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(Circulation Research. 2002;90:754.)
© 2002 American Heart Association, Inc.

Editorials

Novel AT₁ Receptor–Independent Functions of Losartan

Junichi Sadoshima

From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, The University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ.

Correspondence to Junichi Sadoshima, MD, PhD, Cardiovascular Research Institute UMDNJ, New Jersey Medical School, 185 South Orange Ave, MSB G-609, Newark, NJ 07103-2714. E-mail sadoshju@umdnj.edu

Key Words: losartan • cyclooxygenase-2 • indomethacin • platelet aggregation • EXP3179

A lthough currently available angiotensin II type 1 (AT₁) receptor blockers (ARBs) share a common mechanism of action, blocking AT₁ receptors, their receptor binding kinetics and biological actions are not identical.¹ Two ARBs, namely losartan and candesartan cilexetil, are prodrugs that are converted to active drugs in vivo. After oral administration, losartan undergoes the first-pass metabolism in the liver and is converted into EXP3174, whose affinity to the AT₁ receptor is 10 times higher than that of losartan. It should be noted that losartan is not a typical prodrug because it has significant ARB activity and only 14% of the administered dose is converted to EXP3174.² This indicates that pharmacological effects of losartan are mediated not only by losartan itself but also by EXP3174 and possibly other metabolites as well.

There is growing evidence to suggest that losartan has AT₁ receptor–independent actions primarily related to antiinflammatory and antiaggregatory mechanisms (Table). These actions have been speculated to be independent of the AT₁ receptor blockade primarily because these properties are not shared by other ARBs, such as candesartan and valsartan, or by angiotensin-converting enzyme inhibitors. Furthermore, losartan blocks vasoconstriction and platelet aggregation induced by the thromboxane A2 (TXA2) analog, U46619, and displaces ligand binding to the TXA2 receptor, suggesting that losartan can act as a dual-receptor antagonist.³ Interestingly, EXP3174 and irbesartan, another ARB, both of which have the imidazole moiety of biphenyl tetrazole in their structure similar to losartan, interact with the TXA2 receptor. Thus, the chemical structure appears . . . [Full Text of this Article]

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