Angiotensin II delivery and binding at the microvascular endothelium and cardiac myocyte surfaces in perfused rat hearts.
Peptide delivery toward its targets in an intact organ is equally as important as its routing from the systemic circulation to cell surface receptor sites. A physical model pertinent to a heart perfusion technique in Sprague-Dawley rats is presented describing reversible binding of angiotensin II and/or antagonist (DUP 753, losartan) with the microvascular endothelial receptor subtypes as well as with the cardiac myocyte receptor subtypes that are exposed to the perfusate by CHAPS-treatment. Analysis of the collected effluents are curve-fitted with a conservation equation and a first-order Bessel function. The results suggest that angiotensin II delivery and binding to the pool of receptor subtypes both at the level of the microvascular endothelium and cardiac myocyte sites differ marginally in binding affinities. The findings postulate that angiotensin II can have access to the myocyte site in an intact heart by an endothelial angiotensin II-receptor-internalization process. In addition, considering that the AT1- and AT2-receptor subtypes are present in equal proportions and have equal binding affinities with angiotensin II, the results of the 3H-DUP 753 binding indicated approximately 3-3.5 times higher affinity to the AT1-receptors subtype than angiotensin II at both the endothelial and myocyte sites. In the presence of losartan, angiotensin II binding showed higher affinity with the exposed unopposed AT2-receptor subtype than with the receptor pool, which could be due to alterations in the AT2-receptor structure and configuration. This increase in the binding affinity of angiotensin II with the AT2-receptor subtype may be categorized under the direct effect of the AT1-antagonist modality in producing cardioprotective effects.
Bikhazi
A B
AB
Departments of Physiology, Surgery, and Physics, American University of Beirut, Lebanon. ab04@aub.edu.lb
Haddad
R E
RE
Nahle
Z A
ZA
Bitar
K M
KM
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D066298:In Vitro Techniques; D019808:Losartan / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000378:metabolism*
D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019808:Losartan