A potent noncompetitive Angiotensin II antagonist induces only competitive inhibition of Angiotensin III responses

Sarcosyl¹, cysteinylmethyl S-⁸-angiotensin II [(Sar¹, Cys-Me⁸) Ang II] was examined for antagonism of angiotensin (Ang) responses in isolated rabbit atrial and aortic tissues. (Sar¹, Cys-Me⁸) Ang II competitively antagonized Ang II responses in aorta at a concentration of 5n M. Concentrations of the antagonist greater than 5n M resulted in noncompetitive antagonism of Ang II responses in cardiac and vascular smooth muscle. These actions of (Sar¹, Cys-Me⁸) Ang II were significant (p < 0.01) and depressed maximal responses to Ang II as much as 80%. In contrast, (Sar¹, Cys-Me⁸) Ang II at concentrations up to 10^-6 M did not significantly alter maximal responses to Ang III at any concentration in any of the experimental preparations. The antagonist did competitively inhibit Ang III concentration-dependent responses in the aorta and, to a lesser extent, in isolated atria. Saralasin was a competitive antagonist of Ang II and III in atrial and aortic preparations. Norepinephrine responses in cardiac and vascular tissues were not altered by these antagonists. The different types of antagonism exhibited by (Sar¹, Cys-Me⁸) Ang II against Ang II and III in identical preparations demonstrate the potential for the existence of separate Ang receptors.