Abstract
Azelnidipine is a new dihydropyridine calcium channel blocker that causes minimal stimulation of the sympathetic nervous system despite its significant depressor effect. In the present study, we examined the effects of oral or intravenous administration of azelnidipine on cardiovascular and renal sympathetic nerve activity (RSNA) responses to air-jet stress in conscious, unrestrained stroke-prone spontaneously hypertensive rats. Oral administration of high-dose azelnidipine (10 mg/kg per day) or nicardipine (150 mg/kg per day) for 10 days caused a significant and comparable decrease in blood pressure, but low-dose azelnidipine (3 mg/kg per day) did not. Air-jet stress increased mean arterial pressure (MAP), heart rate (HR) and RSNA. High-dose azelnidipine significantly attenuated the increases in MAP, HR and RSNA in response to air-jet stress while nicardipine did not. Low-dose azelnidipine significantly attenuated the pressor response with a trend of decrease in RSNA. Intravenous injection of azelnidipine induced a slowly developing depressor effect. To obtain a similar time course of decrease in MAP by azelnidipine, nicardipine was continuously infused at adjusted doses. Both drugs increased HR and RSNA significantly, while the change in RSNA was smaller in the azelnidipine group. In addition, intravenous administration of azelnidipine attenuated the responses of MAP, HR, and RSNA to air-jet stress; by comparison, the inhibitory actions of nicardipine were weak. In conclusion, oral or intravenous administration of azelnidipine inhibited cardiovascular and sympathetic responses to air-jet stress. This action of azelnidipine may be mediated at least in part by the inhibition of the sympathetic nervous system.
Similar content being viewed by others
Article PDF
References
Alderman MH, Cohen H, Roque R, Madhavan S : Effect of long-acting and short-acting calcium antagonists on cardiovascular outcomes in hypertensive patients. Lancet 1997; 349: 594–598.
Grossman E, Messerli FH : Effect of calcium antagonists on sympathetic activity. Eur Heart J 1998; 19: F27–F31.
Grossman E, Messerli FH : Effect of calcium antagonists on plasma norepinephrine levels, heart rate, and blood pressure. Am J Cardiol 1997; 80: 1453–1458.
Binggeli C, Corti R, Sudano I, Luscher TF, Noll G : Effects of chronic calcium channel blockade on sympathetic nerve activity in hypertension. Hypertension 2002; 39: 892–896.
Esler M : The sympathetic system and hypertension. Am J Hypertens 2000; 13: 99S–105S.
Julius S : Effect of sympathetic overactivity on cardiovascular prognosis in hypertension. Eur Heart J 1998; 19: F14–F18.
Mancia G, Grassi G, Giannattasio C, Seravalle G : Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. Hypertension 1999; 34: 724–728.
McDougall SJ, Paull JR, Widdop RE, Lawrence AJ : Restraint stress: differential cardiovascular responses in Wistar-Kyoto and spontaneously hypertensive rats. Hypertension 2000; 35: 126–129.
Kaushik RM, Mahajan SK, Rajesh V, Kaushik R : Stress profile in essential hypertension. Hypertens Res 2004; 27: 619–624.
Kamarck TW, Eranen J, Jennings JR, et al: Anticipatory blood pressure responses to exercise are associated with left ventricular mass in Finnish men: Kuopio Ischemic Heart Disease Risk Factor Study. Circulation 2000; 102: 1394–1399.
Jennings JR, Kamarck TW, Everson-Rose SA, Kaplan GA, Manuck SB, Salonen JT : Exaggerated blood pressure responses during mental stress are prospectively related to enhanced carotid atherosclerosis in middle-aged Finnish men. Circulation 2004; 110: 2198–2203.
Gianaros PJ, Bleil ME, Muldoon MF, et al: Is cardiovascular reactivity associated with atherosclerosis among hypertensives? Hypertension 2002; 40: 742–747.
Zakopoulos NA, Tsivgoulis G, Barlas G, et al: Time rate of blood pressure variation is associated with increased common carotid artery intima-media thickness. Hypertension 2005; 45: 505–512.
Waldstein SR, Siegel EL, Lefkowitz D, et al: Stress-induced blood pressure reactivity and silent cerebrovascular disease. Stroke 2004; 35: 1294–1298.
Kuramoto K, Ichikawa S, Hirai A, Kanada S, Nakachi T, Ogihara T : Azelnidipine and amlodipine: a comparison of their pharmacokinetics and effects on ambulatory blood pressure. Hypertens Res 2003; 26: 201–208.
