title: The coronary endothelium behaves as a functional diffusion barrier for intravascular Angiotensin II.
abstract: Diverse intracoronary hormones cause their cardiac effects solely via activation of their coronary endothelial luminal membrane (CELM) receptors. To test this hypothesis for Ang II, we synthesized: a) two large polymers of Ang II (Ang II-POL) and Losartan (Los-POL) which act only in the CELM's AT1R because they cannot cross the endothelial barrier and b) biotin-labeled Ang II (Ang II-Biotin) and Ang II-POL-Biotin to be identified by microscopy in tissues. Sustained coronary perfusion of Ang II (potentially diffusible) or Ang II-POL caused a positive inotropic effect (PIE) and an increase in coronary perfusion pressure (CPP) of equal magnitude that were blocked by Losartan and Los-POL. However, Ang II effects, in contrast to Ang II-POL effects, were transient due to desensitization and resulted in tachyphylaxis to a second administration of Ang II or Ang II-POL. Furthermore, if Ang II and Ang II-POL acted differently on the same receptor; a competition of effects would be expected. This was demonstrated by infusing simultaneously a molar ratio of Ang II:Ang II-POL. As this molar ratio decreased, Ang II-induced desensitization and tachyphylaxis decreased. Intravascularly-administered Ang II-Biotin and Ang II-POL-Biotin remained bound and confined to the endothelium. Our results support the hypothesis and indicate intravascular Ang II, not by mass exchange with the interstitium, but by an action restricted to the CELM's AT1R, causes release of endothelial chemical messengers that exert physiological effects and modulate the effects and metabolism of paracrine Ang II. Endocrine Ang II controls and communicates with its paracrine counterparts solely through endothelial receptors.
authors.affiliation: Dept of Physiology, Facultad. de Medicina de la UASLP, Mexico. rrubio@uaslp.mx
authors.forename: Rafael
authors.initials: R
authors.lastname: Rubio
authors.forename: David
authors.initials: D
authors.lastname: Torres-Tirado
authors.forename: Jesus
authors.initials: J
authors.lastname: Castillo-Hernandez
authors.forename: Erika
authors.initials: E
authors.lastname: Chi-Ahumada
authors.forename: Juan
authors.initials: J
authors.lastname: Ramiro-Diaz
authors.forename: Maureen
authors.initials: M
authors.lastname: Knabb
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001710:Biotin / Q000737:chemistry; D003331:Coronary Vessels / Q000378:metabolism; D003911:Dextrans / Q000737:chemistry; D004058:Diffusion; D004730:Endothelium, Vascular / Q000378:metabolism*; D019808:Losartan / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D019899:Paracrine Communication; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D003911:Dextrans; D011108:Polymers; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D001710:Biotin; D019808:Losartan