RATE OF DESENSITIZATION OF CORONARY VASOCONSTRICTION INDUCED BY POLYMERS OF ANGIOTENSIN II IS DETERMINED BY THE POLYMER MOLECULAR WEIGHT

Abstract

We have shown that Angiotensin II (AngII) does not diffuse across the vessel wall, remains intravascularily and acts solely in coronary endothelial luminal membrane AngII type 1 receptors (CELM‐AT1R) as do large size, non‐diffusible, polymer of AngII (AngII‐Pol, 15,000 kDa). A sustained intracoronary infusion (SCI) of AngII causes a transient coronary vasoconstriction (V) effect that reaches a maximum, decays gradually and by 2 min is back to control (desensitization; DES). These effects are due to CELM‐AT1R density decrease. In contrast, SCI of AngII‐Pol causes a sustained V and CELM‐AT1R density remains constant explaining why AngII‐Pol did not cause DES. These findings lead us to hypothesize: the rate of DES (RDES) is inversely proportional to molecular weight of AngII‐Pol (MWAngII‐Pol). To test this hypothesis we synthesized AngII‐Pols of various MW (kDa): 1, 9, 37, 438, 3140, 12566. AngII moieties were bound to Pol by its amino group. In Langendorff constant flow perfused isolated guinea pig hearts, AngII‐Pols were separately SCI for 16 min. We found RDES vary inversely with MWAngII‐Pol. Also a primary SCI of AngII causes that a secondary AngII administration gives a depressed response (tachyphylaxis, T). However, in the case of a primary SCI of AII‐Pols the T effect also varied inversely with MWAngII‐Pol. These results confirm our hypothesis and indicate that MWAngII‐Pol is the determining factor for RDES and T and that the chemical alteration of AngII into AngII‐Pol is not. Possibly RDES and T dependence on MWAngII‐Pol results from an inversely proportional CELM‐AT1R rate of internalization.