Abstract
Calcium channel blockers have been widely used for the treatment of hypertension because several clinical trials have demonstrated their strong action on lowering blood pressure and their role in preventing cardiovascular events such as stroke and coronary heart disease. However, there have been few reports on the effects on cerebral hemodynamics when blood pressure is lowered with this class of drug. In this study, we used positron emission tomography and acetazolamide challenge tests to measure cerebral blood flow and cerebrovascular reserve before and after administration of a novel calcium channel blocker, azelnidipine, in nine hypertensive patients (mean age, 66.1 years) with ischemic white matter lesions. Systemic blood pressure was significantly decreased from baseline (153.8±15.5/92.1±8.5 mmHg) after treatment with azelnidipine (138.4±16.3/81.8±6.2 mmHg). The baseline global cerebral blood flow values before and after treatment were 40.1±7.2 mL/min/100 g and 39.2±8.2 mL/min/100 g, respectively. The cerebrovascular reserve values before and after treatment were 58.6±21.7% and 56.3±21.3%, respectively. Differences in these parameters were not significant. A regional analysis showed no statistical differences in regional cerebral blood flow or cerebral perfusion reserve throughout the brain before and after treatment. No associations between the decreased blood pressure and the changes in cerebral blood flow or cerebrovascular reserve were found in the whole brain or in the deep white matter with ischemic lesions. In conclusion, we found that the cerebral blood flow and cerebral vascular reserve were preserved after blood pressure lowering with azelnidipine administration in hypertensive patients with ischemic white matter lesions. Azelnidipine, a novel calcium channel blocker, could be a feasible antihypertensive regimen in terms of cerebral circulation in patients with ischemic white matter lesions.
Similar content being viewed by others
Article PDF
References
Goldstein LB, Adams R, Alberts MJ, et al: Primary prevention of ischemic stroke. A guideline from the American Heart Association/American Stroke Association Stroke Council cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke 2006; 37: 1583–1633.
Sacco RL, Adams R, Albers G, et al: Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Circulation 2006; 113: e409–e449.
Papadopoulos DP, Papademetriou V : Aggressive blood pressure control and stroke prevention: role of calcium channel blockers. J Hypertens 2008; 26: 844–852.
Hatazawa J, Shimosegawa E, Osaki Y, et al: Long-term angiotensin-converting enzyme inhibitor perindopril therapy improves cerebral perfusion reserve in patients with previous minor stroke. Stroke 2004; 35: 2117–2122.
Oku N, Kitagawa K, Imaizumi M, et al: Hemodynamic influences of losartan on the brain in hypertensive patients. Hypertens Res 2005; 28: 43–49.
Ogasawara K, Noda A, Yasuda S, Kobayashi M, Yukawa H, Ogawa A : Effect of calcium antagonist on cerebral blood flow and oxygen metabolism in patients with hypertension and chronic major cerebral artery occlusion: a positron emission tomography study. Nucl Med Commun 2003; 24: 71–76.
Akopov SE, Simonian NA, Kazarian AV : Effects of nifedipine and nicardipine on regional cerebral blood flow distribution in patients with arterial hypertension. Methods Find Exp Clin Pharmacol 1996; 18: 685–692.
Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM : Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam scan study. Stroke 2003; 34: 1126–1129.
Prins ND, van Dijk EJ, den Heijer T, et al: Cerebral smallvessel disease and decline in information processing speed, executive function and memory. Brain 2005; 128: 2034–2041.
Toyoda K : Cerebral white matter lesions and microbleeds: tiny but meaningful indicators of hypertensive damage. Hypertens Res 2008; 31: 3–5.
Matsushita K, Kuriyama Y, Nagatsuka K, Nakamura M, Sawada T, Omae T : Periventricular white matter lucency and cerebral blood flow autoregulation in hypertensive patients. Hypertension 1994; 23: 565–568.
Kimura Y, Hirooka Y, Sagara Y, Sunagawa K : Long-acting calcium channel blocker, azelnidipine, increases endothelial nitric oxide synthase in the brain and inhibits sympathetic nerve activity. Clin Exp Hypertens 2007; 29: 13–21.
