The mechanism by which aminoglycoside antibiotics cause vasodilation of canine cerebral arteries

Abstract

1. The effects of aminoglycoside antibiotics were examined in canine cerebral arteries and in cultured cerebrovascular smooth muscle cells stimulated with oxyhemoglobin (OxyHb), a blood constituent which has been implicated in the pathogenesis of cerebrovascular spasm.

2. In cerebral arterial rings precontracted with OxyHb (10 μM), the aminoglycosides caused a concentration-dependent decrease in isometric tension. The EC₅₀s for the relaxation were 0.46±0.1 mM (n=6), 0.53±0.08 mM (n=12), 1.6±0.3 mM (n=7) and 3.9±0.5 mM (n=5) for neomycin, gentamicin, streptomycin and kanamycin, respectively. This order of potency corresponds approximately to the number of positive charges in the molecules.

3. The aminoglycosides also inhibited the contractions to prostaglandin F_2α (1 μM) and depolarizing concentrations of potassium chloride (60 mM). The order of potency was neomycin>gentamicin>streptomycin>kanamycin.

4. The relaxation was maintained in vascular preparations denuded of endothelium.

5. Neomycin (5 mM) abolished the Ca²⁺-independent contraction to PGF_2α.

6. In Fura-2-loaded cerebrovascular smooth muscle cells, OxyHb (1 μM) significantly enhanced the concentration of intracellular calcium ([Ca²⁺]_i) by 330%. The administration of neomycin, gentamicin, kanamycin and streptomycin in concentrations corresponding to the EC₅₀ from contractility studies, reduced the effects of OxyHb on [Ca²⁺]_i by about 50% to 221±35 nM (n=7), 270±31 nM (n=7), 229±33 nM (n=6) and 240±6 nM (n=5), respectively.

7. These results suggests that the effects of the aminoglycosides on the OxyHb-induced contraction and the long-term increase in [Ca²⁺]_i, may arise from several effects, including inhibition of PLC, protection of calcium extrusion mechanisms, and interference with the process of [Ca²⁺]_i accumulation.

Full Text

The Full Text of this article is available as a PDF (317.2 KB).