Contractile effects by intracellular angiotensin II via receptors with a distinct pharmacological profile in rat aorta

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Abstract
We studied the effect of intracellular angiotensin II (Ang II) and related peptides on rat aortic contraction, whether this effect is pharmacologically distinguishable from that induced by extracellular stimulation, and determined the Ca2+ source involved. Compounds were delivered into the cytoplasm of de‐endothelized aorta rings using multilamellar liposomes. Contractions were normalized to the maximum obtained with phenylephrine (10−5 M). Intracellular administration of Ang II (incorporation range: 0.01–300 nmol mg−1) resulted in a dose‐dependent contraction, insensitive to extracellular administration (10−6 M) of the AT1 receptor antagonist CV11947, the AT2 receptor antagonist PD 123319, or the non‐selective AT receptor antagonist and partial agonist saralasin ([Sar1,Val5,Ala8]‐Ang II (P−1 Ang II was incorporated. Contraction was partially desensitized to a second intracellular Ang II addition after 45 min (PPPP2+‐free external medium. These results support the existence of an intracellular binding site for Ang II in rat aorta. Intracellular stimulation induces contraction dependent on Ca2+‐influx but not on Ins(1,4,5)P3 mediated release from intracellular Ca2+‐stores. Intracellular Ang I and saralasin induce contraction, possibly via the same binding site. Pharmacological properties of this putative intracellular receptor are clearly different from extracellular stimulated AT1 receptors or intracellular angiotensin receptors postulated in other tissue. British Journal of Pharmacology (1999) 126, 1133–1138; doi:10.1038/sj.bjp.0702421