The mechanism by which aminoglycoside antibiotics cause vasodilation of canine cerebral arteries.
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. In cerebral arterial rings precontracted with OxyHb (10 microM), 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. The aminoglycosides also inhibited the contractions to prostaglandin F2alpha (1 microM) and depolarizing concentrations of potassium chloride (60 mM). The order of potency was neomycin > gentamicin > streptomycin > kanamycin. The relaxation was maintained in vascular preparations denuded of endothelium. Neomycin (5 mM) abolished the Ca2+-independent contraction to PGF2alpha. In Fura-2-loaded cerebrovascular smooth muscle cells, OxyHb (1 microM) 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. 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.
Gergawy
M
M
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Vollrath
B
B
Cook
D
D
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009355:Neomycin / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D000900:Anti-Bacterial Agents; D010108:Oxyhemoglobins; D011189:Potassium Chloride; D015237:Dinoprost; D009355:Neomycin; D002118:Calcium