Metabolic Consequences of Beta-Adrenergic Receptor Blockade for the Acutely Ischemic Dog Myocardium^[*]

Summary

In an experimental study in 50 dogs the myocardial uptake of free fatty acids (FFAs) after beta-blockade was determined using radioiodinated heptadecanoic acid as a metabolic tracer. All 4 beta-blockers used (metoprolol, timolol, propranolol and pindolol) lowered the uptake of FFAs in the normal canine heart. Uptake of FFAs was also diminished after coronary artery occlusion per se, but administration of beta-blockers exerted little additional influence on the uptake of FFAs. This observation was qualitatively parallelled by the uptake of ²⁰¹T1 in concomitant experiments. Plasma FFA levels were increased by pindolol (non-selective with intrinsic sympathomimetic activity), not changed by metoprolol (a cardioselective betablocking agent) and lowered by timolol and propranolol (both nonselective compounds). The extent of ischemic tissue, as reflected by uptake of iodoheptadecanoic acid and ²⁰¹T1, was diminished by metoprolol but not by other beta-blockers. Regional distribution of both tracers, as shown in the endo-epicardial uptake ratios, was hardly influenced by beta-blockade, except for a small increase of ²⁰¹T1 uptake in non-occluded endocardium. Uptake of ²⁰¹T1 as well as of iodoheptadecanoic acid in the ischemic area was increased by metoprolol, timolol and propranolol and decreased by pindolol. We conclude that beta-blocking agents confer different effects on myocardial uptake and metabolism of FFAs which might possibly be related to their different inherent properties.

Zusammenfassung

Bei 50 Hunden wurde die Myokardspeicherung freier Fettsäuren nach Beta-Blockade mit Hilfe der radiojodierten Heptadekansäure als Stoffwechsel-Tracer bestimmt. Alle 4 Beta-Blocker (Metoprolol, Timolol, Propranolol und Pindolol) setzten die Speicherung freier Fettsäuren in normalen Hundeherzen herab. Die Speicherung freier Fettsäuren wurde auch durch Verschluß einer Koronararterie an sich verringert, jedoch übte die Verabreichung von Beta-Blockern nur einen geringen zusätzlichen Einfluß auf die Speicherung freier Fettsäuren aus. Diese Beobachtung wurde in begleitenden Versuchen über die Speicherung von ²⁰¹T1 qualitativ bestätigt. Die Konzentration freier Fettsäuren im Plasma wurden durch Pindolol (nicht-selektiv mit eigener sympathomimetischer Aktivität) erhöht, durch Metoprolol (ein herzspezifischer Beta-Blocker) nicht vermindert und durch Timolol und Propranolol (beide nichtselektive Verbindungen) herabgesetzt. Das Ausmaß des ischämischen Gewebes wiedergegeben durch die Speicherung der Jodheptadekansäure und des ²⁰¹T1 wurde durch Metoprolol, jedoch nicht durch die anderen Beta-Blocker vermindert. Die durch das endo-/epikardiale Speicherungsverhältnis nachgewiesene regionale Verteilung der beiden Tracer wurde auch die Beta-Blockade kaum beeinflußt, mit Ausnahme eines geringen Anstiegs der ²⁰¹T1 Speicherung im nicht betroffenen Endokard. Die Speicherung sowohl des ²⁰¹T1 als auch der Jodheptadekansäure im ischämischen Gebiet wurde durch Metoprolol, Timolol und Propranolol erhöht und durch Pindolol herabgesetzt. Wir schließen daraus, daß Beta-Blocker verschiedene Wirkungen auf die myokardiale Speicherung und den Stoffwechsel freier Fettsäuren ausüben und daß diese möglicherweise mit deren verschiedenen Ausgangseigenschaften in Zusammenhang stehen.

