CORONARY VASOCONSTRICTION INDUCED BY POLYMERS OF ANG II IS PROPORTIONAL TO LUMINAL ENDOTHELIAL AT1 RECEPTORS DENSITY

Abstract

We have shown that intravascular AngII does not diffuse across the coronary vessel wall and acts solely in coronary endothelial luminal membrane AngII receptors (CELM‐AT1R) and its sustained intracoronary infusion causes transient vasoconstriction effects (+V). This contrasted with the sustained +V by a large size, non‐diffusible polymer of AngII (15,000 kDa, AngIIPol) that unquestionably activate solely CELM‐AT1R. We also show that AngII transient +V paralleled a decrease of CELM‐AT1R density (AT1RD), but, for AngIIPol the AT1RD remained constant. HYPOTHESIS; transiently of +V effects depends directly on AT1RD both are inversely determined by the molecular weight (MW) of AT1R agonist. To test this hypothesis we synthesized AngIIPol's (included AngII) of various MW (kDa): 1.3, 2.7, 11, 47, 527, 3270 and 15000. In isolated constant flow (8ml/min) perfused Langendorff guinea pig hearts AII‐Pol's were separately intracoronary given for 16 min and coronary perfusion pressure measure as an index V. All AngIIPol's caused the same maximal +V (+Vmax) that decayed with time at a rate and to a stable level of +V, both inversely proportional to MW. During AngIIpol's infusion AT1RD decayed parallel to +V; the relationship +V‐‐AT1RD was linear. Further dependence of +V on AT1RD was demonstrated by two successive administrations of AngIIPol's, the primary dose caused a +Vmax but the +Vmax to the secondary dose was depressed; a tachyphylaxis which was inversely proportional to the logarithm of MW. These results support our hypothesis and indicate that AT1R internalization is dependent on MW.