Author + information
- Received July 25, 1990
- Revision received December 17, 1990
- Accepted January 10, 1991
- Published online August 1, 1991.
- Lars Rydén, MD, FACC†,
- Hiroyuki Tadokoro, MD,
- Per-Ove Sjöquist, PhD,
- Carl Regardh, PhD,
- Shiro Kobayashi, MD,
- Eliot Corday, MD, FACC and
- J.Kevin Drury, MD, FACC
- ↵†Current address and address for reprints: Lars Rydén, MD, Department of Cardiology, Thoracic Clinics, Karolinska Sjukhuset, S-10401 Stockholm, Sweden.
Plasma and myocardial tissue concentrations of metoprolol wre studied in ischemic and nonischemic areas of 22 pigs after 90 (n = 19) and 16 (n = 3) min of left anterior descending coronary artery occlusion. Group A (n = 6) received simultaneous intravenous metoprolol (0.2 mg/kg body weight) and tritium-labeled (3H)-metoprolol (0.2 mg/kg) retrogradely into the coronary vein. In group B (n = 5), metoprolol and 3H-metoprolol were administered in the same way, but at half the volume to study the influence of derived coronary venous pressure on the myocardial concentration of drug. In group C (n = 3), metoprolol was given retrogradely and saline solution was infused into the left anterior descending artery before induced death to wash out metoprolol from the coronary veins. To rule out a possible influence of the development of myocardial necrosis on drug distribution, metoprolol was retroinfused after 1 min of arterial occlusion in three pigs (group D). In group E (n = 5), metoprolol (0.2 mg/kg) was infused anterogradely into the left anterior descending artery.
Peak plasma concentration was significantly higher after intravenous infusion of metoprolol (1,188 ± 503 nmol/liter) than after coronary venous infusion (417 ± 155 nmol/liter; p < 0.001). In groups A and B, the nonischemic myocardial concentration of metoprolol was 250 to 300 pmol/g, whether the drug was infused intravenously or into the coronary vein. Coronary venous retroinfusion, however, resulted in a substantial accumulation of metoprolol in the ischemic myocardium. In group A pigs, subendocardial myocardial concentration was 16,800 ± 7,774, midmyocardial 39,590 ± 18,043 and subepicardial 57,143 ± 29.030 pmol/g (mean ± SE). The ischemic myocardial concentration in pigs from group B was somewhat less pronounced, probably secondary to a lower coronary venous pressure (15 ± 3 mm Hg with the lower volume of infusion (6.1 ± 0.3 ml) in group B compared with 32 ± 5 mm Hg with a 14 ± 1 ml infusion in group A. Coronary artery anterograde administration resulted in myocardial ischemic and nonischemic zone drug concentrations similar to those observed after retroinfusion into the coronary vein. With both modes of administration, there was a transmyocardial gradient from a somewhat lower drug concentration in the subendocardium, toward an increasing level in the midmyocardium, to the highest concentration in the subepicardial zone of the ischemic myocardium.
Coronary venous retroinfusion resulted in pronounced drug accumulation in the ischemic myocardium. The derived coronary venous pressure during infusion influenced the concentration of drug. The ischemic myocardial levels and distribution pattern were similar to those seen with coronary artery anterograde infusion. The high tissue levels of drug were not affected by saline solution flush. These findings suggest that coronary venous retroinfusion may deliver drugs to a microvascular level of ischemic myocardium, with a distribution similar to that achieved after direct arterial infusion.
☆ This study was supported in part by Grants HL 146444-14 and HL 17651-14 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland: the Swedish Society of Medicine, Stockholm, Sweden and the Medallion Group of Cedars-Sinai Medical Center Los Angeles, California.
- Received July 25, 1990.
- Revision received December 17, 1990.
- Accepted January 10, 1991.