Pulmonary angiotensin converting enzyme ligand binding kinetics

We measured the pulmonary venous concentration venus time curves of the pulmonary Angiotensin Converting Enzyme (ACE) ligands ³Hramiprilat (RMP) and ¹⁸F-fluorocaptopril (CAP) and a reference indicator ¹²⁵I-albumin (HSA) following four sequential arterial bolus injections in isolated rabbit lungs. The first two boluses included trace amounts of ³H-RMP and ¹⁸F-CAP injected at 200 and 600 ml/min. The third bolus was the same as the first two, but with a large dose of unlabeled RMP (15-20 nmoles) injected at 200 ml/min. The fourth bolus was the same as the first two and was injected at 200 ml/min. The % uptakes of ³H-RMP and ¹⁸F-CAP for the first two boluses were 44 ± 1 (SE) and 41 ± 4 at 200 ml/min and 42 ± 1 and 42 ± 3 at 600 ml/min, respectively. The coinjection of a large dose of unlabeled RMP reduced the % uptake of ³H- RMP and ¹⁸F-CAP to 22 ± 4 and 21 ± 5, respectively, and the % uptakes of ³H- RMP and ¹⁸F-CAP following the fourth bolus injection were 11 ± 3 and 14 ± 4, respectively. We used a distributed-in-space-and-time model that fit the data if only the Trans form is the ACE ligand and it binds rapidly to ACE relative to the capillary transit time (TT), and if the Cis-to-Trans conversion rate and the bound ligand dissociation rate are slow relative to TT. The model estimate of the number of binding sites for these ligands in the rabbit lung was about 4.5 nmoles.