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CAS 114798-26-4
PharmaCompass
CAS 114798-26-4
Also known as: 114798-26-4, Lortaan, Dup 89, Cozaar, Losartan potassium, Hyzaar
Molecular Formula
C22H23ClN6O
Molecular Weight
422.917  g/mol
InChI Key
PSIFNNKUMBGKDQ-UHFFFAOYSA-N
FDA UNII
JMS50MPO89

An antagonist of ANGIOTENSIN TYPE 1 RECEPTOR with antihypertensive activity due to the reduced pressor effect of ANGIOTENSIN II.
Losartan is an Angiotensin 2 Receptor Blocker. The mechanism of action of losartan is as an Angiotensin 2 Receptor Antagonist.
1 2D Structure

CAS 114798-26-4

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
[2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol
2.1.2 InChI
InChI=1S/C22H23ClN6O/c1-2-3-8-20-24-21(23)19(14-30)29(20)13-15-9-11-16(12-10-15)17-6-4-5-7-18(17)22-25-27-28-26-22/h4-7,9-12,30H,2-3,8,13-14H2,1H3,(H,25,26,27,28)
2.1.3 InChI Key
PSIFNNKUMBGKDQ-UHFFFAOYSA-N
2.1.4 Canonical SMILES
CCCCC1=NC(=C(N1CC2=CC=C(C=C2)C3=CC=CC=C3C4=NNN=N4)CO)Cl
2.2 Other Identifiers
2.2.1 UNII
JMS50MPO89
2.3 Synonyms
2.3.1 Depositor-Supplied Synonyms

1. 114798-26-4

2. Lortaan

3. Dup 89

4. Cozaar

5. Losartan Potassium

6. Hyzaar

7. Losartan [inn:ban]

8. Losartan Monopotassium Salt

9. Unii-jms50mpo89

10. [3h]losartan

11. C22h23cln6o

12. Mk-954

13. Losartan (inn)

14. Losartic (tn)

15. [3h]-losartan

16. Chebi:6541

17. Mk954

18. Dup-753

19. Jms50mpo89

20. [2-butyl-5-chloro-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol

21. 2-butyl-4-chloro-1-((2'-(1h-etrazol-5-yl) (1,1'-biphenyl)-4-yl)methyl)-1h-imidazole-5-methanol

22. Dup 753

23. Mfcd00865831

24. (2-butyl-4-chloro-1-{[2'-(1h-tetrazol-5-yl)biphenyl-4-yl]methyl}-1h-imidazol-5-yl)methanol

25. 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1h-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole

26. (1-((2'-(1h-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1h-imidazol-5-yl)methanol

27. Cl23623

28. Ncgc00095125-01

29. Dsstox_cid_3227

30. Cozaar (tn)

31. Dsstox_rid_76933

32. Dsstox_gsid_23227

33. 1h-imidazole-5-methanol, 2-butyl-4-chloro-1-((2'-(1h-tetrazol-5-yl)(1,1'- Biphenyl)-4-yl)methyl)-

34. 2-butyl-4-chloro-1-[[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1h-imidazole-5-methanol

35. Q-201321

36. Allisartan

37. 2-butyl-4-chloro-1-[p-(o-1h-tetrazol-5ylphenyl)benzyl]imidazole-5-methanol

38. 2-n-butyl-4-chloro-5-hydroxymethyl-1-[[2'-(1h-tetrazol-5-yl)-biphenyl-4-yl]methyl]imidazole

39. Hsdb 7043

40. (2-butyl-4-chloro-1-{[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl}-1h-imidazol-5-yl)methanol

41. [2-butyl-5-chloranyl-3-[[4-[2-(2h-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol

42. 2-butyl-4-chloro-1-[[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl-1h-imidazole-5-methanol

43. Cas-114798-26-4

44. Sr-01000763170

45. Losartic

46. [2-butyl-5-chloro-3-[[4-[2-(1h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol

