The pharmacokinetics of 125I-atrial natriuretic factor in anaesthetized rats: Effects of neutral endopeptidase inhibition with candoxatrilat (cas 123898-42-0) and of ANF-C receptor blockade

Add time:08/20/2019    Source:sciencedirect.com

The effects of candoxatrilat (cas 123898-42-0) (cis-4-[[2-carboxy-3-(2-methoxyethoxy)propyl]-1-cyclo-pentanecarbonylamino]-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-[125I]iodotyrosyl28)ANF (125I-ANF) were studied in both intact and nephrectomized anaesthetized rats. HPLC analysis was used to verify that the 125I-labelled material isolated by solid phase extraction of rat plasma was intact ANF. In intact animals, clearance of 125I-ANF was biphasic with a T12α of 17 sec and T12β of 95 sec. Volume of distribution (Vd) was 564 mL/kg and plasma clearance (Clp) 248 mL/min/kg. Candoxatrilat, over the dose range 0.01–10 mg/kg i.V., increased T12β (by a maximum of 56%) and decreased Clp (by up to 52%) with no effect on T12α or Vd. C-ANF4–23 (10 μg/kg + 1 μg/kg/min i.v.) reduced Vd (by 57%) and Clp (by 54%) with no effect on T12β, whilst abolishing the T12α 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 T12β. Combining the two agents resulted in a substantial decrease in Clp (76%) whilst the reduction in Vd and increase in T12β were comparable to those seen with C-ANF4–23 and candoxatrilat alone, respectively. In nephrectomized rats, the pharmacokinetics of 125I-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 T12β (153%) and decreases in Vd (55%) and Clp (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 125I-ANF, together accounting for at least 75% of the total clearance of this peptide in the rat.

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