Comparison of the antagonistic effects of different angiotensin II receptor blockers in human coronary arteries.
BACKGROUND
Angiotensin II (Ang II) is a potent vasoconstrictor and a deleterious factor in cardiovascular pathophysiology. Ang II receptor blockers (ARBs) have recently been introduced into clinical practice for treatment of hypertension and congestive heart failure.


OBJECTIVE
This study was undertaken to evaluate the inhibitory effects of ARBs on vasoconstriction in humans.


METHODS
Vasomotor tone was analyzed in endothelium denuded, human coronary artery (HCA) segments. Ang II type 1 (AT(1)) and type 2 (AT(2)) receptor mRNA expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR).


RESULTS
Ang II was a potent vasoconstrictor (pEC(50) = 7.7). At 1 nM of the AT(1) receptor antagonists, candesartan and valsartan, the maximum contraction was depressed to 57 and 50% of Ang II, respectively, indicating insurmountability. Although generally considered surmountable, the presence of 100 nM losartan elicited a depression of the Ang II response to 32%. Its active metabolite, EXP 3174 (1 nM), abolished the Ang II contraction. The AT(1) receptor antagonists had the following order of blocking effect; EXP 3174 > candesartan = valsartan > losartan. The AT(2) receptor antagonist, PD 123319 (100 nM) significantly attenuated the Ang II contraction (E(max) = 62% of Ang II). RT-PCR of HCA smooth muscle cells demonstrated expression of both AT(1) and AT(2) receptor mRNA.


CONCLUSIONS
Ang II contraction in HCA is mediated mainly by AT(1) but also involves AT(2) receptors. The active metabolite of losartan, EXP 3174, is the most efficacious AT(1) receptor antagonist in HCA.
Pantev
Emil
E
Division of Experimental Vascular Research, Department of Internal Medicine, Lund University Hospital, Lund, Sweden.
Stenman
Emelie
E
Wackenfors
Angelica
A
Edvinsson
Lars
L
Malmsjö
Malin
M
D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D003331:Coronary Vessels / Q000187:drug effects*; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D014661:Vasoconstriction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D012333:RNA, Messenger; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; C066026:losartan carboxylic acid; D014633:Valine; D019808:Losartan; C081643:candesartan