47. Losartan Monopotassium

48. Oscaar

49. Pubchem9176

50. Spectrum_001713

51. Schembl60

52. Spectrum2_001677

53. Spectrum3_000998

54. Spectrum4_001126

55. Spectrum5_001466

56. D03aqg

57. D0dd0k

58. Epitope Id:140137

59. Ec 601-329-8

60. Ac1l1h3q

61. Oprea1_644635

62. Bspbio_002695

63. Gtpl590

64. Kbiogr_001611

65. Kbioss_002193

66. Bidd:gt0286

67. Spectrum1504268

68. Spbio_001893

69. Gtpl3941

70. Jsp001094

71. Dtxsid7023227

72. Bdbm82258

73. Ctk8e7663

74. Kbio2_002193

75. Kbio2_004761

76. Kbio2_007329

77. Kbio3_001915

78. Molport-003-666-553

79. Molport-006-167-607

80. Psifnnkumbgkdq-uhfffaoysa-n

81. Bcpp000183

82. Hms1922j13

83. Hms2093e22

84. Pharmakon1600-01504268

85. Ks-00000gi2

86. Nsc_3961

87. Zinc3873160

88. Tox21_111435

89. Bg0556

90. Ccg-39095

91. Gp6564

92. Nsc758699

93. Stl419984

94. Akos015917390

95. Akos015994740

96. Tox21_111435_1

97. Ab07507

98. Api0007066

99. Bcp9000861

100. Cs-2116

101. Db00678

102. Ks-5004

103. Mcule-5204931675

104. Nsc-758699

105. 124750-99-8 (mono-potassium Salt)

106. Ncgc00095125-02

107. Ncgc00095125-03

108. Ncgc00095125-05

109. Ak326126

110. An-15301

111. Hy-17512

112. I497

113. Ls-78746

114. Sc-47229

115. Sbi-0206766.p001

116. Ab0013723

117. Rt-013597

118. Bg01711748

119. Bg01711749

120. Cas_114798-26-4

121. Ft-0631074

122. C07072

123. D08146

124. 54244-ep2269989a1

125. 54244-ep2270011a1

126. 54244-ep2272841a1

127. 54244-ep2277879a1

128. 54244-ep2287165a2

129. 54244-ep2287166a2

130. 54244-ep2292620a2

131. 54244-ep2295053a1

132. 54244-ep2295406a1

133. 54244-ep2298772a1

134. 54244-ep2298776a1

135. 54244-ep2298779a1

136. 54244-ep2301923a1

137. 54244-ep2301931a1

138. 54244-ep2301936a1

139. 54244-ep2305219a1

140. 54244-ep2308562a2

141. 54244-ep2308839a1

142. Ab01563296_01

143. 798l264

144. A803239

145. L000351

146. I14-9710

147. Sr-01000763170-3

148. Sr-01000763170-4

149. Brd-k76205745-001-02-5

150. F2173-0506

151. [2-butyl-5-chloro-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]-4-imidazolyl]methanol

152. 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1h-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole

153. 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1h-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole

154. (1-((2'-(2h-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1h-imidazol-5-yl)methanol

155. (1-((2'-(2h-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1h-imidazol-5-yl)methanol

156. (1-((2-(1h-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1h-imidazol-5-yl)methanol

157. (2-butyl-4-chloro-1-[[2'-(2h-tetrazol-5-yl)-4-biphenylyl]methyl]-1h-imidazol-5-yl)methanol

158. (2-butyl-4-chloro-1-{[2'-(2h-tetrazol-5-yl)biphenyl-4-yl]methyl}-1h-imidazol-5-yl)methanol

159. [2-butyl-4-chloro-1-({4-[2-(2h-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1h-imidazol-5-yl]methanol

160. {2-butyl-5-chloro-3-[2'-(2h-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3h-imidazol-4-yl}-methanol

161. 1h-imidazole-5-methanol, 2-butyl-4-chloro-1-[[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- (9ci)

162. 1h-imidazole-5-methanol, 2-butyl-4-chloro-1-[[2'-(1h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-(9ci)

163. 1h-imidazole-5-methanol, 2-butyl-4-chloro-1-[[2'-(2h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-

164. 2-butyl-4-chloro-1-[[2'-(2h-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1h-imidazole-5-methanol

165. 2-butyl-4-chloro-5-(hydroxymethyl)-1-[[2'-(1h-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole

2.4 Create Date
2005-03-25
3 Chemical and Physical Properties
Molecular Weight 422.917 g/mol
Molecular Formula C22H23ClN6O
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count5
Rotatable Bond Count8
Exact Mass422.162 g/mol
Monoisotopic Mass422.162 g/mol
Topological Polar Surface Area92.5 A^2
Heavy Atom Count30
Formal Charge0
Complexity520
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 4  
Drug NameCOZAAR
Active IngredientLOSARTAN POTASSIUM
CompanyMERCK SHARP DOHME (Application Number: N020386)

