Thin and thick filament regulation of contractility in experimental cerebral vasospasm.
OBJECTIVE
Cerebral vasospasm is a potentially fatal consequence of aneurysmal subarachnoid hemorrhage and influences the prognosis of the patient. The purpose of this study was to evaluate the status of thin (actin) and thick (myosin) filament regulation of smooth muscle contraction in the double-subarachnoid hemorrhage canine model of cerebral vasospasm and to determine the effects of a kinase inhibitor reported to be effective in vasospasm, HA1077, on thin and thick filament regulation.


METHODS
Cerebral vasospasm was assessed by vertebral angiography. Myosin regulatory light chain phosphorylation was measured using glycerol-urea gels, whereas protein levels of the thin filament-associated protein calponin were measured by Western blot.


RESULTS
The basilar arteries of dogs in which subarachnoid hemorrhage was induced narrowed to 36% +/- 2.0% of their size on the first day (n = 12). The phosphorylation of the regulatory light chain tended to increase, but the change did not reach statistical significance (35% +/- 5.9% [n = 12] versus 25% +/- 4.8% [n = 10] in control arteries). In contrast to this increase, significant degradation of calponin was observed in the samples from vasospastic dogs (85.4% +/- 5.45% [n = 5] versus 15.2% +/- 6.21% [n = 5]; P < 0.01). Prophylactic treatment with intravenous injections of HA1077 at 0.67 mg/kg b.i.d. significantly inhibited vasospasm (diameters, 65% +/- 10.2% of Day 1 diameters [n = 5]; P < 0.05), and calponin degradation (57.8% +/- 13.9% [n = 4]) was substantially reduced.


CONCLUSIONS
These data suggest that degradation of the thin filament-associated protein calponin plays a role in cerebral vasospasm and that the antivasospastic action of HA1077 is, at least in part, due to prevention of calponin degradation.
Kim
I
I
Signal Transduction Group, Boston Biomedical Research Institute Massachusetts 02114-2500, USA.
Leinweber
B D
BD
Morgalla
M
M
Butler
W E
WE
Seto
M
M
Sasaki
Y
Y
Peterson
J W
JW
Morgan
K G
KG
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000199:Actins / Q000502:physiology*; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000502:physiology; D004285:Dogs; D008840:Microfilament Proteins; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D018994:Myosin Light Chains / Q000502:physiology; D009218:Myosins / Q000502:physiology*; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D020301:Vasospasm, Intracranial / Q000503:physiopathology*; D000096985:Calponins
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000199:Actins; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D018994:Myosin Light Chains; D009218:Myosins; D014665:Vasodilator Agents; D000096985:Calponins; C049347:fasudil