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Effective Improvement of the Cerebral Vasospasm After Subarachnoid Hemorrhage with Low-Dose Nitroglycerin

Ito, Yoshifumi; Isotani, Eiji; Mizuno, Yusuke; Azuma, Hiroshi*; Hirakawa, Kimiyoshi

Journal of Cardiovascular Pharmacology: January 2000 - Volume 35 - Issue 1 - p 45-50

In the rabbit subarachnoid hemorrhage (SAH) model, the sensitivity of spastic basilar arteries to nitric oxide (NO) was enhanced whereas the endothelial function to release/produce NO became impaired, as described previously. We assumed from these results that low-dose NO might selectively dilate spastic arteries without influencing normal or systemic blood vessels; therefore, we investigated whether exogenous low-dose NO effectively improves cerebral vasospasm. Low-dose NO was derived from a small size of the tape containing nitroglycerin, which is not invasive and is clinically available. The experimental SAH was induced by injecting autologous blood into the cisterna magna of the rabbit. Experiments were performed on the following three groups: (a) SAH group with nitroglycerin tape (nitroglycerin group), (b) SAH group with placebo tape (placebo group), and (c) saline group injected with saline instead of blood. The tape containing 0.675 mg nitroglycerin was applied once daily for 2 days onto the skin area of the rabbit's ear. Angiograms were performed once before cisternal injection of blood and/or saline and again on day 2. On day 2 the basilar artery was isolated and sliced into 2-mm ring preparations. Relaxations of the basilar artery to acetylcholine, sodium nitroprusside, and calcium ionophore A23187, as well as the contractile responses to serotonin and endothelin-1, were measured. The diameter of the basilar artery on day 2 was reduced to 69.6 ± 2.2% (n = 7) before the injection of autologous blood. The angiographic vasospasm of the basilar artery was partially but significantly (p < 0.0001) improved to the percentage diameter of 89.4 ± 1.4% (n = 7) by the application of low-dose nitroglycerin, which did not affect the systemic blood pressure and heart rate. In the basilar artery preparations harvested from SAH rabbits on day 2, the impaired acetylcholine-induced endothelium-dependent relaxation was partially but significantly (p < 0.001) improved in the nitroglycerin group. However, this group remained unaffected in the increased sensitivity to nitroglycerin and the contractile responses to serotonin and endothelin-1. Low-dose nitroglycerin tape effectively improved the cerebral vasospasm after SAH without any significant changes in the systemic circulation and would be one of the useful and noninvasive treatments for cerebral vasospasm. The results seem to be partially affected by the effective dilation of the spastic artery and the improvement of the impaired endothelium-dependent relaxation with low-dose NO.

Department of Neurosurgery, School of Medicine, and *Department of Medicinal Chemistry, Institute for Medical and Dental Engineering, Tokyo Medical and Dental University, Tokyo, Japan

Received October 30, 1998; revision accepted August 9, 1999.

Address correspondence and reprint requests to Dr. Y. Ito at Department of Neurosurgery, School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan. E-mail:

© 2000 Lippincott Williams & Wilkins, Inc.