Intracoronary angiotensin II causes inotropic and vascular effects via different paracrine mechanisms.
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-gamma-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 heterogeneous endothelium.
Castillo-Hernandez
Jesus R
JR
Departamento de Fisiologia, Facultad de Medicina, UASLP, Av. Venustiano Carranza 2405, San Luis Potosi, SLP. 78210, Mexico.
Rubio-Gayosso
Ivan
I
Sada-Ovalle
Isabel
I
Garcia-Vazquez
Alicia
A
Ceballos
Guillermo
G
Rubio
Rafael
R
D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D019899:Paracrine Communication / Q000187:drug effects* / Q000502:physiology; D051381:Rats
D002316:Cardiotonic Agents; D000804:Angiotensin II