Pharmacokinetic analysis of coronary venous retroinfusion: A comparison with anterograde coronary artery drug administration using metoprolol as a tracer

Abstract

Plasma and myocardial tissue concentrations of metoprolol were 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 less than 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, mid-myocardial 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 mid-myocardium, 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Myocardial gene transfer by selective pressure-regulated retroinfusion of coronary veins

“…These findings are consistent with previous observations that an epicardial to endocardial gradient exists if drugs are delivered to the myocardium through the coronary veins. [14][15][16] Transfection efficacy may be influenced by modifications of the retroinfusion fluid. Although physiological temperature and the use of cristalloid solution as opposed to whole blood 21 for retroinfusion was taken into account in this study, transfection efficacy might be further enhanced by drugs such as serotonin, bradykinin or L-NAME as demonstrated in isolated rabbit hearts.…”

“…[14][15][16] More recently, we could demonstrate that pressure-regulated retroinfusion was able to target dobutamine selectively to the ischemic myocardium without systemic effects. 17 Similar results were obtained in patients undergoing retroinfusion supported high risk PTCA or stent implantation.…”

Potential of gene therapy as a treatment for heart failure

“…Access to the myocardium can be achieved with this approach regardless of atherosclerosis severity or coronary artery obstruction. Numerous studies showed that retrograde coronary venous infusion is an alternate myocardial delivery method for cardioprotective drugs (21,22). Shortly thereafter, retrograde venous infusion was also explored as a method for gene transfer.…”

Calcitonin gene-related peptide in myocardial ischaemia and reperfusion in the pig

“…The tip of the catheter was positioned at the intended level of arterial occlusion. The central lumen of the catheter was used for blood sampling from, or infusion of drugs into the myocardium supplied by the occluded portion of the LAD Ž w x. for details see 14,15 . Before insertion of the balloon Ž .…”