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

• Published in: British journal of pharmacology 1996-09, Vol.119 (2), p.239-244
• Main Authors: Gutkowska, Jolanta, Schiller, Peter W.
• Format: Article
• Language: English
• Subjects: ANF; Animals; Atrial Natriuretic Factor - blood; Biological and medical sciences; Blood Pressure - drug effects; cyclic GMP; Cyclic GMP - urine; diuresis, natriuresis, kaliuresis; Dose-Response Relationship, Drug; Female; Fundamental and applied biological sciences. Psychology; hypotension; Kidney - drug effects; Kidney - ultrastructure; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Oligopeptides - pharmacology; Opioid Peptides - pharmacology; opioid receptors; Opioids; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu - agonists; Urine; Vertebrates: urinary system; μ‐opioid agonists
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15977.x

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.