ELSEVIER European Journal of Pharmacology 259 (1994) 27-36 Renal actions of the angiotensin AT 2 receptor ligands CGP 42112 and PD 123319 after blockade of the renin-angiotensin system David Macari, Steven Whitebread, Frederic Cumin, Marc De Gasparo, Nigel Levens Cardiovascular Research, K 125 9.08, Ciba-Geigy Ltd., Basel, CH 4002, Switzerland (Received 30 December 1993; revised MS received 22 March 1994; accepted 29 March 1994) ~g Abstract The purpose of this study was to investigate whether the selective angiotensin AT e receptor ligands, CGP 42112B (Nic-Tyr-(N~-benzoyloxycarbonyl-Arg)Lys-His-Pro-Ile-OH)and PD 123319 ((s)-l-[[4-(dimethylamino)-3-methyl-phenyl]methyl]- 5-(diphenylacetyl)-4,5,6,7-tetrahydro-lH-imidazo[4,5-c]-pyridine-6-carboxylic acid) are agonists at angiotensin receptors influenc- ing blood pressure and renal function in the enalaprilat-treated anesthetized rat. The agonist angiotensin II significantly increased blood pressure and renal vascular resistance. Glomerular filtration rate was unchanged by angiotensin II. Effective renal blood flow decreased significantly in response to angiotensin II leading to a significant increase in filtration fraction. Angiotensin II did not induce significant change in urinary potassium excretion or free water formation but significantly increased both urine volume and urinary sodium excretion. At doses up to 3 orders of magnitude greater than angiotensin II, CGP 42112B also significantly increased blood pressure, filtration fraction, glomerular filtration rate, urine volume and urinary sodium excretion, but did not significantly affect effective renal blood flow or renal vascular resistance. The selective angiotensin AT 2 receptor ligand PD 123319 had no significant effects on blood pressure nor any measured parameter of renal function. The changes in blood pressure and renal function produced by angiotensin II and CGP 42112B could be completely blocked by the angiotensin AT 1 receptor antagonist losartan. The results therefore only support a role for angiotensin AT 1 receptors and not angiotensin AT 2 receptors in the control of renal function in the rat and demonstrate that at high doses the angiotensin AT z selective ligand CGP 42112B behaves as an agonist at angiotensin AT 1 receptors. Key words: Angiotensin AT 1 receptor; Angiotensin AT 2 receptor; Angiotensin II; Kidney 1. Introduction While the majority of studies would suggest that the renal actions of angiotensin II are mediated by an- giotensin AT 1 receptors, there have been several re- cent reports suggesting that selective angiotensin AT 2 receptor ligands such as PD 123177 and PD 123319 can affect renal function. (Cogan et al., 1991; Wong et al., 1991; Loutzenhiser et al., 1991; Bovee et al., 1991; Keiser et al., 1992; Clark et al., 1993; Mento et al., 1992). PD 123177 and PD 123319 are selective for the angiotensin AT 2 receptor subtype but only within a certain range of concentrations (Whitebread et al., 1991; Chiu et al., 1989). Since, in the aforementioned studies, PD 123177 and PD 123319 were used at very * Corresponding author. Tel. 0041 61 696 4046, fax 0041 61 696 5808. Elsevier Science B.V. SSDI 0014-2999(94)00203-J high doses and, in the majority of cases, produced effects qualitatively similar to angiotensin AT x receptor antagonists, the possibility exists that PD 123177 and PD 123319 influence renal function by interacting with the angiotensin ATx receptor subtype. Thus, a role for the angiotensin AT z receptor in the control of renal function has not been convincingly demonstrated. The hypothesis that the angiotensin AT 2 receptor plays a role in the control of renal function in the rat has recently been reassessed by investigating the ac- tions of the selective angiotensin AT 2 ligands CGP 42112B and PD 123319 in the sodium-depleted rat (Macari et al., 1993). In these studies, PD 123319 was inactive but CGP 42112B influenced many parameters of renal function. Since the renal actions of CGP 42112B were observed only at high doses and resem- bled those produced by the AT 1 receptor antagonist losartan it was concluded that CGP 42112B affected