RENAL EFFECTS OF TAPP, A HIGHLY SELECTIVE MU-OPIOID AGONIST

1 The effect of i.v. administration of TAPP, a highly selective and ex clusively peripherally-acting mu-opioid receptor agonist, on urine out put, urinary sodium, potassium and cyclic GMP, and on plasma immunorea ctive atrial natriuretic factor (IR-ANF) levels was studied in conscio us normally hydrated female rats (200-250 g). 2 TAPP treatment produce d a significant dose-dependent increase of urine output and urinary so dium, potassium and cyclic GMP excretion during the first hour. The hi ghest TAPP dose used (2.5 mg kg(-1) body weight) elicited a 10 fold el evation of urine output from 0.23 +/- 0.06 ml h(-1) to 2.5 +/- 0.3 ml h(-1) (n=18) accompanied by augmented sodium [from 17.0+/-4.7 mu Eq h( -1) to 79+/-12.7 mu Eq h(-1), n=18 (P<0.001)], potassium [from 9.5+/-2 .5 mu Eq h(-1) to 39.4+/-6.6 mu Eq h(-1), n=18 (P<0.005)], and cyclic GMP excretion [from 191+/-21 pmol h(-1) to 1340+/-322 pmol h(-1), n=18 (P<0.001)]. Plasma IR-ANF rose from 22+/-4 pg ml(-1) to 508+/-22 pg m l(-1) (n=18) (P<0.001) 5 min after administration of TAPP (2500 mu g k g(-1)). 3 TAPP lowered systemic blood pressure, also in a dose-related manner, 1-5 min after injection. This decrease in blood pressure was transient and did not last more than 10 min. 4 Pretreatment with the o pioid antagonist naloxone (0.8 mg per rat) abolished the diuretic, nat riuretic and kaliuretic effect of TAPP (250 mu g kg(-1)): urine output dropped from 1.16+/-0.15 ml h(-1), n=12, to the control value of 0.15 +/-0.06 ml h(-1), n=12 (P<0.001), sodium excretion fell from 57.5+/-11 mu Eq h(-1), to 21.3+/-8.5 mu Eq h(-1), n=12 (P<0.001), and potassium excretion decreased from 45.4+/-9.7 mu Eq h(-1), n=12, to 16.1+/-7.0 mu Eq h(-1), (P<0.001).5 Pretreatment with anti-ANF serum (0.4 ml) abo lished the diuretic effect of TAPP: urine output diminished significan tly from 1.93+/-0.28 to 0188+/-0.29 ml h(-1) (P<0.01) (n=6). The TAPP- induced diuretic action, increased sodium/potassium excretion and elev ated urinary cyclic GMP levels were also reversed by anti-ANF antibodi es. 6 Since TAPP is totally unable to cross the blood-brain barrier, t he ensemble of these observations led to the conclusion that the diure tic, natriuretic, kaliuretic and hypotensive effects produced by this mu-opioid agonist through interaction with peripheral mu-opioid recept ors occur via ANF release.