2 of 4  
Drug NameLOSARTAN POTASSIUM
Active IngredientLOSARTAN POTASSIUM
CompanyALEMBIC PHARMS LTD (Application Number: A090428); AUROBINDO PHARMA (Application Number: A090083); CADISTA PHARMS (Application Number: A201170); HETERO LABS LTD V (Application Number: A203835); IPCA LABS LTD (Application Number: A200290); LUPIN LTD (Application Number: A078232); MACLEODS PHARMS LTD (Application Number: A202230); MYLAN (Application Number: A091590); PRINSTON INC (Application Number: A091497); SANDOZ (Application Number: A077424); TEVA (Application Number: A076958); TORRENT PHARMS (Application Number: A090467); UNICHEM LABS LTD (Application Number: A203030); UPSHER-SMITH LABS (Application Number: A090544); VIVA HLTHCARE (Application Number: A091541); VIVIMED GLOBAL (Application Number: A090382); WATSON LABS (Application Number: A091129); WEST-WARD PHARMS INT (Application Number: A077459); ZYDUS PHARMS USA INC (Application Number: A078243)

3 of 4  
Drug NameHYZAAR
Active IngredientHYDROCHLOROTHIAZIDE; LOSARTAN POTASSIUM
CompanyMERCK SHARP DOHME (Application Number: N020387)

4 of 4  
Drug NameLOSARTAN POTASSIUM AND HYDROCHLOROTHIAZIDE
Active IngredientHYDROCHLOROTHIAZIDE; LOSARTAN POTASSIUM
CompanyALEMBIC PHARMS LTD (Application Number: A091617); AUROBINDO PHARMA (Application Number: A091629); CADISTA PHARMS (Application Number: A201845); IPCA LABS LTD (Application Number: A201682); LUPIN LTD (Application Number: A078245); MACLEODS PHARMS LTD (Application Number: A202289); MYLAN (Application Number: A091652); PRINSTON INC (Application Number: A204901); SANDOZ (Application Number: A077948); TEVA PHARMS (Application Number: A077157); TORRENT PHARMS (Application Number: A090528); UNICHEM LABS LTD (Application Number: A204832); WEST-WARD PHARMS INT (Application Number: A077732); ZYDUS PHARMS USA INC (Application Number: A078385)

4.2 Therapeutic Uses

Angiotensin II Type 1 Receptor Blockers; Anti-Arrhythmia Agents; Antihypertensive Agents

National Library of Medicine's Medical Subject Headings. Losartan. Online file (MeSH, 2014). Available from, as of September 2, 2014: http://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html


Cozarr is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents, including diuretics. /Included in US product label/

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


Cozarr is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients. /Included in US product label/

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


Cozaar is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio =300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, Cozaar reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation). /Included in US product label/

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


Angiotensin II receptor antagonists /including losartan/ have been used in the management of congestive heart failure. /NOT included in US product label/

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2066


EXPL THER Camurati-Engelmann disease (CED) is a rare disorder, with approximately 250 described cases in the literature. Treatment options are limited, and have been sub-optimal so far. Patient & methods: A prepubertal girl aged 9 years was diagnosed with CED. Treatment with losartan was initiated at a daily dose of 0.75 mg/kg. Over a period of 12 weeks, the dose was gradually increased to 1.0 mg/kg per day. The patient was reviewed in clinic regularly, and underwent thorough clinical assessments 9, 17, and 38 months after treatment initiation. The patient experienced marked clinical improvements with losartan. In particular, losartan treatment led to the almost complete elimination of the previously severe and incapacitating pain, with an increased ability to walk and perform physical activities. There was also a considerable improvement in body composition with increased lean and adipose tissue. Notably, the improvement in fat deposition had not been previously observed with other treatments in CED. Hematology, liver and renal function tests were within normal ranges at presentation, and remained so over the course of treatment.[Ayyavoo A et al; J Clin Endocrinol Metab. 2014 Aug 20:jc20142025.

Epub ahead of print]


4.3 Drug Warning

/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Cozaar as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Cozaar as soon as possible. These adverse outcomes are usually associated with the use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Cozaar, unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


Neonates with a history of in utero exposure to Cozaar If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


Symptomatic hypotension has been reported in patients receiving losartan, especially in volume- and/or salt-depleted patients (e.g., those receiving diuretics).

