Losartan attenuates the antimigratory effect of diclofenac in spontaneously hypertensive rats.
Many patients with hypertension, particularly elderly patients, take nonsteroidal antiinflammatory drugs (NSAIDs) and antihypertensive agents. However, few studies describe the effect of the association of antihypertensive agents with NSAIDs on inflammatory response in hypertension. To investigate this, spontaneously hypertensive rats (SHRs) were treated with either diclofenac alone or diclofenac combined with losartan (an AT1 angiotensin II antagonist). The leukocyte-endothelial interaction was then observed using intravital microscopy. Blood pressure of SHR (169.6+/-3.6) was increased by diclofenac (186.4+/-2.9), reduced by losartan (152.6+/-3.5), and reduced by the combination of the 2 (158.9+/-3.7). All the treatments tested reduced the number of rollers, adherent and migrated leukocytes, and the expression of endothelial intercellular adhesion molecule-1 and P-selectin. The association of losartan reduced the effect of diclofenac on leukocyte migration. Neither treatment tested increased the venular shear rate or modified the venular diameters, number of circulating leukocytes, and L-selectin expression on granulocytes. The reduction of CD11/CD18 expression induced by diclofenac alone was hindered by losartan. A pharmacokinetic interference between losartan and diclofenac was ruled out since no significant differences were observed in the plasma concentrations of each drug when they were associated. In conclusion, although diclofenac does not interfere with the losartan antihypertensive effect, losartan attenuates the effect of diclofenac has on leukocyte behavior and expression of adhesion molecules. Losartan has an antimigratory effect, reducing leukocyte migration by reducing ICAM-1 and P-selectin expression. Losartan may hinder the full expression of the antimigratory effect of diclofenac.
Martinez
Luis Lopez
LL
Laboratory of Hypertension and Inflammation, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Oliveira
Maria Aparecida
MA
Miguel
Ana Silvia
AS
Rastelli
Viviani Milan Ferreira
VM
Cruz
José Walber Miranda C
JW
Tostes
Rita C A
RC
Carvalho
Maria Helena Catelli
MH
Nigro
Dorothy
D
Fortes
Zuleica Bruno
ZB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D004008:Diclofenac / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D004347:Drug Interactions; D004487:Edema / Q000097:blood / Q000150:complications / Q000188:drug therapy; D005434:Flow Cytometry; D005753:Gastric Mucosa / Q000187:drug effects; D006973:Hypertension / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D007150:Immunohistochemistry; D007958:Leukocyte Count; D036904:Leukocyte Rolling / Q000187:drug effects*; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D019808:Losartan / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000959:Antihypertensive Agents; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D019808:Losartan