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Renal responses of anaesthetized Milan hypertensive (MHS) and Milan normotensive (MNS) rats to des-[Glu18-Ser19-Gly20-Leu21-Gly22]r atrial natriuretic peptide-4–23 (cANP4–23) a specific ligand for atrial natriuretic petide (ANP) clearance receptors were examined.The peptide was administered intravenously as an initial bolus injection (10 μg/kg body weight) followed by constant infusion (1 μg/min per kg body weight) for 30 min. Glomerular filtration rate, urine flow, sodium excretion and mean blood pressures were measured. Using the same protocol, plasma ANP levels were determined.Plasma ANP levels were significantly increased in both Milan strains (from 9.5±1.8 to 23.7±3.2 fmol/ml in MHS rats and from 9.8±1.2 to 15.9±1 fmol/ml in MNS rats). This increase was significantly greater in the MHS than in the MNS rats. The cANP4–23 infusions were diuretic and natriuretic in both strains of rats but despite a greater rise in plasma ANP level, the renal response was attenuated in the MHS compared with that in the MNS rats. Furthermore, the time course differed in that the hypertensive rats had a diuresis of slower onset. During cANP4–23 infusion, the mean blood pressure decrease was greater in the MHS rats, consistent with the fact that phenylephrine-precontracted isolated MHS rat aortae were threefold more sensitive to ANP-induced relaxation than were MNS rat aortae. Displacements of [125I]-rANP by rANP and cANP4–23 in isolated renal glomeruli indicated that MHS rats have similar amounts of cANP receptors but with a higher affinity for cANP than have MNS rats.cANP4–23 infusion increased plasma ANP more in MHS than in MNS rats. Renal responses were attenuated in the MHS rat compared with those in MNS rats. These differential actions cannot be explained in terms of glomerular ANP receptor densities, although aortic ring sensitivities differ between the two strains of rat.