MODULATION OF ANP-DEPENDENT EFFECTS OF ENDOTHELIN BY INHIBITORS OF NEUTRAL ENDOPEPTIDASE AND CGMP PHOSPHODIESTERASE

Endothelin 3 (ET(3)) infusion increases the concentration of atrial na triuretic peptide (ANP) in plasma, which in turn raises hematocrit (Hc t) through a transcapillary shift of plasma fluid and proteins into th e interstitium, thereby reducing plasma volume (PV). The level of ANP bioactivity in peripheral target tissues is a function of ANP secretor y rate and the turnover rate of ANP and its intracellular effector mec hanisms. Neutral endopeptidase (NEP) is a widely distributed enzyme th at participates in ANP catabolism, whereas cGMP-phosphodiesterase (PDE ) degrades the intracellular second messenger of ANP. Therefore, we ex amined the consequences of inhibition of NEP and PDE on the ANP-depend ent activity described above using the NEP inhibitor SQ 28,603 and the cGMP-PDE inhibitor zaprinast (M&B 22,948). In anesthetized, bilateral ly nephrectomized rats, infusion of SQ 28,603 alone reduced mean arter ial 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 ET(3) (25 ng/kg/min) and SQ 2 8,603 caused MAP to increase by 12.8 +/- 2.2%, an effect identical wit h that observed after ET(3) alone (12.7 +/- 2.3%), whereas the increas e in Hct of 9.4 +/- 0.4% was greater (P < .05) than the 7.5 +/- 0.4% i ncrease seen with ET(3) alone. ET(3) increased plasma ANP concentratio n (599 +/- 135 vs. 108 +/- 13 pg/ml in vehicle-infused rats; P < .0001 ); ET(3) and SQ 28,603 infused simultaneously increased plasma ANP eve n further (810 +/- 166 pg/ml). Pretreatment with anti-rat ANP antiseru m abolished the increase in Hct seen with ET(3) or ET(3) plus SQ 28,60 3 infusion, but increased MAP by 23.8 +/- 1.9% (P < .002 vs. ET(3) or ET(3) plus SQ 28,603). Infusion of M&B 22,948 alone did not affect pla sma ANP concentration or Hct but lowered MAP by 8.1 +/- 0.5% (P < .001 ); this decrease was not prevented by pretreatment with anti-rat ANP a ntiserum. Simultaneous infusion of ET(3) and M&B 22,948 prevented the ET(3) mediated increase in MAP (+0.6 +/- 2.8%), and attenuated the inc rease in Hct to 5.3 +/- 0.5%; the increase in plasma ANP concentration was also somewhat attenuated in this group (474 +/- 57 pg/ml) compare d with ET(3) infused alone. Pretreatment with anti-rat ANP antiserum a bolished the increase in Hct seen with ET(3) plus M&B 22,948 but did n ot affect the change in MAP. These results indicate that the consequen ces of ET-induced increases in plasma ANP concentration can be selecti vely modulated by inhibition of NEP to potentiate ANP-dependent effect s of ET(3) on blood pressure and vascular permeability. Inhibition of cGMP-PDE, on the other hand, leads to effects that seem to be largely independent of ANP. This lack of specificity may place significant con straints on the interpretation of experimental data with this approach and its ultimate clinical utility.