Abstract
Introduction
Cerebral vasospasm is a severe complication of subarachnoid hemorrhage (SAH). The calcium channel inhibitor nimodipine has been used for treatment of cerebral vasospasm. No evidence-based recommendations for local nimodipine administration at the site of vasospasm exist. The purpose of this study was to quantify nimodipine's local vasodilatory effect in an ex vivo model of SAH-induced vasospasm.
Methods
SAH-induced vasospasm was modeled by contracting isolated segments of rat superior cerebellar arteries with a combination of serotonin and a synthetic analog of prostaglandin A2. A pressure myograph system was used to determine vessel reactivity of spastic as well as non-spastic arteries.
Results
Compared to the initial vessel diameter, a combination of serotonin and prostaglandin induced considerable vasospasm (55 ± 2.5 % contraction; n = 12; p < 0.001). Locally applied nimodipine dilated the arteries in a concentration-dependent manner starting at concentrations as low as 1 nM (n = 12; p < 0.05). Concentrations higher than 100 nM did not relevantly increase the vasodilatory effect. Nimodipine's vasodilatory effect was smaller in spastic than in non-spastic vessels (n = 12; p < 0.05), which we assume to be due to structural changes in the vessel wall.
Conclusion
The described ex vivo model allows to investigate the dose-dependent efficacy of spasmolytic drugs prior to in vivo experiments. Low concentrations of locally applied nimodipine have a strong vasodilatory effect, which is of relevance when considering the local application of nimodipine in cerebral vasospasm.
Similar content being viewed by others
References
Keyrouz SG, Diringer MN (2007) Clinical review: prevention and therapy of vasospasm in subarachnoid hemorrhage. Crit Care 11(4):220
Sehba FA, Bederson JB (2006) Mechanisms of acute brain injury after subarachnoid hemorrhage. Neurol Res 28(4):381–398
Al-Tamimi YZ, Orsi NM, Quinn AC, Homer-Vanniasinkam S, Ross SA (2010) A review of delayed ischemic neurologic deficit following aneurysmal subarachnoid hemorrhage: historical overview, current treatment, and pathophysiology. World Neurosurg 73(6):654–667
Kassell NF, Helm G, Simmons N, Phillips CD, Cail WS (1992) Treatment of cerebral vasospasm with intra-arterial papaverine. J Neurosurg 77(6):848–852
Harrod CG, Bendok BR, Batjer HH (2005) Prediction of cerebral vasospasm in patients presenting with aneurysmal subarachnoid hemorrhage: a review. Neurosurgery 56(4):633–654, discussion 633–654
Allen GS, Henderson LM, Chou SN, French LA (1974) Cerebral arterial spasm. 1. In vitro contractile activity of vasoactive agents on canine basilar and middle cerebral arteries. J Neurosurg 40(4):433–441
Allen GS, Henderson LM, Chou SN, French LA (1974) Cerebral arterial spasm. 2. In vitro contractile activity of serotonin in human serum and CSF on the canine basilar artery, and its blockage by methylsergide and phenoxybenzamine. J Neurosurg 40(4):442–450
Allen GS, Gold LH, Chou SN, French LA (1974) Cerebral arterial spasm. 3. In vivo intracisternal production of spasm by serotonin and blood and its reversal by phenoxybenzamine. J Neurosurg 40(4):451–458
Allen GS, Gross CJ, Henderson LM, Chou SN (1976) Cerebral arterial spasm. Part 4: in vitro effects of temperature, serotonin analogues, large nonphysiological concentrations of serotonin, and extracellular calcium and magnesium on serotonin-induced contractions of the canine basilar artery. J Neurosurg 44(5):585–593
van Gijn J, Rinkel GJE (2001) Subarachnoid haemorrhage: diagnosis, causes and management. Brain 124(2):249–278
Bederson JB, Levy AL, Ding WH et al (1998) Acute vasoconstriction after subarachnoid hemorrhage. Neurosurgery 42(2):352–360, discussion 360–362
