ROLE OF ENDOGENOUS ATRIAL-NATRIURETIC-PEPTIDE IN REGULATING SODIUM-EXCRETION IN SPONTANEOUSLY HYPERTENSIVE RATS - EFFECTS OF NEUTRAL ENDOPEPTIDASE INHIBITION

To explore whether pathophysiological plasma levels of atrial natriuretic peptide (ANP) actually involve sodium excretion in spontaneously hypertensive rats (SHR), we examined the in vivo and ex vivo effects of ANP and an endopeptidase inhibitor, thiorphan, on urinary sodium excretion and the elimination rate of ANP. We found the following: 1) The basal plasma ANP level was higher in 16-week-old SHR than in Wistar-Kyoto (WKY) rats (109 +/- 10 [SEM] versus 63 +/- 4 pg/ml, p < 0.001). Thiorphan (30 mg/kg i.v.) significantly increased plasma ANP by 60% in both SHR and WKY rats. However, increases in urinary sodium excretion (+290% versus +130%, p < 0.05) and cyclic GMP (+160% versus + 60%, p < 0.05) were greater in SHR than in WKY rats. Urinary excretion of ANP was markedly increased by thiorphan, and its increase was greater in SHR than in WKY rats. 2) The thiorphan-induced natriuresis was substantially attenuated by antiserum for ANP but not by a bradykinin receptor antagonist. 3) Isolated SHR kidneys excreted 50% less sodium than WKY rat kidneys at perfusion pressures of 100 and 160 mm Hg (p < 0.05). Urinary sodium excretion was increased at the perfusate ANP level of 100 pg/ml, a concentration similar to the SHR plasma ANP (+70% at 160 mm Hg). 4) After bolus administration of ANP to the isolated kidney, the ANP concentration of the recirculating perfusate decreased rapidly in a log-linear fashion. Pretreatment with thiorphan significantly prolonged the elimination half-life of ANP to a greater degree in the SHR kidney than in the WKY rat kidney (+75% versus +36%, p < 0.05). Thus, endogenous ANP may keep the pressure-natriuresis curve to the left and consequently facilitate sodium excretion in SHR. Moreover, the enzymatic degradation of ANP seems to be increased in SHR kidneys.