Modulation of ANP-dependent effects of endothelin by inhibitors of neutral endopeptidase and cGMP phosphodiesterase

JP Valentin, C Qiu, E Wiedemann, DG Gardner and MH Humphreys

Division of Nephrology, San Francisco General Hospital, California, USA.

Endothelin 3 (ET3) infusion increases the concentration of atrial natriuretic peptide (ANP) in plasma, which in turn raises hematocrit (Hct) through a transcapillary shift of plasma fluid and proteins into the interstitium, thereby reducing plasma volume (PV). The level of ANP bioactivity in peripheral target tissues is a function of ANP secretory rate and the turnover rate of ANP and its intracellular effector mechanisms. Neutral endopeptidase (NEP) is a widely distributed enzyme that participates in ANP catabolism, whereas cGMP-phosphodiesterase (PDE) degrades the intracellular second messenger of ANP. Therefore, we examined the consequences of inhibition of NEP and PDE on the ANP- dependent activity described above using the NEP inhibitor SQ 28,603 and the cGMP-PDE inhibitor zaprinast (M&B 22,948). In anesthetized, bilaterally nephrectomized rats, infusion of SQ 28,603 alone reduced mean arterial pressure (MAP) by 2.5 +/- 0.5% and increased Hct by 4.6 +/- 0.3% (P < .01 for both), leading to a calculated decrease in PV of 7.5 +/- 0.6%. These changes were prevented by pretreatment with rabbit anti-rat ANP antiserum. Simultaneous infusion of ET3 (25 ng/kg/min) and SQ 28,603 caused MAP to increase by 12.8 +/- 2.2%, an effect identical with that observed after ET3 alone (12.7 +/- 2.3%), whereas the increase in Hct of 9.4 +/- 0.4% was greater (P < .05) than the 7.5 +/- 0.4% increase seen with ET3 alone. ET3 increased plasma ANP concentration (599 +/- 135 vs. 108 +/- 13 pg/ml in vehicle-infused rats; P < .0001); ET3 and SQ 28,603 infused simultaneously increased plasma ANP even further (810 +/- 166 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 273, Issue 2, pp. 744-752, 05/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics

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