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Abstract: Diverse intracoronary agonists cause cardiac effects while acting on coronary endothelial luminal membrane (CELM) receptor. Our data show: a) the presence of AT1R in isolated CELM and in all cardiac cell types and b) sustained intracoronary infusions of Ang II–POL, a large sized molecule (~15,000 kDa) confined to the vessel lumen that can only act on CELM''s AT1R or Ang II (~1 kDa); both exert the same maximum positive inotropic (PIE) and coronary constriction (CPP). The effects of these two agonists are blocked by Losartan and by Sar-POL; a large size antagonist (~15,000 kDa) that acts only on CELM. Ang II effects are transient due to desensitization and cause tachyphylaxis to Ang II and toward Ang II–POL suggesting that both Ang II and Ang II–POL act on the same receptor group. In contrast, Ang II–POL effects are sustained and do not cause tachyphylaxis. The results show that intravascular Ang II and Ang II–POL act differentially by an unknown mechanism on CELM''s AT1R and suggest that intravascular Ang II and Ang II–POL cause PIE and CCP by activation limited to CELM''s AT1R through an unknown mechanism that is space-confined to the CELM''s AT1R. [Copyright &y& Elsevier]

Abstract: We hypothesized that Angiotensin II (Ang II), like other circulating hormones, acts exclusively intravascularly. To activate or block solely intravascular Ang II receptors, Ang II and its peptide receptor blocker saralasin (Sar) were covalently coupled to a inert polymer (POL, MW >4000 kD) forming Ang II-POL and Sar-POL. These two nonpermeable polymers, Ang II and Sar, were intracoronarily administered into the isolated, saline-perfused rat hearts. Ang II-POL and Ang II caused a dose-dependent ventricular positive inotropic (+I) and vasoconstrictor effects (+V) which were blocked by Sar. Sar-POL blocked their +I but not their +V. Thus, Ang II and Ang II-POL act on endothelial luminal receptors through paracrine mechanisms. +I were blocked solely by purinoceptor antagonists and paralleled by augmented venous release of ATP degradation products (adenosine, inosine and hypoxanthine). In contrast, +V were blocked solely by aspirin, indomethacin or a thromboxane A2 receptor antagonist. Intracoronary administration of ATP-γ-S and U46169, a purinergic, and TXA2 agonists, respectively, mimicked +I and +V. The results indicate that ATP is the paracrine inotropic mediator while thromboxane A2 is the vasoconstrictor mediator. Thus, the +I and +V distinct effects by intracoronary Ang II indicate that its diverse mechanism of action along the coronary vascular tree may be due to a functionally heterogenous endothelium. [Copyright &y& Elsevier]