EREBRAL arterial vasospasm is the leading cause of morbidity and mortality in patients who survive subarachnoid hemorrhage (SAH). 24 Oxyhemoglo- bin (HbO 2 ) appears to be responsible for producing vaso- spasm post-SAH. 8,10,14,25,29,30,40,42 Experimental evidence has indicated that the iron in HbO 2 causes vasospasm by gen- erating free radicals and lipid peroxides. 2–4,7,27,40,42 Al- though it is the ferrous (Fe ++ ) state of iron that catalyzes these reactions, proponents of the free radical hypothesis have studied only chelators of ferric (Fe +++ ), or free iron, 13,18,47 such as deferoxamine, as potential therapies for vasospasm and thus have had only limited success. Other authors propose that vasospasm results from a regional disruption in the balance of vasoconstrictive and vasodilatory regulation. Vasodilation is normally main- tained by nitric oxide (NO) 12,20,21,31 and/or other dilators. 28,34 The NO binds to the heme moiety of the enzyme guanyl cyclase, which catalyzes the conversion of guanosine tri- phosphate to cyclic guanosine-59-phosphate in smooth- muscle cells and thereby decreases intracellular free cal- cium levels, causing vascular smooth-muscle cells to relax. 31 The heme moiety of guanyl cyclase is ferrous. 43 Because NO preferentially reacts with Fe ++ , we believe that the ferrous component of HbO 2 competitively binds NO in SAH, limiting the availability of NO for vasodi- lation. We hypothesized that the Fe ++ liberated post-SAH in- duces vasospasm, either by catalyzing the generation of free radicals or by quenching NO and that chelating Fe ++ should prevent vasospasm. We examined this hypothesis in a primate model of SAH and 2,29-dipyridyl, a chelator of Fe ++ that acts intracellularly and evidently penetrates the blood-brain barrier. Materials and Methods Twelve cynomolgus monkeys (eight males and four females), each weighing between 3 and 7.2 kg, were randomly divided into two groups. Craniotomies were performed in all animals and an autologous blood clot was placed around the right middle cerebral artery (MCA) after the arachnoid membrane was removed, as described elsewhere. 11,39 Seven animals (three males and four females) received a continuous intravenous infusion of 2,29-dipy- ridyl (70 mg/kg) for 14 days. Five male control animals received an intravenous infusion of saline, the vehicle for the dipyridyl solution, in a volume equal to that delivered in the experimental group (10–15 ml/kg/day). Two additional animals were used in a pilot J Neurosurg 88:298–303, 1998 298 Role of ferrous iron chelator 2,29-dipyridyl in preventing delayed vasospasm in a primate model of subarachnoid hemorrhage LAURA L. HORKY, M.D., RYSZARD M. PLUTA, M.D., PH.D., ROBERT J. BOOCK, PH.D., AND EDWARD H. OLDFIELD, M.D. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland Object. Oxyhemoglobin (HbO 2 ) causes vasospasm after subarachnoid hemorrhage (SAH). The most likely spasmo- genic component of HbO 2 is iron. Various iron chelators, such as deferoxamine, have prevented vasospasm in vivo with limited success. However, only chelators of iron in the ferric state have been studied in animal models of vasospasm after SAH. Because free radical formation requires the ferrous (Fe ++ ) moiety and Fe ++ is a potent binder of the vasodila- tor nitric oxide, the authors hypothesized that iron in the ferrous state causes vasospasm and that chelators of Fe ++ , such as 2,29-dipyridyl, may prevent vasospasm. This study was undertaken to investigate the influence of 2,29-dipyridyl on vasospasm after induction of SAH in a primate model. Methods. Twelve cynomolgus monkeys were randomly divided into two groups and then both groups underwent placement of an arterial autologous blood clot in the subarachnoid space around the right middle cerebral artery (MCA). The five animals in the control group received intravenously administered saline and the seven treated animals received intravenously administered chelator (2,29-dipyridyl) for 14 days. Sequential arteriography for assessment of MCA diameter was performed before and on the 7th day after SAH. Conclusions. Prevention of cerebral vasospasm by means of treatment with continuous intravenous administration of 2,29-dipyridyl is reported in a primate model of SAH. This result provides insight into the possible mechanism of delayed vasospasm after aneurysmal SAH and provides a potential preventive therapy for it. KEY WORDS • vasospasm • subarachnoid hemorrhage • ferrous iron chelator • dipyridyl • cynomolgus monkey C J. Neurosurg. / Volume 88 / February, 1998