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2067


Adverse effects occurring in at least 1% of patients with hypertension receiving losartan potassium and at a higher incidence than with placebo include upper respiratory infection, dizziness, nasal congestion, back pain, leg pain, muscle cramp, and sinusitis. The incidence of adverse effects was not affected by age, gender, or race. In patients receiving losartan potassium for the treatment of diabetic nephropathy, urinary tract infection, diarrhea, anemia, asthenia/fatigue, hypoglycemia, back pain, chest pain, cough, bronchitis, diabetic vascular disease, influenza-like disease, cataracts, cellulitis, hyperkalemia, hypotension, muscular weakness, sinusitis, gastritis, hypoesthesia, infection, knee pain, and leg pain occurred with an incidence of at least 5% and were reported more frequently than in those receiving placebo.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2068


Sensitivity reactions, including anaphylactoid reactions and/or angioedema, have been reported with use of angiotensin II receptor antagonists, including losartan. Losartan is not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2067


Because the renin-angiotensin-aldosterone (RAA) system appears to contribute substantially to maintenance of glomerular filtration in patients with congestive heart failure in whom renal perfusion is severely compromised, renal function may deteriorate markedly (e.g., oliguria, progressive azotemia, renal failure, death) in these patients during therapy with an ACE inhibitor or an angiotensin II receptor antagonist (e.g., losartan potassium). Increases in BUN and serum creatinine may occur in patients with unilateral or bilateral renal artery stenosis.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2067


Antihypertensive effects of Cozaar have been established in hypertensive pediatric patients aged 6 to 16 years. There are no data on the effect of Cozaar on blood pressure in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 sq m.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


Geriatric use: No overall differences in safety and efficacy for the treatment of hypertension relative to younger adults, but increased sensitivity cannot be ruled out.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2068


Blood pressure reduction may be smaller in black patients compared with nonblack patients; losartan should be used in combination with a diuretic. There is no evidence that the benefits of therapy in reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to black patients.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2068


Drugs that act directly on the renin-angiotensin system (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) cause fetal and neonatal morbidity and mortality when administered during pregnancy during the second and third trimesters. ACE inhibitors also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy. Losartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving.Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.All women of childbearing potential should be advised to report pregnancy to their clinician as soon as possible.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2067


When losartan is used in fixed combination with hydrochlorothiazide, the usual cautions, precautions, and contraindications associated with hydrochlorothiazide must be considered in addition to those associated with losartan.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2067


Deterioration of renal function may occur. Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with creatinine clearances of 30 mL/minute or less.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2068


Systemic exposure to losartan and its active metabolite may be increased. Initial dosage adjustment recommended. Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with hepatic impairment because the dosage of losartan potassium in the fixed-combination tablets exceeds the recommended initial dosage.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2068


Hyperkalemia may occur, especially in patients with renal impairment with or without diabetes mellitus or in those receiving concomitant therapy with a potassium-sparing diuretic (e.g., amiloride, spironolactone, triamterene) and/or potassium supplements or salt substitutes containing potassium.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2067


... Long-term losartan administration does not significantly reduce hepatic venous pressure gradient in patients with cirrhosis treated after a variceal bleeding episode, and it caused hypotension & reduced glomerular filtration rate in patients with moderate liver failure. Therefore, losartan is not an alternative to propranolol in preventing variceal rebleeding. /Salt not specified/

Gonzalez-Abraldes J, et al; Gastroenterology 121 (2): 382-8 (2001)


