Cross-Talk Between AT1 and AT2Angiotensin Receptors in Rat Anococcygeus Smooth Muscle

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Abstract
Schild regressions for the selective AT1 and AT2 receptor antagonists, losartan and PD123319 (S-[+]-1-[(4-dimethylamino]-3-methylphenyl)methyl]-5-[diphenylacetyl]-4,5,6,7-tetrahydro-1H-imidazol[4,5-c]pyridine-6-carboxilic acid), respectively, were calculated to analyze the heterogeneity of receptor populations in the rat anococcygeus muscle. For a one-receptor system, the Schild regression has a slope of unity and an intercept of KB for competitive antagonists. However, in a two-receptor system, a deviation from the single-receptor plot will occur. This is predicated on the assumption that the secondary receptor is less sensitive to the antagonist than the primary receptor. Results showed that the Schild regression for losartan did not produce a slope of unity, and PD123319 did not produce any effect. However, tissue incubation with losartan plus PD123319 resulted in a Schild regression that has a slope of unity and a pKB of 9.32. In the presence of prazosin, an α1-adrenoceptor antagonist, losartan did not produce any effect. Conversely, PD123319 enhanced the angiotensin II (Ang II)-induced contraction in a concentration-dependent fashion, suggesting an inhibitory AT2-mediated effect. This effect was confirmed with assays that showed a relaxant response induced by Ang II on precontracted tissues incubated with prazosin. PD123319 andNG-nitro-l-arginine methyl ester [nitric-oxide (NO) synthase inhibitor)] markedly inhibited the relaxant response of Ang II. In contrast, losartan did not produce any significant effect. Consequently, results show that the mechanism underlying the AT2-mediated effect is highly dependent on NO generation. Results indicate the presence of a heterogeneous angiotensin receptor population in the rat anococcygeus muscle following a negative cross-talk relationship between the AT1 and AT2 subtypes.