THE CORONARY ENDOTHELIUM AS A FUNCTIONAL AND PHYSICAL BARRIER FOR ENDOCRINE ANGIOTENSIN II

Abstract

Circulating/endocrine Angiotensin II (AII) may remain intravascularily, does not diffuse across the vessel wall and acts only in the luminal endothelial membrane (LEM). We synthesized 15,000 kDa polymers of AII (AII‐Pol) and Saralasin (Sar‐Pol) that due to their size, remain intravascularily and act solely in the LEM's AII receptors (L‐AT1).In isolated perfused rat hearts AII and AII‐Pol both induces equally a positive inotropism and vasoconstriction. However, their ways of action differ; AII causes desensitization but AII‐Pol does not. Simultaneous infusion of both agonists show that as AII‐Pol/Ang II ratio raises, AII's desenzitization dwindles and is blocked. Desensitization is attributed to L‐AT1 internalization and is expected AII to induce L‐AT1 internalization but not so AII‐Pol. In LEM sampled during sustained stimulation with AII or AII‐Pol we show AII decreases L‐AT1 expression but no so AII‐Pol. The effects of both agonists were blocked by the non‐permeant Sar‐Pol. These results indicate that Ang II and Ang II‐Pol act and compete for the same L‐AT1.To demonstrate the action of AII is restricted to L‐AT1, we intracoronary infused biotin labeled AII (AII‐B). Micrographs reveal AII‐B retained luminally and co localized with endothelial markers.We conclude that the coronary endothelium is a functional and physical barrier for circulating AII. Funded by CONACYT SEP‐42567, 2004 C01 156.