We describe a 62-year-old man who developed Henoch-schonlein purpura while taking losartan. In October 1996, he was admitted with a one week history of palpable purpura of the lower limb, polyarthralgias, and pedal edema. He had been healthy until 3 months before admission when enalapril maleate, 10 mg/d, was prescribed for moderate hypertension. Two weeks before admission enalapril therapy was stopped becaused of a persistent cough attributed to the use of this drug, and losartan potassium , 50 mg/d was given instead. Other medications were not administered. A skin biopsy specimen reveled leukocytoclastic vasculitis with IgA deposition along dermal vessel walls. He had mild leukocytosis (white blood cell, 12x 10^9/L) with anormal differential cell count, an increased erythrocyte sedimentation rate (60mm/hr), microscopic hematuria, red blood casts, and proteinuria (protein level, 1 g/d), with normal renal function. Results of tests for antinuclear and antineutrophil cytoplasmic antibodies, rheumatoid factor, cryoglobulins, circulating immune complexes, and serum complement were all negative or within normal limits. The serum level of IgA was 5.4 g/L (normal range, 0.9-4.1g/L). Results of serological tests for viruses, mycoplasma, Treponema pallidum, and rickettsia were negative. Treatment with losartan was discontinued and atenolol, 50 mg/d, was given instead. The skin lesions faded quickly. Eight days after admission, the patient no longer had symptoms of Henoch-Schonlein purpura. At that time treatment with atenolol was stopped and use of losartan potassium 25 mg/d, was reinstated with the patients informed consent and under intensive clinical surveillance. Two days later, use of losartan had to be definitively discontinued because new skin lesions appeared and urinary finding suggestive of glomerulonephritis increased. Cessation of losartan therapy resulted in rapid fading of the purpura. Use of atenolol was restarted, and the adverse affect have not recurred.The temporal relationship and recurrence on reexposure strongly suggests that the use of losartan induced Henoch-Schonlein purpura in this patient.

Bosch X; Arch Intern Med 158(2): 191-192 (1998)


Two cases in which 49- and 69-yr-old women presented with persistent metallic taste, and tickling cough or burning feeling on the tongue and complete loss of taste after receiving 50 mg of oral losartan daily for 1 wk or 10 mg of oral losartan daily for 3 months as therapy for hypertension, are reported. After discontinuation of losartan therapy, symptoms disappeared in both cases. /Salt not specified/

Herringa M; Ann. Intern. Med. 129: 72 (1998)


Do not co-administer aliskiren with Cozaar in patients with diabetes. Avoid use of aliskiren with Cozaar in patients with renal impairment (GFR <60 mL/min).

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


4.4 Drug Indication

May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Losartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors.


FDA Label


5 Pharmacology and Biochemistry
5.1 Pharmacology

Losartan is the first of a class of antihypertensive agents called angiotensin II receptor blockers (ARBs). Losartan and its longer acting active metabolite, E-3174, are specific and selective type-1 angiotensin II receptor (AT1) antagonists which block the blood pressure increasing effects angiotensin II via the renin-angiotensin-aldosterone system (RAAS). RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: AT1 and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure.


Losartan is the potassium salt form of losartan, a non-peptide angiotensin II antagonist with antihypertensive activity. Losartan potassium selectively and competitively blocks the binding of angiotensin II to the angiotensin I (AT1) receptor. Angiotensin II, formed from angiotensin I by angiotensin-converting enzyme (ACE), stimulates the adrenal cortex to synthesize and secrete aldosterone, which decreases the excretion of sodium and increases the excretion of potassium. Angiotensin II also acts as a vasoconstrictor in vascular smooth muscle. Losartan potassium, by blocking the binding of angiotensin II to the AT 1 receptor, promotes vasodilatation and decreases the effects of aldosterone.


5.2 MeSH Pharmacological Classification

Angiotensin II Type 1 Receptor Blockers

Agents that antagonize ANGIOTENSIN II TYPE 1 RECEPTOR. Included are ANGIOTENSIN II analogs such as SARALASIN and biphenylimidazoles such as LOSARTAN. Some are used as ANTIHYPERTENSIVE AGENTS.


Anti-Arrhythmia Agents

Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade.


Antihypertensive Agents

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety

LOSARTAN


5.3.2 FDA UNII

JMS50MPO89


5.3.3 Pharmacological Classes

Mechanisms of Action [MoA]

Angiotensin 2 Receptor Antagonists


Established Pharmacologic Class [EPC]

Angiotensin 2 Receptor Blocker


5.4 ATC Code

C - Cardiovascular system
C09 - Agents acting on the renin-angiotensin system
C09C - Angiotensin ii antagonists, plain
C09CA - Angiotensin ii antagonists, plain
C09CA01 - Losartan


5.5 Absorption, Distribution and Excretion

Absorption

Losartan is well absorbed and undergoes substantial first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. When given with a meal, absorption is slows down and Cmax decreases.


Route of Elimination

Following oral administration of losartan, 35% of the dose is recovered in the urine and about 60% in the feces. Following an intravenous dose, 45% is recovered in the urine and 50% in the feces.


