Renal effects of TAPP, a highly selective μ‐opioid agonist

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Abstract
1 The effect of i.v. administration of TAPP, a highly selective and exclusively peripherally-acting μ-opioid receptor agonist, on urine output, urinary sodium, potassium and cyclic GMP, and on plasma immunoreactive atrial natriuretic factor (IR-ANF) levels was studied in conscious normally hydrated female rats (200–250 g). 2 TAPP treatment produced a significant dose-dependent increase of urine output and urinary sodium, potassium and cyclic GMP excretion during the first hour. The highest TAPP dose used (2.5 mg kg−1 body weight) elicited a 10 fold elevation 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 μEq h−1 to 79 ± 12.7 μEq h−1, n = 18 (P < 0.001)], potassium [from 9.5 ± 2.5 μEq h−1 to 39.4 ± 6.6 μEq 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 ml−1 (n = 18) (P < 0.001) 5 min after administration of TAPP (2500 μg kg−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 opioid antagonist naloxone (0.8 mg per rat) abolished the diuretic, natriuretic and kaliuretic effect of TAPP (250 μg 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 μEq h−1, to 21.3 ± 8.5 μEq h−1, n = 12 (P < 0.001), and potassium excretion decreased from 45.4 ± 9.7 μEq h−1, n = 12, to 16.1 ± 7.0 μEq h−1, (P < 0.001). 5 Pretreatment with anti-ANF serum (0.4 ml) abolished the diuretic effect of TAPP: urine output diminished significantly from 1.93 ± 0.28 to 0.88 ± 0.29 ml h−1 (P < 0.01) (n = 6). The TAPP-induced diuretic action, increased sodium/potassium excretion and elevated urinary cyclic GMP levels were also reversed by anti-ANF antibodies. 6 Since TAPP is totally unable to cross the blood-brain barrier, the ensemble of these observations led to the conclusion that the diuretic, natriuretic, kaliuretic and hypotensive effects produced by this μ-opioid agonist through interaction with peripheral μ-opioid receptors occur via ANF release.