Phosphodiesterase 5 Inhibition Attenuates Cerebral Vasospasm and Improves Functional Recovery After Experimental Subarachnoid Hemorrhage

Abstract

Background Cerebral vasospasm is an independent predictor of poor outcome after subarachnoid hemorrhage (SAH). The nitric oxide-cyclic GMP (NO-cGMP) vasodilatory pathway is strongly implicated in its pathophysiology. Preliminary studies suggest that phosphodiesterase 5 (PDE5) – an enzyme that degrades cGMP – may play a role, as the PDE5 inhibitor sildenafil was found to reduce vasospasm after SAH. However, several questions that are critical when considering translational studies remain unanswered. Objective To elucidate the mechanism of action of sildenafil against vasospasm, and to assess whether sildenafil attenuates SAH-induced neuronal cell death, improves functional outcome after SAH, or causes significant physiological side effects when administered at therapeutically relevant doses. Methods SAH was induced via endovascular perforation in male C57BL6 mice. Beginning two hours later, mice received sildenafil citrate (0.7, 2 or 5mg/kg P.O. BID) or vehicle. Neurological outcome was assessed daily. Vasospasm was determined on post-SAH Day 3. Brain PDE5 expression and activity, cGMP content, neuronal cell death, arterial blood pressure (BP), and intracranial pressure (ICP) were examined. Results We found that PDE5 activity (but not expression) is increased after SAH, leading to decreased cGMP levels. Sildenafil attenuates this increase in PDE5 activity and restores cGMP levels after SAH. Post-SAH initiation of sildenafil was found to reduce vasospasm, decrease neuronal cell death, and markedly improve neurological outcome, without causing significant physiological side effects. Conclusion Sildenafil–an FDA-approved drug with a proven track record of safety in humans –is a promising new therapy for vasospasm and neurological deficits following SAH.

Large Vessel Vasospasm Is Not Associated with Cerebral Cortical Hypoperfusion in a Murine Model of Subarachnoid Hemorrhage

“…In addition, perfusion was examined in vivo, whereas vasospasm was analyzed ex vivo. The time point of 72 h was chosen because our data and other studies have reported that vasospasm peaks 72 h after induction of SAH in the murine endovascular filament perforation model [16,23,24]. Although we cannot rule out that a correlation between vasospasm and cortical perfusion may have been present at earlier time points, the lack of correlation at 72 h indicates that large vessel vasospasm is of limited relevance in the murine model.…”

“…This time point was selected to determine the impact on cortical perfusion at the peak of CV [16,23,24]. We analyzed the vessel volume of a 2.5-mm vessel segment of the left MCA distal of the carotid T, which is a highly sensitive parameter for evaluating vasospasm [28].…”

“…Although these changes occur with faster temporal dynamics in mice than humans-peaking 3 days after SAH in mice [16,23,24] compared to 7 to 10 days in humans [3]-murine models have become an important tool for basic research on the pathophysiology of SAH. The majority of experimental studies to date have focused on CV [12][13][14][15][16][17][18][19][20].…”

Intracranial Aneurysm and Sildenafil

“…Ballard et al suggested that sildenafi l also acts on PDE-1 and PDE-2, which are involved in controlling cerebral circulation ( 11 ). Studies on mice have demonstrated that sildenafi l decreases cerebral vasospasm by increasing and restoring cGMP levels ( 12 ). Th e reported adverse eff ects of sildenafi l include headache, visual disturbances, pupil-sparing third nerve palsy, and transient hypertension, and these symptoms suggest that sildenafi l also aff ects brain microvasculature regulation ( 13 , 14 ).…”

Potential Implications of HCN Channel Dysfunction after Subarachnoid Hemorrhage

“…Based on available evidence (Garthwaite et al, 2006), it is likely that NO affects the function of HCN through cGMP gating of these channels. However, an increase in phosphodiesterase-5 activity and consequent decrease in cGMP occurs in cortical neurons after experimental SAH (Han et al, 2012). It is therefore possible that cGMP downregulation seen in vivo would further exacerbate the magnitude of HCN channel inhibition and thereby enhance the degree of neuronal excitability.…”