Journal of hypertension · 1994
Mechanisms underlying the augmented responses of deoxycorticosterone acetate-salt hypertensive rats to neutral endopeptidase inhibitors.
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Hirata Y, Suzuki Y, Suzuki E, Hayakawa H, Kimura K, Goto A, Omata M, Minamino N, Kangawa K, Matsuo H
Аннотация
OBJECTIVE: To explore the mechanisms for augmented neutral endopeptidase inhibitor-induced natriuresis in deoxycorticosterone acetate (DOCA)-salt rats.
METHODS: We examined effects of a neutral endopeptidase-inhibitor, candoxatril, on plasma and urinary brain natriuretic peptide (BNP) levels, the influence of a specific atrial natriuretic peptide (ANP) receptor antagonist, HS-142-1, on the response to candoxatril, and the renal neutral endopeptidase activity in DOCA-salt rats.
RESULTS: Candoxatril decreased blood pressure and increased urinary sodium excretion, both of which were greater in DOCA-salt rats than in normotensive control rats. These effects were associated with a significant rise in the plasma BNP level and the plasma ANP level in DOCA-salt rats. Urinary ANP excretion also increased, but urinary BNP excretion was not changed by candoxatril. Pretreatment with a specific ANP receptor antagonist (HS-142-1) diminished the effect of candoxatril on urinary sodium excretion, blood pressure and urinary cyclic GMP excretion. Urinary neutral endopeptidase-like activity was greater in DOCA-salt rats than in control rats. Northern blot analysis revealed that the ratio of renal neutral endopeptidase messenger RNA (mRNA) to beta-actin mRNA was comparable between the two groups.
CONCLUSIONS: The neutral endopeptide inhibitor exerted its hypotensive and natriuretic effects mainly via the potentiation of the endogenous natriuretic peptides, including BNP. The augmented response of DOCA-salt rats also seems to be mediated by both the downregulation of clearance receptors and an increase in renal neutral endopeptidase activity.
METHODS: We examined effects of a neutral endopeptidase-inhibitor, candoxatril, on plasma and urinary brain natriuretic peptide (BNP) levels, the influence of a specific atrial natriuretic peptide (ANP) receptor antagonist, HS-142-1, on the response to candoxatril, and the renal neutral endopeptidase activity in DOCA-salt rats.
RESULTS: Candoxatril decreased blood pressure and increased urinary sodium excretion, both of which were greater in DOCA-salt rats than in normotensive control rats. These effects were associated with a significant rise in the plasma BNP level and the plasma ANP level in DOCA-salt rats. Urinary ANP excretion also increased, but urinary BNP excretion was not changed by candoxatril. Pretreatment with a specific ANP receptor antagonist (HS-142-1) diminished the effect of candoxatril on urinary sodium excretion, blood pressure and urinary cyclic GMP excretion. Urinary neutral endopeptidase-like activity was greater in DOCA-salt rats than in control rats. Northern blot analysis revealed that the ratio of renal neutral endopeptidase messenger RNA (mRNA) to beta-actin mRNA was comparable between the two groups.
CONCLUSIONS: The neutral endopeptide inhibitor exerted its hypotensive and natriuretic effects mainly via the potentiation of the endogenous natriuretic peptides, including BNP. The augmented response of DOCA-salt rats also seems to be mediated by both the downregulation of clearance receptors and an increase in renal neutral endopeptidase activity.