THE PHARMACOKINETICS OF I-125 ATRIAL-NATRIURETIC-FACTOR IN ANESTHETIZED RATS - EFFECTS OF NEUTRAL ENDOPEPTIDASE INHIBITION WITH CANDOXATRILAT AND OF ANF-C RECEPTOR BLOCKADE

The effects of candoxatrilat (cis-4-{[2-carboxy-3-(2-methoxyethoxy)propyl]-1-cyclopentanecarbonylamino}-1-cyclohexane carboxylic acid) and the ring-deleted atrial natriuretic factor (ANF) analogue C-ANF4-23 (des[Gln18, Ser19, Gly20, Leu21, Gly22]ANF4-23-NH2) on the clearance of (3-[I-125]iodotyrosyl28)ANF (I-125-ANF) were studied in both intact and nephrectomized anaesthetized rats. HPLC analysis was used to verify that the I-125-labelled material isolated by solid phase extraction of rat plasma was intact ANF. In intact animals, clearance of I-125-ANF was biphasic with a T1/2alpha of 17 sec and T1/2beta of 95 sec. Volume of distribution (V(d)) was 564 mL/kg and plasma clearance (Cl(p)) 248 mL/min/kg. Candoxatrilat, over the dose range 0.01-10 mg/kg i.v., increased T1/2beta (by a maximum of 56%) and decreased Cl(p) (by up to 52%) with no effect on T1/2alpha or V(d). C-ANF4-23 (10 mug/kg + 1 mug/kg/min i. v.) reduced V(d) (by 57%) and Cl(p) (by 54%) with no effect on T1/2beta, whilst abolishing the T1/2alpha phase in over 50% of animals. Increasing the dose of C-ANF4-23 did not increase the effect on any of these parameters, apart from a small increase in T1/2beta. Combining the two agents resulted in a substantial decrease in Cl(p) (76%) whilst the reduction in V(d) and increase in T1/2beta were comparable to those seen with C-ANF4-23 and candoxatrilat alone, respectively. In nepbrectomized rats, the pharmacokinetics of I-125-ANF and the changes induced by candoxatrilat were similar to those observed in intact animals, whilst the effects of C-ANF4-23 alone were greater than in intact animals. The combination of C-ANF4-23 and candoxatrilat again produced a substantial increase in T1/2beta (153%) and decreases in V(d) (55%) and Cl(p) (78%) in nephrectomized animals, although these changes could not be distinguished from those seen in intact animals treated with the same combination. Our studies indicate that neutral endopeptidase and ANF-C receptors are both major, and approximately equal, clearance mechanisms for I-125-ANF, together accounting for at least 75% of the total clearance of this peptide in the rat.