Phosphodiesterase 5 inhibitor, zaprinast, selectively increases cerebral blood flow in the ischemic penumbra in the rat brain.
BACKGROUND
Guanosine 3', 5'-cyclic monophosphate (cGMP) acts as a relaxant second messenger in the cerebral vessels. cGMP-specific phosphodiesterase type 5 (PDE5) inhibitor increases intracellular cGMP levels. This study investigated the effect of the PDE5 inhibitor on the ischemic brain.


METHODS
Regional cerebral blood flow (rCBF), cGMP concentration, and infarction volume were measured in the rat middle cerebral artery occlusion model. Ten minutes after ischemia, the animals received an intravenous (i.v.) infusion of vehicle (phosphate-buffered saline), PDE5 inhibitor, zaprinast (10 mg/kg), or nitric oxide donor, S-nitroso-N-acetyl-penicillamine (SNAP, 100 microg/kg). rCBF was measured continuously by laser-Doppler flowmetry in the ischemic penumbra of the ischemic and contralateral sides under continuous blood pressure monitoring. cGMP concentrations were determined using the enzyme immunoassay and infarct volumes were estimated by 2,3,5-triphenyltetrazolium chloride staining.


RESULTS
The administration of zaprinast significantly increased rCBF in the ischemic brain compared with the pre-drug control value despite the decreased mean blood pressure, whereas it did not affect rCBF in the contralateral side. The cGMP concentration was significantly higher in the ischemic cortex compared with the contralateral side. SNAP infusion increased the cGMP concentration in the bilateral cortices to a similar extent. The volume of cerebral infarction was significantly decreased by zaprinast administration.


CONCLUSIONS
The PDE5 inhibitor zaprinast may selectively increase CBF in the ischemic brain via increased cGMP levels, thus providing a new strategy against acute cerebral infarction.
Gao
Feng
F
Department of Neurosurgery, University of Yamanashi, Faculty of Medicine, Yamanashi 409-3898, Japan.
Sugita
Masao
M
Nukui
Hideaki
H
D000704:Analysis of Variance; D000818:Animals; D001776:Blood Circulation Time / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002545:Brain Ischemia / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D007839:Functional Laterality; D007124:Immunoenzyme Techniques / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D020030:Nitric Oxide Donors / Q000008:administration & dosage; D010396:Penicillamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D011688:Purinones / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects*; D013778:Tetrazolium Salts; D013997:Time Factors
D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; C110881:S-nitro-N-acetylpenicillamine; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D010396:Penicillamine; C011145:zaprinast; D006152:Cyclic GMP