Systemic administration of phosphodiesterase V inhibitor, sildenafil citrate, for attenuation of cerebral vasospasm after experimental subarachnoid hemorrhage.
OBJECTIVE
One of the phosphodiesterase isoenzymes, Type V (PDE V), specifically hydrolyzes cyclic guanosine monophosphate to cause vasoconstriction. This study analyses the effect of PDE V inhibition with sildenafil citrate (SC) on cerebral vasospasm and its effect on apoptotic changes of the vascular endothelium.


METHODS
Twenty-four rabbits were divided into four groups. The first group was composed of sham-surgery animals. The second group was the subarachnoid hemorrhage (SAH) group, in which cerebral vasospasm was induced. In the third group, sham-surgery rabbits were treated with SC. In the fourth group, animals were treated with SC after SAH. SC was administered for 48 hours, 0.7 mg/kg, three times per day in Groups 3 and 4. Basilar artery lumen circumferences were measured in all groups by computerized image analysis. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) method was used to evaluate the rate of apoptosis between SAH and SC-treated SAH groups. Results were compared by analysis of variance and paired t tests, and P values less than 0.05 were considered significant.


RESULTS
Basilar artery circumferences between groups were significantly different (P < 0.001). SC (0.7 mg/kg, three times per d) significantly dilated the basilar arteries in both the sham-surgery group (2370 +/- 233 microm; P = 0.039) and the SAH group (2142 +/- 195 microm; P = 0.006) after 48 hours of treatment. The TUNEL method for apoptosis revealed that actual numbers of the apoptotic endothelial cells per cross section after SAH in the control (no treatment) (73 +/- 2) and SC-treated (0.7 mg/kg) groups(76 +/- 3) were not significantly different (P > 0.05).


CONCLUSIONS
The vasodilatory effect of SC was observed to be significant on normal cerebral vessels and after SAH-induced vasospasm. SC did not prevent apoptosis of the endothelium in our study, which suggests that prevention of apoptosis is not necessary in the treatment of cerebral vasospasm.
Atalay
Basar
B
Department of Neurosurgery, Baskent University Faculty of Medicine, Ankara, Turkey. basara@baskent-ank.edu.tr
Caner
Hakan
H
Cekinmez
Melih
M
Ozen
Ozlem
O
Celasun
Bulent
B
Altinors
Nur
N
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000503:physiopathology; D001783:Blood Flow Velocity / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines; D011817:Rabbits; D000068677:Sildenafil Citrate; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D013450:Sulfones; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage; D020301:Vasospasm, Intracranial / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5