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The effects of an intracellular calcium antagonist HA 1077 on delayed cerebral vasospasm in dogs

Acta Neurochirurgica volume 90, pages 53–59 (1988)Cite this article

Summary

The effectiveness of calcium antagonists on a chronic cerebral vasospasm after an SAH is still under debate. Calcium channel blockers such as nimodipine, nefedipine etc. can dilate spastic arteries by intrathecal administration, but not by systemic (iv or po) use. HA 1077 is a novel and potent calcium antagonist vasodilator which is considered to act by employing different mechanisms from the usual calcium channel blockers since it inhibits 1. calcium ionophore A 23187 induced contraction in arterial strips and 2. phenylephrine induced contraction in calcium free media, suggesting that its site of action is in the intracellular space. HA 1077 is water soluble and relatively stable in light.

In the present study, the efficacy of HA 1077 was evaluated on dogs by using the spiral arterial strips in vitro and by angiography in vivo. In the arterial strips from the control dogs, a 50% relaxation of KCl (15 mM) induced contraction was obtained by a 10−6 M HA 1077 for the “intracranial” basilar and middle cerebral arteries, while a 10−5 M was needed to obtain the same effect for the “extracranial” common carotid and vertebral arteries, indicating that HA 1077 is more effective for the intracranial arteries. A vasospasm was produced by the “two haemorrhage” model of Varsoset al. The average angiographic diameter of the basilar artery was reduced to 60% of the control on SAH day 7. Intravenous infusion of HA 1077 (0.5–3 mg/kg/30 min) significantly dilated the spastic basilar artery (up to 20–30%), for over 2 hours. A fall in the systemic BP remained less than 20% during this time. Such spasmolytic effects by intravenous administration could not have been obtained with the usual calcium channel blockers. HA 1077 may be suitable for the treatment of a vasospasm in humans as well.

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References

  1. Allen GS (1977) Cerebral arterial spasm: A discussion of present and future research. Neurosurgery 1: 142–148

    Google Scholar 

  2. Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SG, Chou SN, Kelly DL, Weir BK, Crabbe RA, Lavik PJ, Rosenbloom SB, Dorsey FC, Ingram CR, Mellits DE, Bertsch LA, Boisvert DP, Hundley MB, Johnson RK, Strom JA, Transou CR (1983) Cerebral arterial spasm—A controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 308: 619–624

    Google Scholar 

  3. Asano T, Hidaka H (1985) Intracellular Ca++ antagonist, HA 1044: Pharmacological properties different from those of nicardipine. J Pharmacol Exp Ther 233: 454–458

    Google Scholar 

  4. Auer LM, Ito Z, Suzuki A, Ohta H (1982) Prevention of symptomatic vasospasm by topically applied nimodipine. Acta Neurochir (Wien) 63: 297–302

    Google Scholar 

  5. Auer LM, Schneider GH, Auer T (1986) Computerized tomography and prognosis in early aneurysm surgery. J Neurosurg 65: 217–221

    Google Scholar 

  6. Barry KJ, Mikkelsen RB, Shucart W, Kenough EM, Garvis V (1985) Isolation and characterization of calcium-accumulating sub-cellular membrane fractions from cerebral arteries. J Neurosurg 62: 729–736

    Google Scholar 

  7. Espinosa F, Weir B, Overton T, Castor W, Grace M, Boisvert D (1984) A randomized placebo-controlled double blind trial of nimodipine after SAH in monkeys Part 1: Clinical and radiological findings. J Neurosurg 60: 1167–1175

    Google Scholar 

  8. Fleckenstein A (1977) Specific pharmacology of calcium in myocardium, cardiac pacemakers and vascular smooth muscle. Ann Rev Pharmacol Toxicol 17: 149–166

    Google Scholar 

  9. Frazee JG, Bevan JA, Bevan RD, Jones KR (1985) Effect of diltiazem on experimental chronic cerebral vasospasm in the monkey. J Neurosurg 62: 912–917

    Google Scholar 

  10. Gioia AE, White RP, Bakhitian B, Robertson JT (1985) Evaluation of the efficacy of intrathecal nimodipine in canine models of chronic cerebral vasospasm. J Neurosurg 62: 721–728

    Google Scholar 

  11. Grotenhuis JA, Bettag W, Fiebach O, Dabir K (1984) Intracarotid slow bolus injection of nimodipine during angiography for treatment of cerebral vasospasm after SAH. J Neurosurg 61: 231–240

