The development of aortic aneurysms is a progressive inflammatory process involving proliferation and migration of smooth muscle cells, infiltration and differentiation of monocytes and degradation of the internal elastic lamina. Since calcium channel blockers exert multiple beneficial effects in the vascular system we investigated the effect of the benzothiazepine-type calcium channel blocker diltiazem (DIL) on aneurysm formation.

Angiotensin II infusion (ATII, 4 weeks, 1.44 mg/kg bw/d) induced massive aneurysm formation in ApoE-deficient mice that was almost completely blocked by co-treatment with DIL (100 mg/kg bw/day). Additional treatment with phenylephrine (PHE, 18 mg/kg bw/d) to counteract the blood pressure-lowering effect of DIL had no influence on the beneficial effect of DIL. Moreover DIL prevented the ATII-induced mRNA expression of pro-inflammatory cytokines in the aortic arch after 6 days of ATII treatment due to a reduced amount of locally infiltrated macrophages and an attenuated systemic CCL12 level in the sera.

Subcutaneously implanted matrigel plugs filled with CCL2 (600 ng/ml) induced a recruitment of Ly6C⁺-monocytes in ApoE-deficient mice that could be reduced by co-treatment with DIL (30 mM).

ATII-treatment of cultured fibroblasts induced IL6 mRNA expression that could be blocked by DIL. Moreover DIL acutely diminished the IL6-induced IL-1b and CCL12 mRNA expression in peritoneal macrophages (10 mM) and was able to reduce the LPS-induced IL-1b release in RAW264.7 macrophages.

These observations indicate that DIL has a beneficial blood pressure-independent effect on aneurysm formation by preventing ATII-induced expression of pro-inflammatory cytokines, monocyte infiltration into the vessel wall and macrophage-derived production of pro-inflammatory cytokines.