Pharmacological characterization of angiotensin-induced depolarizations of rat superior cervical ganglion in vitro.
1. The depolarizing responses to angiotensin II and angiotensin III of the rat superior cervical ganglion have been characterized in vitro, by the use of peptidase inhibitors, peptide and non-peptide antagonists and dithiothreitol (DTT). 2. Angiotensin II and III depolarized the ganglion in a concentration-related manner. Angiotensin II was approximately 30 fold more potent than angiotensin III. 3. The endopeptidase inhibitor, bacitracin, increased the potency of angiotensin II and III by approximately 4 and 20 fold respectively. The aminopeptidase inhibitor, amastatin, further increased the potency of angiotensin III (but not angiotensin II) by approximately 4 fold. In the presence of bacitracin and amastatin, angiotensin II and III were equipotent. 4. The peptide antagonist [Ile7]angiotensin III (0.01-0.3 microM) produced a non-parallel rightward displacement of the angiotensin II concentration-response curve, with a suppression of the maximum response. The potency of [Ile7]angiotensin III was increased by bacitracin and amastatin. 5. The AT1-selective non-peptide antagonist losartan (DuP 753; 0.03 and 0.1 microM) produced a parallel rightward displacement of the angiotensin II concentration-response curve, with an apparent pKB of 8.3 +/- 0.1. A higher concentration of losartan (0.3 microM) depressed the maximum agonist response by 32 +/- 6.5%, possibly reflecting non-competitive behaviour of the antagonist. The potency of losartan was not influenced by bacitracin. 6. The AT2-selective non-peptide antagonist, PD123177 (3 microM) failed to antagonize the angiotensin II-induced depolarizations. 7. DTT (1 mM) produced a 22% reduction of the maximum response to angiotensin II.8. We conclude that the angiotensin II-induced depolarizations of the rat superior cervical ganglion are mediated by angiotensin II receptors of the AT1 subclass. The ability of peptidase inhibitors to modify the potency of peptide agonists and antagonists highlights the difficulties associated with the use of peptide agents to characterize angiotensin II receptors in this preparation.
Hawcock
A B
AB
Neuropharmacology Department, Glaxo Group Research Ltd., Ware, Hertfordshire.
Barnes
J C
JC
Michel
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AD
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000805:Angiotensin III / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001414:Bacitracin / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D005728:Ganglia, Sympathetic / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D013777:Tetrazoles / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D009467:Neuromuscular Depolarizing Agents; D009842:Oligopeptides; D010455:Peptides; D011480:Protease Inhibitors; D013777:Tetrazoles; D000804:Angiotensin II; D000805:Angiotensin III; D001414:Bacitracin; C014623:angiotensin III, Ile(8)-; C016977:amastatin; D019808:Losartan; D004229:Dithiothreitol