    Google Scholar 

  12. Hartshorne DJ, Mrwa U (1982) Regulation of smooth muscle actomyosin. Blood Vessels 19: 1–18

    Google Scholar 

  13. Hayashi S, Toda N (1977) Inhibition by Cd2+, verapamil and papaverine of Ca2+-induced contractions in isolated cerebral and peripheral arteries of the dog. Br J Pharmacol 60: 35–43

    Google Scholar 

  14. Ishikawa T, Inagaki M, Watanabe M, Hidaka H (1985) Relaxation of vascular smooth muscle by HA-1004, an inhibitor of cyclic nucleotide-dependent protein kinase. J Pharmacol Exp Ther 235: 495–499

    Google Scholar 

  15. Kassell NF, Sasaki T, Colohan ART, Nazar G (1985) Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 16: 562–572

    Google Scholar 

  16. Kazda S, Towart R (1982) Nimodipine: a new calcium antagonist drug with a preferential cerebrovascular action. Acta Neurochir (Wien) 63: 259–265

    Google Scholar 

  17. Krueger C, Weir B, Nosko M, Cook D, Norris S (1985) Nimodipine and chronic vasospasm in monkeys: Part 2: Pharmacological studies of vessels in spasm. Neurosurgery 16: 137–140

    Google Scholar 

  18. Nosko M, Weir B, Krueger C, Cook D, Norris S, Overton T, Boisvert D (1985) Nimodipine and chronic vasospasm in monkeys: Part 1: Clinical and radiological findings. Neurosurgery 16: 129–136

    Google Scholar 

  19. Saito I, Ueda Y, Sano K (1977) Significance of vasospasm in the treatment of ruptured intracranial aneurysms. J Neurosurg 47: 412–429

    Google Scholar 

  20. Saveland H, Ljunggren B, Brandt L, Messeter K (1986) Delayed ischemic deterioration in patients with early aneurysm operation and intravenous nimodipine. Neurosurgery 18: 146–150

    Google Scholar 

  21. Takayasu M, Suzuki Y, Shibuya M, Asano T, Kanamori M, Okada T, Kageyama N, Hidaka H (1986) The effects of HA compound calcium antagonists on delayed cerebral vasospasm in dogs. J Neurosurg 65: 80–85

    Google Scholar 

  22. Toda N, Ozaki T, Ohta T (1977) Cerebrovascular sensitivity to vasoconstricting agents induced by subarachnoid hemorrhage and vasospasm in dogs. J Neurosurg 46: 293–303

    Google Scholar 

  23. Varsos VG, Liszczak TM, Han DH, Kistler JP, Vielma J, Black PM, Heros RC, Zervas NT (1983) Delayed cerebral vasospasm is not reversible by aminophyllme, nifedipine, or papaverine in a “two-hemorrhage” canine model. J Neurosurg 58: 11–17

    Google Scholar 

  24. Voldby B, Peterson OF, Buhl M, Jakobson P, Ostergaard R (1984) Reversal of cerebral arterial spasm by intrathecal administration of a calcium antagonist (Nimodipine). Acta Neurochir (Wien) 70: 243–254

    Google Scholar 

  25. Weir B (1984) Calcium antagonists, cerebral ischemia and vasospasm. Can J Neurol Sci 11: 239–246

    Google Scholar 

  26. White RP (1979) Multiplex origins of cerebral vasospasm. In: Price TR, Nelson E (eds) Princeton conference on cerebrovascular diseases. Raven Press, New York, pp 307–319

    Google Scholar 

  27. Zabramski J, Spetzler RF, Bonstelle C (1986) Chronic cerebral vasospasm: Effect of calcium antagonists. Neurosurgery 18: 129–135

    Google Scholar 

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Author notes

  1. M. Shibuya

    Present address: Department of Neurosurgery, Nagoya University, Nagoya, Japan

Affiliations

  1. Department of Neurosurgery, Nagoya University, Nagoya, Japan

    Y. Suzuki, M. Takayasu, T. Asano, T. Harada, I. Ikegaki & S. Satoh

  2. Department of Pharmacology, Nagoya University, Nagoya, Japan

    H. Hidaka

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  1. M. Shibuya
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  2. Y. Suzuki
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  3. M. Takayasu
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  4. T. Asano
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  5. T. Harada
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  6. I. Ikegaki
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  7. S. Satoh
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  8. H. Hidaka
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Shibuya, M., Suzuki, Y., Takayasu, M. et al. The effects of an intracellular calcium antagonist HA 1077 on delayed cerebral vasospasm in dogs. Acta neurochir 90, 53–59 (1988). https://doi.org/10.1007/BF01541267

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  • DOI: https://doi.org/10.1007/BF01541267

Keywords

  • Calcium antagonist
  • chronic cerebral vasospasm
  • HA 1077
  • subarachnoid haemorrhage