. (1973). The relationship between epicardial ST-segment changes and myocardial metabolism during acute coronary insufficiency. Circulation Research, 32, 725-730. Kerzner, J., Wolf, M., Kosowsky, 8. D., and Lown, B. (1973). Ventricular ectopic rhythms following vagal stimulation in dogs with acute myocardial infarction. Circulation, 41, 44-50.
Kjekshus, J. K., Maroko, P. R., and Sobel, B. E. (1972). Distribution of myocardial injury and its relation t o epicardial ST-segment changes after coronary artery occlusion in the dog. Cardiovascular Research, 6, 4 9 M 9 9 . Kjekshus. J. S., and Mjm, 0. D. (1973). Effect of inhibition of lipolysis on infarct size after experimental coronary artery occlusion. Journal of Clinical Inuesligation, 53, 1770-1 718. Krasnow, N. (1971). Biochemical and physiologic response to isoproterenol in patients with left ventricular failure. American Journal of Cardiology, 21, 73-81.
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Our failure to demonstrate associated changes in collateral blood flow and lactate production when ST-segment elevation was increased may not be in direct conflict with the observations of Maroko et a1 (1971), that isoproterenol increases infarct size. The data, however, suggest that a critical evaluation of the determinants of STsegment change following coronary occlusions is necessary before it can be accepted as an accurate guide to acute myocardial ischaemic injury. It is likely that vasodilatation at the centre of an infarct is already maximal due to vasoactive metabolites of ischaemia (Berne and Rubio, 1969), and anaerobic glycolysis may also be operating at a maximum level (Rovetto et al, 1973). Isoprenaline might direct available energy in these critically ischaemic zones from the maintenance of cell integrity to the production of mechanical energy, with resultant increase in STsegment elevation and accelerated cell necrosis. The effects of the drug on changes in regional myocardial contractility are thus of interest (Puri, 1974), but were not evaluated in the present experiments.
778 Norris, Smith,Singh, Nisbet, John, and Hurley
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