Key result
The active metabolite of losartan, EXP 3174 (1 nM), abolished Ang II contraction and was the most efficacious AT1 receptor antagonist in human coronary arteries compared to candesartan and valsartan.
Why the study?
Do different ARBs have varying inhibitory effects on Ang II-induced vasoconstriction in human coronary arteries?
Do different ARBs have varying inhibitory effects on Ang II-induced vasoconstriction in human coronary arteries?
In human coronary arteries, Ang II contraction is mediated mainly by AT1 receptors, and EXP 3174 (losartan's active metabolite) is the most efficacious antagonist among those tested.
ARBs may differ in coronary AT1 blockade potency; hypothesis-generating for differential effects on ischemic outcomes.
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. AIMS: 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.
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Pantev et al. (2002) studied this question. Angiotensin II Receptor Blockers (candesartan, valsartan, losartan, EXP 3174, PD 123319) vs. Angiotensin II alone was evaluated on Vasoconstriction / maximum contraction. The active metabolite of losartan, EXP 3174 (1 nM), abolished Ang II contraction and was the most efficacious AT1 receptor antagonist in human coronary arteries compared to candesartan and valsartan.
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