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Atorvastatin preconditioning attenuates the production of endothelin-1 and prevents experimental vasospasm in rats

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Abstract

Objective

Induced endothelin-1 (ET-1) production and decreased nitric oxide synthase (NOS) bioavailability have been found in aneurysmal subarachnoid hemorrhage (SAH). Atorvastatin is recognized to have pleiotropic effects including increasing NOS bioavailability as well as reducing inflammation and oxidative damage other than reducing dyslipidemia. This study is of interest to examine the effect of atorvastatin on ET-1/endothelial nitric oxide synthase (eNOS) in experimental SAH.

Methods

A rodent double-hemorrhage SAH model was employed. Animals were randomly assigned as sham-operated, SAH, vehicle plus SAH, 5 mg/day atorvastatin treatment plus SAH and 5 mg/day atorvastatin precondition plus SAH groups. Administration with atorvastatin (5 mg/day) was initiated 1 week before (precondition) and 24 hr later (treatment). Cerebrospinal fluid samples were collected at 72 hr after second SAH. ET-1 (ELISA) was measured. The basilar arteries (BAs) were harvested and sliced, and their cross-sectional areas were measured. Radiolabeled NOS assay kit was used to detect eNOS.

Results

Morphologically, convoluted internal elastic lamina, distorted endothelial cells and myonecrosis of the smooth muscle were predominantly observed in the BA of SAH and vehicle-treated SAH groups, which was not detected in the atorvastatin-preconditioned SAH group or the healthy controls. Significant vasospasm was noted in the vehicle group (lumen potency 64.5%, compared with the sham group, p ≤ 0.01) and less prominent in the atorvastatin treatment group (lumen potency, 76.6%, p < 0.05). In addition, increased ET-1 levels were found in all the animals subject to SAH (SAH only, SAH plus vehicle and SAH plus atorvastatin reversal) except in the atorvastatin precognition group when compared with the healthy controls (no SAH). Likewise, the levels of expressed NOS in BAs is induced in the atorvastatin groups (both atorvastatin treatment and precondition) when compared with that in the SAH group (p < 0.01).

Conclusion

This study offers first evidence that atorvastatin in the preconditioning status reduces the level of ET-1, which corresponds to its antivasospastic effect in the condition of chronic vasospasm. Although there is increased expression of NOS in both atorvastatin precondition and reversal groups, BA’s lumen potency is significantly increased in the atorvastatin precondition group when compared with the SAH group (p < 0.01).

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Abbreviations

BA:

basilar artery

CTA:

computed tomography angiography

DSA:

digital substration angiography

eNOS:

endothelial nitric oxide synthase

ET-1:

endothelin-1

IEL:

internal elastic lamina

MRA:

magnetic resonance angiography

PBS:

phosphate-buffered saline

SAH:

subarachnoid hemorrhage

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Authors and Affiliations

  1. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Chih-Zen Chang, Chih-Long Lin, Shiuh-Lin Hwang, Shen-Long Howng & Aij-Lie Kwan

  2. Department of Neurosurgery, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Road, Kaohsiung, Taiwan, Republic of China

    Chih-Zen Chang, Shu-Chuan Wu, Chih-Long Lin, Shiuh-Lin Hwang, Shen-Long Howng & Aij-Lie Kwan

  3. Department of Neurosurgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

    Chih-Zen Chang

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  1. Chih-Zen Chang
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Correspondence to Shen-Long Howng.

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Comments

Treatment of SAH related vasospasm remains a major clinical problem, for which new vasoactive and neuroprotective drug therapies are very much needed.

Quite recently, prior use of statins has been reported to reduce SAH related neurological deficits. Although clinical studies on the subject have been controversial, a recent meta-analysis confirms the beneficial effect of statin using on SAH induced vasospasm, ischemic deficits, and neurological injury (1). The molecular basis for the protective effect of statins after SAH is a subject of intense investigation.

Another promising drug therapy for vasospasm are endothelin antagonists that are undergoing clinical trials for the treatment of SAH induced vasospasm. The molecular basis for their use in vasospasm has been well demonstrated in animal models of SAH.

The data reported by Chang et al. shows that statin use prior to SAH reduces SAH related vasospasm and neurological deficits by increasing eNOS production and decreasing endothelin-1 levels, which might suggest that atorvastatin preconditioned rats, had a healthier endothelium or a less severe inflammatory response as a reaction to the SAH.

This study by Chang et al. links the effects of statins to the biology of endothelins, which are well documented to have an important role in vasospasm in animal models. As such, this study contributes to our understanding of why statin use may be beneficial for SAH patients.

1. Sillberg VA, Wells GA, Perry JJ. Do Statins Improve Outcomes and Reduce the Incidence of Vasospasm After Aneurysmal Subarachnoid Hemorrhage? A Meta-Analysis. Stroke 2008;39:2622-2626.

Juhana Frösen

Mika Niemelä

Juha Hernesniemi

Helsinki, Finland

Aij-Lie Kwan same contribution as the first author.

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Chang, CZ., Wu, SC., Lin, CL. et al. Atorvastatin preconditioning attenuates the production of endothelin-1 and prevents experimental vasospasm in rats. Acta Neurochir 152, 1399–1406 (2010). https://doi.org/10.1007/s00701-010-0652-3

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  • DOI: https://doi.org/10.1007/s00701-010-0652-3

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