Effects of the neutral endopeptidase inhibitor, SQ 28,603, on regional haemodynamic responses to atrial natriuretic peptide or proendothelin‐1 [1–38] in conscious rats

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Abstract
1 Regional haemodynamic responses to atrial natriuretic peptide (ANP, 0.5 nmol kg−1) or proendothelin-1 [1–38] (1.0 nmol kg−1) were assessed in the same conscious Long Evans rats before and 20 min after administration of the novel neutral endopeptidase (NEP) inhibitor, SQ 28,603 (50 mg kg−1, i.v.). In a separate experiment, responses to endothelin-1 (0.5 nmol kg−1), angiotensin I (0.25 nmol kg−1) and angiotensin II (0.12 nmol kg−1) were measured before and after administration of SQ 28,603. 2 SQ 28,603 alone had no significant cardiovascular effects but caused significant prolongation of the hypotensive, tachycardic and renal and mesenteric vasoconstrictor effects of ANP. However, the early vasodilator and late vasoconstrictor responses in the hindquarters were not affected significantly. 3 SQ 28,603 caused significant attenuation of the pressor effects of proendothelin-1 [1–38] but the associated bradycardia was unchanged. SQ 28,603 caused a significant inhibition of the renal and mesenteric vasoconstrictor effects of proendothelin-1 and also inhibited the initial vasodilator and subsequent vasoconstrictor responses in the hindquarters vascular bed. 4 SQ 28,603 had no significant effects on the haemodynamic responses to endothelin-1, angiotensin I, or angiotensin II. 5 The results are consistent with SQ 28,603 not only inhibiting NEP that is involved in the degradation of ANP, but also suppressing activity of the enzyme involved in the conversion of proendothelin-1 [1–38] to endothelin-1.