Lukic-Panin V, Kamiya T, Zhang H, et al: Prevention of neuronal damage by calcium channel blockers with antioxidative effects after transient focal ischemia in rats. Brain Res 2007; 1176: 143–150.
Iwai M, Chen R, Ide A, et al: The calcium-channel blocker, azelnidipine, enhances the inhibitory action of AT1 receptor blockade on ischemic brain damage. J Hypertens 2006; 24: 2023–2031.
Fazekas F, Kleinert R, Offenbacher H, et al: Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 1993; 43: 1683–1689.
Kanno I, Iida H, Miura S, et al: A system for cerebral blood flow measurement using an H215O autoradiographic method and positron emission tomography. J Cereb Blood Flow Metab 1987; 7: 143–153.
Iadecola C, Davisson RL : Hypertension and cerebrovascular dysfunction. Cell Metab 2008; 7: 476–484.
Ovbiagele B, Saver JL : Cerebral white matter hyperintensities on MRI: current concepts and therapeutic implications. Cerebrovasc Dis 2006; 22: 83–90.
Haws CW, Heistad DD : Effects of nimodipine on cerebral vasoconstrictor responses. Am J Physiol 1984; 247: H170–H176.
Safar ME : Effects of lacidipine on the carotid and cerebral circulations in essential hypertension. J Cardiovasc Pharmacol 1991; 17 (Suppl 4): S51–S54.
Sabbatini M, Bellagamba G, Casado A, Tayebati SK, Venarucci D, Amenta F : Protective effect of treatment with nicardipine on cerebrovascular tree of spontaneously hypertensive rats. Clin Exp Hypertens 2001; 23: 143–155.
Grabowski M, Johansson BB : Nifedipine and nimodipine: effect on blood pressure and regional cerebral blood flow in conscious normotensive and hypertensive rats. J Cardiovasc Pharmacol 1985; 7: 1127–1133.
Farkas E, De Jong GI, Apro E, Keuker JI, Luiten PG : Calcium antagonists decrease capillary wall damage in aging hypertensive rat brain. Neurobiol Aging 2001; 22: 299–309.
Shinyama H, Nagai H, Kawamura T, Narita Y, Nakamura N, Kagitani Y : Effects of long-term treatment with the calcium antagonist AE0047 on cerebrovascular autoregulation and hypertrophy in spontaneously hypertensive rats. J Cardiovasc Pharmacol 1997; 30: 616–622.
Pitt B, Byington RP, Furberg CD, et al: Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT investigators. Circulation 2000; 102: 1503–1510.
Suzuki S, Ohtsuka S, Ishikawa K, Yamaguchi I : Effects of nicardipine on coronary, vertebral and renal arterial flows in patients with essential hypertension. Hypertens Res 2003; 26: 193–199.
Lipsitz LA, Gagnon M, Vyas M, et al: Antihypertensive therapy increases cerebral blood flow and carotid distensibility in hypertensive elderly subjects. Hypertension 2005; 45: 216–221.
Fu CH, Yang CC, Kuo TB : Effects of different classes of antihypertensive drugs on cerebral hemodynamics in elderly hypertensive patients. Am J Hypertens 2005; 18: 1621–1625.
Kaste M, Fogelholm R, Erila T, et al: A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke. Stroke 1994; 25: 1348–1353.
Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the antihypertensive and lipidlowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002; 288: 2981–2997.
Ogihara T, Nakao K, Fukui T, et al: Effects of candesartan compared with amlodipine in hypertensive patients with high cardiovascular risks: candesartan antihypertensive survival evaluation in Japan trial. Hypertension 2008; 51: 393–398.
Julius S, Kjeldsen SE, Weber M, et al: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomized trial. Lancet 2004; 363: 2022–2031.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kimura, Y., Kitagawa, K., Oku, N. et al. Hemodynamic Influences of Azelnidipine, a Novel Calcium Channel Blocker, on Cerebral Circulation in Hypertensive Patients with Ischemic White Matter Lesions. Hypertens Res 31, 2147–2154 (2008). https://doi.org/10.1291/hypres.31.2147
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.31.2147