Kimball M, Velat G, Hoh B (2011) The participants in the International Multi-disciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage. Critical care guidelines on the endovascular management of cerebral vasospasm. Neurocrit Care 15(2):336–341
Kazda S, Towart R (1982) Nimodipine: a new calcium antagonistic drug with a preferential cerebrovascular action. Acta Neurochir (Wien) 63(1–4):259–265
Kazda S, Garthoff B, Krause HP, Schlossmann K (1982) Cerebrovascular effects of the calcium antagonistic dihydropyridine derivative nimodipine in animal experiments. Arzneimittelforschung 32(4):331–338
Freedman DD, Waters DD (1987) “Second generation” dihydropyridine calcium antagonists. Greater vascular selectivity and some unique applications. Drugs 34(5):578–598
Allen GS (1985) Role of calcium antagonists in cerebral arterial spasm. Am J Cardiol 55(3):149B–153B
Brandt L, Andersson KE, Ljunggren B, Säveland H, Ryman T (1988) Cerebrovascular and cerebral effects of nimodipine—an update. Acta Neurochir Suppl (Wien) 45:11–20
Langley MS, Sorkin EM (1989) Nimodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cerebrovascular disease. Drugs 37(5):669–699
Ahmed N, Näsman P, Wahlgren NG (2000) Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Stroke 31(6):1250–1255
Wadworth AN, McTavish D (1992) Nimodipine. A review of its pharmacological properties, and therapeutic efficacy in cerebral disorders. Drugs Aging 2(4):262–286
Biondi A, Ricciardi GK, Puybasset L et al (2004) Intra-arterial nimodipine for the treatment of symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage: preliminary results. AJNR Am J Neuroradiol 25(6):1067–1076
Firat MM, Gelebek V, Orer HS, Belen D, Firat AK, Balkanci F (2005) Selective intraarterial nimodipine treatment in an experimental subarachnoid hemorrhage model. AJNR Am J Neuroradiol 26(6):1357–1362
Hänggi D, Turowski B, Beseoglu K, Yong M, Steiger HJ (2008) Intra-arterial nimodipine for severe cerebral vasospasm after aneurysmal subarachnoid hemorrhage: influence on clinical course and cerebral perfusion. AJNR Am J Neuroradiol 29(6):1053–1060
Hui C, Lau KP (2005) Efficacy of intra-arterial nimodipine in the treatment of cerebral vasospasm complicating subarachnoid haemorrhage. Clin Radiol 60(9):1030–1036
Mayer T, Dichgans M, Straube A et al (2008) Continuous intra-arterial nimodipine for the treatment of cerebral vasospasm. Cardiovasc Interv Radiol 31(6):1200–1204
Sahlin C, Owman C, Chang J-Y, Delgado T, Salford LG, Svendgaard N-A (1990) Changes in contractile response and effect of a calcium antagonist, nimodipine, in isolated intracranial arteries of baboon following experimental subarachnoid hemorrhage. Brain Res Bull 24(3):355–361
Ishiguro M, Wellman TL, Honda A, Russell SR, Tranmer BI, Wellman GC (2005) Emergence of a R-Type Ca2+ Channel (CaV 2.3) Contributes to cerebral artery constriction after subarachnoid hemorrhage. Circ Res 96(4):419–426
Martinez-Lemus LA, Hill MA, Bolz SS, Pohl U, Meininger GA (2004) Acute mechanoadaptation of vascular smooth muscle cells in response to continuous arteriolar vasoconstriction: implications for functional remodeling. FASEB J 18(6):708–710
Hill MA, Potocnik SJ, Martinez-Lemus LA, Meininger GA (2003) Delayed arteriolar relaxation after prolonged agonist exposure: functional remodeling involving tyrosine phosphorylation. Am J Physiol Heart Circ Physiol 285(2):H849–H856
Salomone S, Soydan G, Moskowitz M (2009) Sims. Inhibition of cerebral vasoconstriction by dantrolene and nimodipine. Neurocrit Care 10(1):93–102
Fischer J-G, Mewes H, Hopp H-H, Schubert R (1996) Analysis of pressurized resistance vessel diameter changes with a low cost digital image processing device. Comput Methods Programs Biomed 50(1):23–30
Anschütz S, Schubert R (2005) Modulation of the myogenic response by neurogenic influences in rat small arteries. Br J Pharmacol 146(2):226–233