^* 3rd International Symposium on Radiopharmacology, Freiburg i.Br., September 1983

• References

• 1 Becker L. C., Ferreira R, Thomas M. Mapping of left ventricular blood flow with radioactive microspheres in experimental coronary artery occlusion. Cardiovasc. Res 7: 391-400 1973;
• 2 Blum J. W., Froehli D, Kunz P. Effects of catecholamines on plasma free fatty acids in fed and fasted cattle. Endocrinology 110: 452-460 1982;
• 3 Braunwald E. Control of myocardial oxygen consumption: Physiologic and clinical considerations. Amer. J. Cardiol 27: 416-423 1971;
• 4 Day J. L. The metabolic consequences of adrenergic blockade: A review. Metabolism 24: 987-996 1975;
• 5 Deacon S. P. The effect of atenolol and propranolol upon lipolysis. Brit. J. clin. Pharmacol 5: 123-125 1978;
• 6 Ellis S. Effects on the metabolism. In: Handbook of Experimental Pharmacology. Szekeres L. Ed. 54/1 334-342 Springer, Berlin – Heidelberg – New York: 1980.
• 7 Frishman W. H. The beta-adrenoceptor blocking drugs. Editorial review. Intern. J. Cardiol 2: 165-178 1982;
• 8 Genth Κ, Hoffmann M, Mechthild H. o.ffmann, Schaper W. The effect of beta-adrenergic blockade on infarct size following experimental coronary occlusion. Basic Res. Cardiol 76: 144-151 1981;
• 9 Glaviano V. V., Masters T. N. The effect of intracoronary norepinephrine on cardiac metabolism before and after betaadrenergic blockade. Feder. Proc 26: 771-779 1967;
• 10 Kjekshus JΚ, Mjos O. D. Effect of free fatty acids on myocardial function and metabolism in the ischemic dog heart. J. clin. Invest 51: 1767-1776 1972;
• 11 Liedtke A. J. Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart. Progr. cardiovasc. Dis 23: 321-336 1981;
• 12 Liedtke A. J., Nellis S. H., Whitesell L. F. Effects of regional ischemia on metabolic function in adjacent aerobic myocardium. J. mol. cell. Cardiol 14: 195-205 1982;
• 13 Machulla H. J., Stoecklin G, Kupfernagel C, Freundlieb C, Hoeck A, Vyska K, Feinendegen L. E. Comparative evaluation of fatty acids labeled with C-ll, Cl-34m, Br-77 and 1-123 for metabolic studies of the myocardium. J. nucl. Med 19: 298-302 1978;
• 14 Marchetti G, Merlo L, Noseda V. Myocardial uptake of free fatty acids and carbohydrates after beta-adrenergic blockade. Amer. J. Cardiol 22: 370-374 1968;
• 15 Mjos O. D., Kjekshus J. K., Lekven J. Importance of free fatty acids as a determinant of myocardial oxygen consumption and myocardial ischemic injury during norepinephrine infusion in dogs. J. clin. Invest 53: 1290-1299 1974;
• 16 Mueller H. S., Ayres S. M. Metabolic responses of the heart in acute myocardial infarction in man. Amer. J. Cardiol 42: 363-371 1978;
• 17 Neely J. R., Rovetto M. J., Oram J. F. Myocardial utilization of carbohydrate and lipids. Progr. cardiovasc. Dis 15: 289-329 1972;
• 18 Newman R. J. Comparison of the antilipolytic effect of metoprolol, acebutolol and propranolol in man. Brit. med. J 11: 601-603 1977;
• 19 Oliver M. F., Kurien V. A., Greenwood T. W. Relation between serum free fatty acids and arrhythmias and death after acute myocardial infarction. Lancet 1: 710-714 1968;
• 20 Oliver M. F. Metabolism of the normal and ischaemic myocardium. In: Developments in Cardiovascular Medicine. Dickinson C. J., Marks J. Eds 145-164 University Press; Baltimore: 1978.
