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RATE OF DESENSITIZATION OF CORONARY VASOCONSTRICTION INDUCED BY POLYMERS OF ANG II IS DETERMINED BY THE POLYMER MOLECULAR WEIGHT
Author(s) -
TORRESTIRADO DAVID,
RUBIO RAFAEL
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.848.11
We found a sustained intracoronary infusion (ICI) of Angiotensin II (AII) causes a coronary constriction (V) effect, that in about 2 min decay back to control (desensitization; DES). In addition AII does not diffuse across the vessel wall remaining intravascularily and acts solely in luminal endothelial membrane (LEM) AII receptors (L‐AT 1 R). To unquestionably activate L‐AT 1 R, a large size, non‐diffusible molecule, 15,000 kDa polymer of AII (AII‐Pol) was synthesized. Sustained ICI of AII‐Pol caused sustained V without DES. Furthermore, LEM sampled during infusion either of AII or AII‐Pol show L‐AT 1 R expression gradually decreased by AII but no so AII‐Pol, explaining why AII‐Pol did not cause DES. These findings lead us to hypothesize that the rate of DES is inversely proportional to molecular weight (MW) of AII‐Pol. To test this hypothesis we synthesized AII‐Pol's of various MW (kDa): 1, 9, 37, 438, 3140, 12566. AII moieties were bound to Pol by the AII amino group. AII‐Pol's were separately intracoronarily given for 16 min to isolated Langendorff perfused guinea pig hearts. We found that the rate of decay of DES was slower as AII‐Pol's MW increase. These results confirm our hypothesis and indicate that the chemical alteration of AII is not the determining factor of DES but the MW of AII‐Pol. It is possible that DES results from L‐AT 1 R gradual internalizacion which is slower as AII‐Pol size increases.