A new approach to the treatment of cerebral vasospasm: the angiographic effects of tadalafil on experimental vasospasm

Köktekir, Ender; Yavuz, Erdem; Bayar, Mehmet Akif; Gökçek, Cevdet; Karatay, Mete; Kılıç, Caner

doi:10.1007/s00701-009-0540-x

Cited by 10 publications

(9 citation statements)

References 30 publications

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“…First, we found that post-SAH initiation of sildenafil attenuates vasospasm in an endovascular perforation SAH model, which confirms previous cisterna magna injection SAH studies. 5–6, 8 Second, we document that sildenafil improves neurological outcome after SAH – a critical finding given that numerous studies have shown a dissociation between the vascular and functional benefits of certain SAH therapeutics. 21–22 Third, we found that sildenafil reduces SAH-induced neuronal cell death, which may reflect a reduction in vasospasm-induced ischemia or a direct neuroprotective effect (or both).…”

Section: Discussionmentioning

confidence: 67%

“…Studies to date show the following: 1) acute administration of sildenafil partially relaxes basilar artery vasospasm in dogs 7 ; 2) pre-SAH initiation of sildenafil partially inhibits vasospasm in rabbits 4 ; and 3) post-SAH initiation of sildenafil and other PDE5 inhibitors attenuates vasospasm in rat cisterna magna models of SAH. 568 …”

Section: Discussionmentioning

confidence: 99%

“…3 Several recent studies suggest sildenafil and other PDE5 inhibitors likely reduce vasospasm following SAH. 4–8 Though these results are promising, additional investigation is required before considering translational studies in humans. For example, the following have yet to be examined: 1) whether sildenafil reduces neuronal cell death following SAH; 2) whether sildenafil improves neurological outcome following SAH; and 3) whether sildenafil causes systemic hypotension or exacerbates SAH-induced intracranial hypertension when administered at doses that attenuate vasospasm.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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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.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…1 Vasospasm was detected immediately after SAH (30 mins) but not thereafter, indicating that vasospasm is transient in this mild SAH model. Previous studies using ex vivo arteries 41–43 and in vivo angiography 44,45 in relatively more severe SAH models have detected vasospasm. Specifically, an MRI study of a SAH model by puncturing the vessel found narrowing of vessels but vasoconstriction only reached significance in the right proximal ICA in the acute phase and returned to normal on day 9.…”

Section: Discussionmentioning

confidence: 97%

Multimodal MRI characterization of experimental subarachnoid hemorrhage

et al. 2016

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Subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality. We implemented an in-scanner rat model of mild SAH in which blood or vehicle was injected into the cistern magna, and applied multimodal MRI to study the brain prior to, immediately after (5mins to 4hrs), and up to 7 days after SAH. Vehicle injection did not change arterial lumen diameter, apparent diffusion coefficient (ADC), T2, venous signal, vascular reactivity to hypercapnia, or foot fault scores, but mildly reduce cerebral blood flow (CBF) up to 4hrs, and open-field activity up to 7 days post injection. By contrast, blood injection caused: i) vasospasm 30mins after SAH but not thereafter, ii) venous abnormalities at 3hrs and 2 days, delayed relative to vasospasm, iii) reduced basal CBF and CBF response to hypercapnia 1–4hrs but not thereafter, iv) reduced ADC immediately after SAH but no ADC and T2 changes on day 2 and 7, and v) reduced open-field activities in both SAH and vehicle animals, but no significant differences in open-field activities and foot fault tests between groups. Mild SAH exhibited transient and mild hemodynamic disturbances and diffusion changes, but did not show apparent ischemic brain injury nor functional deficits.

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“…Intrathecal administration of a cell-membrane permeant form of cGMP prevented hemorrhage-associated hemodynamic changes in one rodent model [75]. Additionally, phosphodiesterase-5 inhibitors prevented vasospasm in rodent models [76, 77]. However, these approaches have yet to be explored in human studies.…”

Section: Treatment Of Vasospasmmentioning

confidence: 99%

Nitric Oxide in Cerebral Vasospasm: Theories, Measurement, and Treatment

Siuta

Zuckerman

Mocco

2013

Neurology Research International

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In recent decades, a large body of research has focused on the role of nitric oxide (NO) in the development of cerebral vasospasm (CV) following subarachnoid hemorrhage (SAH). Literature searches were therefore conducted regarding the role of NO in cerebral vasospasm, specifically focusing on NO donors, reactive nitrogen species, and peroxynitrite in manifestation of vasospasm. Based off the assessment of available evidence, two competing theories are reviewed regarding the role of NO in vasospasm. One school of thought describes a deficiency in NO due to scavenging by hemoglobin in the cisternal space, leading to an NO signaling deficit and vasospastic collapse. A second hypothesis focuses on the dysfunction of nitric oxide synthase, an enzyme that synthesizes NO, and subsequent generation of reactive nitrogen species. Both theories have strong experimental evidence behind them and hold promise for translation into clinical practice. Furthermore, NO donors show definitive promise for preventing vasospasm at the angiographic and clinical level. However, NO augmentation may also cause systemic hypotension and worsen vasospasm due to oxidative distress. Recent evidence indicates that targeting NOS dysfunction, for example, through erythropoietin or statin administration, also shows promise at preventing vasospasm and neurotoxicity. Ultimately, the role of NO in neurovascular disease is complex. Neither of these theories is mutually exclusive, and both should be considered for future research directions and treatment strategies.

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A new approach to the treatment of cerebral vasospasm: the angiographic effects of tadalafil on experimental vasospasm

Abstract: Our study results showed that tadalafil has a vasodilatory effect on both acute and chronic periods of cerebral vasospasm. We also concluded that cerebral angiography can be used safely for investigation of cerebral vasospasm in animal studies.

Cited by 10 publications

References 30 publications

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

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

Multimodal MRI characterization of experimental subarachnoid hemorrhage

Nitric Oxide in Cerebral Vasospasm: Theories, Measurement, and Treatment

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