Losartan Attenuates the Antimigratory Effect of Diclofenac in Spontaneously Hypertensive Rats

Abstract

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.

Immunomodulatory effects of diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels

“…Diclofenac inhibits the accumulation of leukocytes and the formation of lesions [16,17]. In addition, it also blocks the migration of leukocytes [15,18]. Our results also indicated a reduction in macrophage migration.…”

“…Similarly, diclofenac's anticonvulsant properties involve the activation of heterotetrameric KCNQ2/KCNQ3 channels, which are responsible for the M current that modulates neuronal excitability and firing [14]. Finally, diclofenac also has many effects in the immune system, including impairing migration and accumulation of leukocytes [15][16][17][18] and diminishing NO production by macrophages [19,20]. We here demonstrate that Kv1.3 is involved in the anti-inflammatory mechanism of diclofenac.…”

Endogenous testosterone increases leukocyte–endothelial cell interaction in spontaneously hypertensive rats

“…It has been demonstrated that leukocyte adhesion depends on shear rate. Low shear rates promote leukocyte adherence to the endothelium in postcapillary venules (Martinez et al, 2005), which would explain the increase in leukocyte adherence observed in SHRs as well as the effects of castration. However, castration did not alter venular blood flow velocity and venular shear rate.…”

“…A great number of mediators are released during the inflammatory response, including LTB 4 , which has been identified as a key mediator of leukocyte-endothelial cell interaction and as a potent chemoattractant responsible for the recruitment of neutrophils to the site of inflammation (Martinez et al, 2005). Although multiple mediators work together in inflammation, LTB 4 has been implicated in the initiation of leukocyte-endothelium interaction during inflammation (Schafer et al, 2005).…”

“…Hemodynamic forces such as flow and resistance may influence the leukocyte-endothelial cell interactions (Martinez et al, 2005). Considering this, the venular diameter and blood flow velocity were measured to calculate the wall shear rate.…”