• 21 Opie L. H. Metabolism of free fatty acids, glucose and catecholamines in acute myocardial infarction. Relation to myocardial ischemia and infarct size. Amer. J. Cardiol 36: 938-953 1975;
• 22 Opie L. H., Thomas M. Propranolol experimental myocardial infarction: Substrate effects. Postgrad, med. J 52 (Suppl. 04) 124-133 1976;
• 23 Opie L. H., Tonsey M, Kennelly B. M. Proposed metabolic vicious circle in patients with large myocardial infarcts and high plasma free fatty acid concentrations. Lancet 11: 890-892 1977;
• 24 Opie L. H. Myocardial infarct size. Part II: Comparison of anti-infarct of betablockade, glucose-insulin-potassium, nitrates, and hyaluronidase. Amer. Heart J 100: 531-532 1980;
• 25 Paris S, Samuel D, Jacques Y, Gâche C, Franchi A, Ailhaud G. The role of serum albumin in the uptake of fatty acids by cultured cardiac cells from chick embryo. Eur. J. Biochem 83: 235-243 1978;
• 26 Poe N. D., Robinson Jr G. D., MacDonald N. S. Myocardial extraction of labeled long-chain fatty acid analogs. Proc. Soc. exp. Biol. Med 148: 215-218 1975;
• 27 Raptis S, Rosenthal J, Welzel D, Moulopoulos S. Effects of cardioselective and non-selective beta-blockade on adrenaline-induced metabolic and cardiovascular responses in man. Eur. J. clin. Pharmacol 20: 17-22 1981;
• 28 Reimer K. A., Lowe J. E., Rasmussen M. M., Jennings R. B. The wavefront phenomenon of ischemic cell death. I. Myocardial infarct size versus duration of coronary artery occlusion in dogs. Circulation 56: 786-794 1977;
• 29 Scheuer J, Brachfeld N. Coronary insufficiency: Relations between hemodynamic, electrical and biochemical parameters. Circ. Res 18: 178-189 1966;
• 30 Schlant R. C. Metabolism of the heart. In: The Heart. Hurst J. W. Ed 107-118 McGraw Hill Co; New York: 1978.
• 31 Schlierf G, Papenberg J, Raetzer H. The effect of l-(Indol-4-yloxy)-3-isopropylamino-propan-2-ol (LB-46, Visken) on carbohydrate and lipid metabolism. Eur. J. clin. Pharmacol 5: 154-157 1973;
• 32 Simonsen S, Kjekshus J. K. The effect of free fatty acids on myocardial oxygen consumption during atrial pacing and catecholamine infusion in man. Circulation 58: 484-491 1978;
• 33 Smith E. F., Schmunk G. A., Gregory A, Carrow B. A., Lefer A. M. Infarct size reduction in cats by the betaadrenergic blocker timolol. Eur. J. Pharmacol 77: 153-158 1982;
• 34 Strauss H. W., Harrison K, Langan J. K., Lebowitz E, Pitt B. Thallium-201 for myocardial imaging. Relation of Tl-201 to regional myocardial perfusion. Circulation 51: 641-645 1975;
• 35 Vik-Mo H, Mjos O. D. Influence of free fatty acids on myocardial oxygen consumption and ischemic injury. Amer. J. Cardiol 48: 361-365 1981;
• 36 Westera G, Van der Wall E. E., Heidendal G. A. K, Van den Bos G. C. A comparison between terminally radioiodinated hexadecanoic acid (I-HA) and Tl-201-thallium chloride in the dog heart. Implications for the use of I-HA for myocardial imaging. Eur. J. nucl. Med 5: 339-343 1980;
• 37 Westera G, Van der Wall E. E., Visser F. C., Den Hollander W, Heidendal G. A.K, Roos J. P. The uptake of iodinated free fatty acids in the (ischemic) dog heart. Indications for a dual uptake mechanism. Int. J. nucl. Med. Biol 10: 231-236 1983;
• 38 William-Olsson T, Fellenius E, Bjorntorp P, Smith U. Differences in metabolic responses to beta-adrenergic stimulation after propranolol or metoprolol administration. Acta med. Scand 205: 201-206 1979;