zaprinast and Subarachnoid-Hemorrhage

Subarachnoid hemorrhage (SAH) is associated with impaired nitric oxide (NO)-mediated cerebral vasodilatation. We tested the hypothesis that SAH causes alterations in the production of, hydrolysis of, or responsiveness to cGMP in the rat basilar artery in vivo. Rats were injected with saline or autologous blood into the cisterna magna. Two days later, effects of vasoactive drugs on basilar artery diameter were examined using a cranial window preparation. Vasodilator responses to ACh, sodium nitroprusside (SNP), and low concentrations (

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acetylcholine; Animals; Basilar Artery; Cerebrovascular Circulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Male; Nitric Oxide; Nitroprusside; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Purinones; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Vasodilation; Vasodilator Agents

Endothelium-dependent relaxations are inhibited during chronic vasospasm after subarachnoid hemorrhage in the canine basilar artery, although the luminal release of endothelium-derived relaxing factor (EDRF) is maintained. The present study investigated the mechanisms underlying the impaired vascular reactivity and in particular whether the loss of responsiveness of the smooth muscle to EDRF is due to an impaired production of cGMP. Bradykinin and nitric oxide evoked concentration-dependent relaxations in isolated canine basilar arteries with and without endothelium, respectively, which were reduced in the subarachnoid hemorrhage group. Relaxations evoked by M&B22,948 (an inhibitor of cGMP phosphodiesterases) were smaller, but those evoked by the lipophilic cGMP analogue 8-bromo-cGMP were potentiated slightly in the subarachnoid hemorrhage group. The resting levels of cGMP in rings with endothelium (reflecting the effect of spontaneous release of EDRF) and those evoked by bradykinin in rings with endothelium and by nitric oxide in rings without endothelium were diminished in the subarachnoid hemorrhage group. These data indicate that the altered endothelium-mediated relaxations of the smooth muscle after subarachnoid hemorrhage is due, at least in part, to an impaired activation of soluble guanylate cyclase leading to a reduced production of cGMP in the smooth muscle.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Basilar Artery; Bradykinin; Cyclic GMP; Dogs; Endothelium, Vascular; Female; Male; Nitric Oxide; Purinones; Radioimmunoassay; Subarachnoid Hemorrhage; Vasodilation