Lacidipine Inhibits Adhesion Molecule and Oxidase Expression Independent of Blood Pressure Reduction in Angiotensin-Induced Vascular Injury

Abstract

Abstract-Dihydropyridines can inhibit gene expression in-vitro and may have a protective vascular effect independent of blood pressure reduction. We tested the hypothesis that lacidipine prevents induction of inducible NO synthase (iNOS), influences leukocyte adhesion and infiltration, inhibits nuclear factor (NF)-B transcription factor activity, and ameliorates end-organ damage in a transgenic rat model of angiotensin (Ang) II-dependent organ sclerosis. We treated rats transgenic for human renin and angiotensinogen (dTGR) from week 4 to 7 with lacidipine (0.3 or 3 mg/kg by gavage). Blood pressure was measured by tail cuff. Organ damage was assessed by histology and immunohistochemistry. Adhesion molecules and cytokines were analyzed by immunohistochemistry. Transcription factors were analyzed by mobility shift assays. Untreated dTGR developed moderate hypertension, cardiac hypertrophy, and severe renal damage with albuminuria. Lacidipine decreased blood pressure slightly at the low dose and substantially at the higher dose. However, both treatments reduced albuminuria and plasma creatinine to the same degree (PϽ0.05). Intercellular adhesion molecule-1 (ICAM-1) was markedly reduced by lacidipine as well as renal neutrophil and monocyte infiltration. Lacidipine reduced mitogen-activated protein (MAP) kinase phosphorylation and iNOS expression in both cortex and medulla. NF-B and AP-1 were activated in dTGR but reduced by lacidipine. Lacidipine ameliorates Ang II-induced end-organ damage independent of blood pressure lowering, perhaps by inhibiting the MAP kinase pathway and NF-B activation.

Targeted Deletion of Angiotensin II Type 1A Receptor Does not Protect Mice from Progressive Nephropathy of Overload Proteinuria

“…Reducing BP of AT 1A ϩ/ϩBSA mice to levels comparable to AT 1A Ϫ/ϪBSA mice resulted in comparable values of protein excretion rate, similar degree of glomerular and tubulointerstitial lesions, and same amount of F4/80-positive cells infiltrating the kidney. Whether this last effect could be due to an anti-inflammatory response induced by lacidipine as it occurred in an Ang II-dependent transgenic rat model (34) could not be completely ruled out. Despite that no compensatory upregulation has been observed in the expression of AT 1B or AT 2 receptors in the mouse line here used (13), it is theoretically possible that the renal pathology observed in AT 1A Ϫ/Ϫ mice could be attributable to changes of those receptors.…”

From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

“…They include: ICAM-1, vascular cell adhesion molecule-1, platelet-endothelial cell adhesion molecule-1; and MCP-1 and osteopontin. 13,60,[100][101][102][103][104][105][106][107] MCP-1 has been shown to be integral to the homing of inflammatory cells into cardiovascular tissue. Within invading inflammatory cells, there is evidence of an activation of a redox-sensitive nuclear transcription factor-kB and increased expression of a proinflammatory mediator cascade that it regulates, including ICAM-1, MCP-1 and tumor necrosis factor-a.…”

“…Cumulative experimental evidence is emerging to suggest the therapeutic role of these agents as immunomodulators. These include: attacking the neuroendocrine-immune interface via antagonists to AT 1 , 101,106,122 ALDO, 12,13,104,123,124 or endothelin A 60,100,107,125 receptors; and preventing intracellular Ca 2+ loading, which is responsible for the induction of oxi/nitrosative stress, by using a dihydropyridine receptor blocker 103,126 or T-type 127 Ca 2+ channel blocker. Shoring up endogenous antioxidant defenses with the administration of an antioxidant, such as PDTC, N-acetylcysteine or probucol, 13,105,108,109,[128][129][130][131] represent other avenues.…”

The Effect of Trandolapril and Its Fixed-Dose Combination With Verapamil on Proteinuria in Normotensive Adults With Type 2 Diabetes

“…Another possible advantage of the combination consists of the capacity of calcium channel blockers to inhibit the expression of adhesion molecules, which prevents leukocyte infiltration in the kidney independent of the antihypertensive effects of the drugs. This fact ameliorates tissue damage in diabetic rats and has not been observed with other antihypertensive drugs such as hydralazine or hydrochlorothiazide (11). In addition, nondihydropyridinic calcium antagonists, unlike dihydropyridines, promote vasodilatation of the efferent arteriole, which renders them more effective to reduce proteinuria (7,8).…”