Volume of Distribution


Clearance


It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


Following oral administration, losartan is well absorbed (based on absorption of radiolabeled losartan) and undergoes substantial first-pass metabolism; the systemic bioavailability of losartan is approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decreased).

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


The pharmacokinetics of losartan and its active metabolite were also determined after IV doses of each component separately in healthy volunteers. The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral (14)C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of (14)C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Neither losartan nor its metabolite accumulate in plasma upon repeated once-daily dosing.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


We studied the functional interaction between transport and metabolism by comparing the transport of losartan and its active metabolite EXP 3174 (EXP) across cell monolayers. Epithelial layers of Caco-2 cells as well as MDR1, MRP-1 and MRP-2 overexpressing cells, in comparison to the respective wildtypes, were used to characterize the transcellular transport of losartan and EXP. Losartan transport in MDCK-MDR1 and Caco-2 cells was saturable and energy-dependent with a significantly greater basolateral-to-apical (B/A) than apical-to-basolateral (A/B) flux (ratio=31+/-1 in MDCK-MDR1 and ratio 4+/-1 in Caco-2 cells). The B/A flux of losartan was inhibited by cyclosporine and vinblastine, inhibitors of P-glycoprotein and MRP. In contrast, no active losartan transport was observed in MRP-1 or MRP-2 overexpressing cells. The metabolite was only transported in Caco-2 cells with a B/A-to-A/B ratio of 5+/-1, while lacking active transport in the MDR1, MRP-1 or MRP-2 overexpressing cells. The B/A flux of EXP was significantly inhibited by cyclosporine and vinblastine. In conclusion, losartan is transported by P-glycoprotein and other intestinal transporters, that do not include MRP-1 and MRP-2. In contrast, the carboxylic acid metabolite is not a P-glycoprotein substrate, but displays considerably higher affinity for other transporters than losartan, that again most probably do not include MRP-1 and MRP-2. /Salt not specified/[Soldner A et al; Br J Pharmacol 129 (6): 1235-43 (2000)] Full text: PMC1571937


... The studies presented here were undertaken to quantify fetal and neonatal exposure to losartan when administered to the dam by oral gavage during early gestation, late gestation, and lactation. Following daily oral dosing of 135 mg/kg/day on GD6-15, fetal drug levels were negligible. However, losartan and its active metabolite, EXP3174 (L-158,641) were readily detectable in fetal plasma on GD 20 (estimated AUC values, 50.70 and 167.70 ug/hr/mL, respectively) and maternal milk during lactation (1.61 and 1.67 ug/mL, respectively). These studies suggest that the relative increased sensitivity of the fetus as compared to the neonate for losartan-induced renal lesions is related to the degree of exposure which is dependent on the time of administration (early gestation vs. late gestation/lactation) and the route of exposure (transplacental or through the milk). Furthermore, the maximum exposure to losartan and EXP3174 correlates with the ontogeny of the renin angiotensin system on approximately GD 17 and the critical period for losartan-induced renal lesions (GD15-20). ...

Spence SG et al; Teratology 53 (4): 245-52 (1996)


5.6 Metabolism/Metabolites

Metabolism

Hepatic. Losartan is metabolized to a 5-carboxylic acid derivative (E-3174) via an aldehyde intermediate (E-3179) primarily by cytochrome P450 (CYP) 2C9 and CYP3A4. E-3174 is an active metabolite with 10- to 40-fold higher potency than its parent compound, losartan. Approxiamtely 14% of losartan is converted to E-3174; however, the AUC of E-3174 was found to be 4- to 8-fold higher than losartan and E-3174 is considered the main contributor to the pharmacologic effects of this medication.


Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. Losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. Following oral and intravenous administration of (14)C-labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to the active metabolite (less than 1% of the dose compared to 14% of the dose in normal subjects) was seen in about one percent of individuals studied.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


5.7 Biological Half-Life

The terminal t1/2 of losartan is 2 hours. The active metabolite has a half-life of 6-9 hours.


The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


5.8 Mechanism of Action

Losartan competitively inhibits the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. Losartan is metabolized to its active metabolite, E-3174, which is 10 to 40 times more potent than losartan and acts as a non-competitive AT1 antagonist. Inhibition of angiotensin II binding to AT1 inhibits its AT1-mediated vasoconstrictive and aldosterone-secreting effects and results in decreased vascular resistance and blood pressure. Losartan is 1,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion. Losartan is effective for reducing blood pressure and may be used to treat essential hypertension, left ventricular hypertrophy and diabetic nephropathy.


