Type V phosphodiesterase expression in cerebral arteries with vasospasm after subarachnoid hemorrhage in a canine model.
Cyclic GMP (cGMP) mediates smooth muscle relaxation in the central nervous system. In subarachnoid hemorrhage (SAH), decreases in intrinsic nitric oxide (NO) cause cerebral vasospasms due to the regulation of cGMP formation by NO-mediated pathways. As phosphodiesterase type V (PDE V) selectively hydrolyzes cGMP, we hypothesized that PDE V may function in the initiation of vasospasm. This study sought to identify the altered PDE V expression and activity in the vasospastic artery in a canine SAH model. We also used this system to examine possible therapeutic strategies to prevent vasospasm. Using a canine model of SAH, we induced cerebral vasospasm in the basilar artery (BA). Following angiographic confirmation of vasospasm on day 7, PDE V expression was immunohistochemically identified in smooth muscle cells of the vasospastic BA but not in cells of a control artery. The isolation of PDE enzymes using a sepharose column confirmed increased PDE V activity in the vasospastic artery only through both inhibition studies, using the highly selective PDE V inhibitor, sildenafil citrate, and Western blotting. Preliminary in vivo experiment using an oral PDE V inhibitor at 0.83 mg kg(-1) demonstrated partial relaxation of the spastic BA. PDE V activity was increased from control levels within the BA seven days after SAH. PDE V expression was most prominent in smooth muscle cells following SAH. These results suggest that clinical administration of a PDE V inhibitor may be a useful therapeutic tool in the prevention of vasospasm following SAH.
Inoha
Satoshi
S
Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. s-inoha@ns.med.Kyushu-u.ac.jp
Inamura
Takanori
T
Ikezaki
Kiyonobu
K
Nakamizo
Akira
A
Amano
Toshiyuki
T
Fukui
Masashi
M
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D015153:Blotting, Western; D002533:Cerebral Angiography; D002536:Cerebral Arteries / Q000201:enzymology* / Q000503:physiopathology; D006152:Cyclic GMP / Q000494:pharmacology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D004285:Dogs; D007150:Immunohistochemistry; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D000068677:Sildenafil Citrate; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000201:enzymology*; D013450:Sulfones; D013997:Time Factors; D020301:Vasospasm, Intracranial / Q000201:enzymology* / Q000209:etiology
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP