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Pharmacodynamics of basic fibroblast growth factor: route of administration determines myocardial and systemic
D F Lazarous1, M Shou, J A Stiber
1Experimental Physiology and Pharmacology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. lazaroud@gwgate.nhlbi.nih.gov
Objective:
We have shown that basic fibroblast growth factor (bFGF/FGF-2) enhances myocardial collateral development in a canine model of progressive coronary occlusion when delivered via the left atrial or intracoronary routes; however, we have found intravenous bFGF ineffective in the same model. Data on the fate and efficacy of intravenous bFGF are limited. We hypothesized that first pass lung uptake might limit myocardial bFGF availability after intravenous injection. We postulated that delivery of bFGF through the distal port of a wedged Swan Ganz catheter might circumvent this problem by restricting exposure of bFGF to a limited number of pulmonary binding sites. This study evaluated differential regional uptake of 125I labeled bFGF following bolus intravenous, Swan Ganz, left atrial, intracoronary, and pericardial delivery.
Methods:
Mongrel dogs were used. Human recombinant bFGF, monoiodinated with 125I, was mixed with cold bFGF to a specific activity of 0.03 microCi/microgram. Approximately 100 micrograms/kg was injected per animal by the intravenous, left atrial, Swan Ganz, intracoronary, or pericardial route. Dogs were killed 15 min or 150 min later. The heart, lungs, liver, spleen, and kidneys were harvested and 125I activity was assessed. Immunohistochemical and pharmacokinetic studies were also performed.
Results:
Serum half life of bFGF was comparable after intracoronary, intravenous and left atrial delivery (50 min); however, there were significant differences with regard to pharmacodynamics. After intracoronary administration, 3-5% of the total bFGF dose was recovered from the heart, with the peptide immunolocalized to the extracellular matrix and vascular endothelium. In contrast, only 1.3% of the injected bFGF was localized to the heart after left atrial administration and 0.5% was recovered after intravenous or Swan Ganz delivery. Pericardial administration resulted in substantial cardiac bFGF delivery; 19% was present at 150 min. Myocardial uptake was similar with Swan Ganz and intravenous delivery, suggesting that the administered dose did not saturate available pulmonary binding sites.
Conclusions:
These data predict efficacy of intracoronary, left atrial, and pericardial bFGF for myocardial angiogenesis, and a lack of efficacy after bolus intravenous and Swan Ganz administration.