The polycationic aminoglycosides modulate the vasoconstrictive effects of endothelin: relevance to cerebral vasospasm.
1. The vasoactive peptide endothelin (ET) has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid haemorrhage. In these studies we investigated the involvement of protein kinase C (PKC) in sustained vasoconstriction induced by ET-1 in canine cerebral arteries. We also examined the ability of the aminoglycoside antibiotics to reverse the effects mediated by ET-1 in canine cerebrovascular smooth muscle cells (CVSMC). 2. The ET(A) receptor antagonist, BQ-123, showed a competitive inhibition of the ET-1 responses. 3. The vasoconstrictor action of both ET-1 (0.5 nM) and phorbol myristate acetate (PMA) (160 nM) was reversed by a selective PKC inhibitor, Ro-32-0432. 4. In cerebral arteries precontracted with ET-1 the aminoglycosides caused a concentration-dependent relaxation. The EC(50s) for the relaxation were as follows: 0.54+/-0.05, 0.63+/-0.01, 1.88+/-0.46 and 2.3+/-0.92 mM for gentamicin, neomycin, streptomycin and kanamycin, respectively. 5. Gentamicin caused a concentration-dependent decrease of the PMA-induced responses in calcium free medium. 6. PKC activity was elevated in CVSMC exposed to ET-1 (170%) and PMA (167%) for a period of time (60 min) corresponding to maximum tonic contraction induced by these agents in arterial rings. 7. The administration of the aminoglycosides to CVSMC, in concentrations corresponding to the EC(50s) from contractility studies, reduced the effects of both ET-1 and PMA on PKC activity to the levels not different from controls. 8. These results show that the aminoglycosides are able to inhibit sustained vasoconstriction induced by ET-1, an effect which is due, at least in part, to the inhibition of PKC.
Wickman
G
G
Department of Pharmacology, University of Alberta, Edmonton AB, Canada, T6G 2H7.
Nessim
M A
MA
Cook
D A
DA
Vollrath
B
B
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D005839:Gentamicins / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects; D007612:Kanamycin / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009355:Neomycin / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011073:Polyamines / Q000494:pharmacology; D000071228:Polyelectrolytes; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D013307:Streptomycin / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D020301:Vasospasm, Intracranial / Q000201:enzymology / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001920:Bradykinin; D019332:Endothelin-1; D005839:Gentamicins; D007211:Indoles; D007612:Kanamycin; D009355:Neomycin; D010456:Peptides, Cyclic; D011073:Polyamines; D000071228:Polyelectrolytes; D011493:Protein Kinase C; D011758:Pyrroles; D013307:Streptomycin; D013755:Tetradecanoylphorbol Acetate; C085989:Ro 32-0432; C072247:cyclo(Trp-Asp-Pro-Val-Leu)