Angiotensin II (formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)), is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor. Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

NIH; DailyMed. Current Medication Information for Cozaar (Losartan Potassium) Tablet, Film-coated (Revised: September 2014). Available from, as of October 13, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5ac32c20-169d-475a-fc8a-934f758d6ab0


We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist. /Salt not specified/

Goldberg MR et al; hepertension 25(1): 37-46 (1995)


IL-1beta is a potent proinflammatory, pro-fibrogenetic and pro-athrosclerosis cytokine which has been shown to play an important role in an expanding number of noninfectious, chronic inflammatory conditions including cardiovascular disease, renal fibrosis, rheumatoid arthritis and even type 2 diabetes. Losartan is an angiotensin II receptor antagonist widely used for the treatment of hypertension, diabetic nephropathy and congestive heart failure. In this study, we attempted to clarify whether losartan has an inhibitory effect on IL-1beta. To further elucidate the molecular mechanism underlying the anti-IL-1beta property of losartan, we studied the LPS+ATP-induced activation of NALP3 inflammasome which controls the muturation and secretion of IL-1beta. LPS and ATP were used to stimulate the release of IL-1beta from thioglycollate-elicited macrophages from BALB/c mice. The production of IL-1beta was evaluated by ELISA assay and NALP3, caspase-1, IL-beta mRNA levels were determined by reverse transcription-polymerase chain reaction. In cultured thioglycollate-elicited macrophages, we observed that LPS + ATP greatly enhanced IL-1 beta secretion (6938.00 +/- 83.45; P < 0.05) and the mRNA levels of NALP3, caspase-1 which are two main components of NALP3 inflammasome (60.88 +/- 8.28; 1.31 +/- 0.04, P < 0.05 for both). The macrophages co-cultured with losartan showed low production of IL-1beta (3907.50 +/- 143.61; P < 0.05) and low production of NALP3, caspase-1mRNA (29.82 +/- 6.92; 1.12 +/- 0.05, P < 0.05 for both). Losartan did not reduce IL-1beta mRNA(P > 0.05). Our results show that the NALP3 inflammasome is up-regulated and activated in the mouse macrophage in response to LPS + ATP stimulation. Losartan is able to suppress the LPS + ATP-induced production of IL-1beta protein. In addition, this effectmay be partially mediated by suppressing NALP3 inflammasome activation.

Wang F et al; Pharmazie 69 (9): 680-4 (2014)


The present study aimed to investigate the molecular pharmacodynamic mechanisms of losartan used in the treatment of hypertension. A total of 12 spontaneously hypertensive rats (SHR) were divided randomly into an SHR group treated with saline and LOS group treated with losartan. Six Wistar-kyoto rats (WKY) were enrolled as the WKY group with saline in the study. The LOS group received 30 mg/kg/day losartan by intragastric injection, while the SHR and WKY were fed the same volume of saline. The dosage was modulated according to the weekly weight. Changes in blood pressure were measured by the indirect tail cuff method. Angiotensin (Ang) II production in the plasma and renal tissue was measured by an immunoradiometric method. Na+/H+ exchanger (NHE)3 and serum and glucocorticoid-inducible kinase (SGK)1 were assessed by quantitative polymerase chain reaction (qPCR) and western blot analysis. When compared with the WKY group, the blood pressure of the SHR and LOS groups were higher prior to treatment with losartan. Following two weeks, blood pressure was reduced and the trend continued to decrease over the following six weeks. The plasma and renal tissue levels of Ang II in the SHR and LOS groups were significantly higher than those in the WKY group. NHE3 and SGK1 were increased at the mRNA and protein level in the SHR group, and losartan reduced the expression of both of them. The results suggested that in hypertensive rats, the circular and tissue renin angiotensin systems were activated, and the increased Ang II stimulated the expression of NHE3 and SGK1, which was reduced by losartan. Therefore, the effects of losartan in hypertension may be associated with the Ang II-SGK1-NHE3 of intra-renal tissue.