Schubert R (2011) Isolated vessels. In: Dhein S, Mohr FW, Delmar M (eds) Practical methods in cardiovascular research. Berlin/Heidelberg: Springer-Verlag; :198–211. Available at: http://www.springerlink.com/content/n1865n4688292807/. Accessed November 9
Vinall PE, Michele JJ, Gordon DA, Simeone FA (1989) Comparison of intraluminally versus extraluminally administered nimodipine on serotonin-induced cerebral vascular responses in vitro and in situ. Stroke 20(8):1065–1070
Chyatte D, Sundt TM Jr (1984) Cerebral vasospasm after subarachnoid hemorrhage. Mayo Clin Proc 59(7):498–505
Tanabe Y, Sakata K, Yamada H, Ito T, Takada M (1978) Cerebral vasospasm and ultrastructural changes in cerebral arterial wall. An experimental study. J Neurosurg 49(2):229–238
Macdonald RL, Weir BK, Grace MG, Chen MH, Martin TP, Young JD (1992) Mechanism of cerebral vasospasm following subarachnoid hemorrhage in monkeys. Can J Neurol Sci 19(4):419–427
Pluta RM, Hansen-Schwartz J, Dreier J et al (2009) Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res 31(2):151–158
Falloon BJ, Stephens N, Tulip JR, Heagerty AM (1995) Comparison of small artery sensitivity and morphology in pressurized and wire-mounted preparations. Am J Physiol Heart Circ Physiol 268(2), H670–H678
Mulvany MJ, Aalkjaer C (1990) Structure and function of small arteries. Physiol Rev 70(4):921–961
Schambach SJ, Bag S, Steil V et al (2009) Ultrafast high-resolution in vivo volume-cta of mice cerebral vessels. Stroke 40(4):1444–1450
Humphrey JD, Baek S, Niklason LE (2007) Biochemomechanics of cerebral vasospasm and its resolution. Ann Biomed Eng 35(9):1485–1497
Anderson GB, Ashforth R, Steinke DE, Findlay JM (2000) CT Angiography for the detection of cerebral vasospasm in patients with acute subarachnoid hemorrhage. Am J Neuroradiol 21(6):1011–1015
Delgado TJ, Brismar J, Svendgaard NA (1985) Subarachnoid haemorrhage in the rat: angiography and fluorescence microscopy of the major cerebral arteries. Stroke 16(4):595–602
Suzuki H, Kanamaru K, Tsunoda H et al (1999) Heme oxygenase-1 gene induction as an intrinsic regulation against delayed cerebral vasospasm in rats. J Clin Invest 104(1):59–66
McKenzie C, MacDonald A, Shaw A (2009) Mechanisms of U46619-induced contraction of rat pulmonary arteries in the presence and absence of the endothelium. Br J Pharmacol 157(4):581–596
Alapati VR, McKenzie C, Blair A, Kenny D, MacDonald A, Shaw AM (2007) Mechanisms of U46619- and 5-HT-induced contraction of bovine pulmonary arteries: role of chloride ions. Br J Pharmacol 151(8):1224–1234
Baek S, Valentín A, Humphrey J (2007) Biochemomechanics of cerebral vasospasm and its resolution: ii. constitutive relations and model simulations. Ann Biomed Eng 35(9):1498–1509
Dreier J, Vajkoczy P, Macdonald RL et al (2009) Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res 31(2):151–158
Dzau VJ, Gibbons GH (1993) Vascular remodeling: mechanisms and implications. J Cardiovasc Pharmacol 21(Suppl 1):1–5
Langille BL (1996) Arterial remodeling: relation to hemodynamics. Can J Physiol Pharmacol 74(7):834–841
Wellman GC (2006) Ion channels and calcium signaling in cerebral arteries following subarachnoid hemorrhage. Neurol Res 28(7):690–702
Rämsch KD, Ahr G, Tettenborn D, Auer LM (1985) Overview on pharmacokinetics of nimodipine in healthy volunteers and in patients with subarachnoid hemorrhage. Neurochirurgia (Stuttg) 28(Suppl 1):74–78
Conflict of interest
We declare that we have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Seker, F., Hesser, J., Neumaier-Probst, E. et al. Dose–response relationship of locally applied nimodipine in an ex vivo model of cerebral vasospasm. Neuroradiology 55, 71–76 (2013). https://doi.org/10.1007/s00234-012-1079-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00234-012-1079-8