Fan X et al; Mol Med Rep 10 (5): 2483-8 (2014)


Tamoxifen (TAM) is a standard adjuvant endocrine therapy in postmenopausal breast cancer patients, but innate or acquired TAM resistance has remained to be a therapeutic challenge for clinicians. The aim of this study was to explore the possible participation of renin-angiotensin system (RAS) in the acquisition of TAM resistance and try to prevent and regress the resistance using an angiotensin II receptor type-1 (AGTR1) blocker, losartan. Establishment of TAM-resistant (TAM-R) cells was accomplished by continuous exposure of MCF-7 cells to 1 umol/L TAM. MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to determine cell growth. Moreover, messenger RNA (mRNA) expression levels of AGTR1 and angiotensin II receptor type-2 (AGTR2) were measured by quantitative real-time polymerase chain reaction. A significant increase of AGTR1 and AGTR2 transcripts was observed in TAM-R cells compared to MCF-7 cells. Interestingly, losartan-TAM combination effectively resensitized TAM-R cells to tamoxifen treatment by inducing cell death. Therefore, our findings suggest an important role of RAS in acquired TAM resistance and targeting of RAS by losartan may overcome TAM resistance phenomenon and provide a novel avenue for treatment of resistant breast cancers.[Namazi S et al; Tumour Biol. 2014 Oct 11.

Epub ahead of print]


Angiotensin-converting enzyme 2 (ACE2) is a new member of the renin-angiotensin system (RAS) and it has been proposed that ACE2 is a potential therapeutic target for the control of cardiovascular disease. The effect of losartan on the ACE2 activity in atherosclerosis was studied. METHODS: Atherosclerosis was induced in New Zealand white rabbits by high-cholesterol diet for 3 months. An Angiotensin II (Ang II) receptor blocker (losartan, 25 mg/kg/d) was given for 3 months. ACE2 activity was measured by fluorescence assay and the extent of atherosclerosis was evaluated by H&E and Oil Red O staining. In addition, the effect of losartan on ACE2 activity in smooth muscle cells (SMCs) in vitro was also evaluated. Losartan increased ACE2 activity in atherosclerosis in vivo and SMCs in vitro. Losartan inhibited atherosclerotic evolution. Addition of losartan blocked Ang II-induced down-regulation of ACE2 activity, and blockade of extracellular signal-regulated kinase (ERK1/2) with PD98059 prevented Ang II-induced down-regulation of ACE2 activity. The results showed that ACE2 activity was regulated in atherosclerotic plaque by losartan, which may play an important role in treatment of atherosclerosis. The mechanism involves Ang II-AT1R-mediated mitogen-activated protein kinases, MAPKs (MAPKs) signaling pathway.[Zhang YH et al; J Renin Angiotensin Aldosterone Syst. 2014 Jul 27. pii: 1470320314542829.

Epub ahead of print]


The present study aimed to investigate the molecular pharmacodynamic mechanisms of losartan used in the treatment of hypertension. A total of 12 spontaneously hypertensive rats (SHR) were divided randomly into an SHR group treated with saline and LOS group treated with losartan. Six Wistar-kyoto rats (WKY) were enrolled as the WKY group with saline in the study. The LOS group received 30 mg/kg/day losartan by intragastric injection, while the SHR and WKY were fed the same volume of saline. The dosage was modulated according to the weekly weight. Changes in blood pressure were measured by the indirect tail cuff method. Angiotensin (Ang) II production in the plasma and renal tissue was measured by an immunoradiometric method. Na+/H+ exchanger (NHE)3 and serum and glucocorticoid-inducible kinase (SGK)1 were assessed by quantitative polymerase chain reaction (qPCR) and western blot analysis. When compared with the WKY group, the blood pressure of the SHR and LOS groups were higher prior to treatment with losartan. Following two weeks, blood pressure was reduced and the trend continued to decrease over the following six weeks. The plasma and renal tissue levels of Ang II in the SHR and LOS groups were significantly higher than those in the WKY group. NHE3 and SGK1 were increased at the mRNA and protein level in the SHR group, and losartan reduced the expression of both of them. The results suggested that in hypertensive rats, the circular and tissue renin angiotensin systems were activated, and the increased Ang II stimulated the expression of NHE3 and SGK1, which was reduced by losartan. Therefore, the effects of losartan in hypertension may be associated with the Ang II-SGK1-NHE3 of intra-renal tissue.

Fan X et al; Mol Med Rep 10 (5): 2483-8 (2014)


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