Yamazato M, Sakima A, Nakazato J, Sesoko S, Muratani H, Fukiyama K : Hypotensive and sedative effects of clonidine injected into the rostral ventrolateral medulla of conscious rats. Am J Physiol Regul Integr Comp Physiol 2001; 281: R1868–R1876.
Sakima A, Yamazato M, Sesoko S, Muratani H, Fukiyama K : Cardiovascular and sympathetic effects of L-glutamate and glycine injected into the rostral ventrolateral medulla of conscious rats. Hypertens Res 2000; 23: 633–641.
Takishita S, Muratani H, Kawazoe N, Tozawa M, Kimura Y, Fukiyama K : Acute effects of manidipine on renal blood flow and sympathetic nerve activity in conscious, spontaneously hypertensive rats. Blood Press 1992; 3: 53–59.
Hosono M, Hiruma T, Watanabe K, et al: Inhibitory effect of cilnidipine on pressor response to acute cold stress in spontaneously hypertensive rats. Jpn J Pharmacol 1995; 69: 119–125.
Mayorov DN, Head GA : AT1 receptors in the RVLM mediate pressor responses to emotional stress in rabbits. Hypertension 2003; 41: 1168–1173.
Zimmerman MC, Lazartigues E, Lang JA, et al: Superoxide mediates the actions of angiotensin II in the central nervous system. Circ Res 2002; 91: 1038–1045.
Gao L, Wang W, Li YL, et al: Sympathoexcitation by central ANG II: roles for AT1 receptor upregulation and NAD(P)H oxidase in RVLM. Am J Physiol Heart Circ Physiol 2005; 288: H2271–H2279.
Mayorov DN, Head GA, De Matteo R : Tempol attenuates excitatory actions of angiotensin II in the rostral ventrolateral medulla during emotional stress. Hypertension 2004; 44: 101–106.
Kishi T, Hirooka Y, Kimura Y, Ito K, Shimokawa H, Takeshita A : Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation 2004; 109: 2357–2362.
Hirooka Y, Sakai K, Kishi T, Ito K, Shimokawa H, Takeshita A : Enhanced depressor response to endothelial nitric oxide synthase gene transfer into the nucleus tractus solitarii of spontaneously hypertensive rats. Hypertens Res 2003; 26: 325–331.
Hirooka Y, Kimura Y, Nozoe M, Sagara Y, Ito K, Sunagawa K : Amlodipine-induced reduction of oxidative stress in the brain is associated with sympatho-inhibitory effects in stroke-prone spontaneously hypertensive rats. Hypertens Res 2006; 29: 49–56.
Jinno T, Iwai M, Li Z, et al: Calcium channel blocker azelnidipine enhances vascular protective effects of AT1 receptor blocker olmesartan. Hypertension 2004; 43: 263–269.
Yamagishi S, Inagaki Y, Nakamura K, Imaizumi T : Azelnidipine, a newly developed long-acting calcium antagonist, inhibits tumor necrosis factor-alpha–induced interleukin-8 expression in endothelial cells through its anti-oxidative properties. J Cardiovasc Pharmacol 2004; 43: 724–730.
Shinomiya K, Mizushige K, Fukunaga M, et al: Antioxidant effect of a new calcium antagonist, azelnidipine, in cultured human arterial endothelial cells. J Int Med Res 2004; 32: 170–175.
Leenen FH, Ruzicka M, Huang BS : Central sympathoinhibitory effects of calcium channel blockers. Curr Hypertens Rep 2001; 3: 314–321.
Murzenok PP, Huang BS, Leenen FH : Sympathoinhibition by central and peripheral infusion of nifedipine in spontaneously hypertensive rats. Hypertension 2000; 35: 631–636.
Huang BS, Leenen FH : Sympathoinhibitory and depressor effects of amlodipine in spontaneously hypertensive rats. J Cardiovasc Pharmacol 2003; 42: 153–160.
Shokoji T, Fujisawa Y, Kiyomoto H, et al: Effects of a new calcium channel blocker, azelnidipine, on systemic hemodynamics and renal sympathetic nerve activity in spontaneously hypertensive rats. Hypertens Res 2005; 28: 1017–1023.
Sakata K, Shirotani M, Yoshida H, et al: Effects of amlodipine and cilnidipine on cardiac sympathetic nervous system and neurohormonal status in essential hypertension. Hypertension 1999; 33: 1447–1452.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nakamoto, M., Ohya, Y., Sakima, A. et al. Azelnidipine Attenuates Cardiovascular and Sympathetic Responses to Air-Jet Stress in Genetically Hypertensive Rats. Hypertens Res 30, 359–366 (2007). https://doi.org/10.1291/hypres.30.359
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.30.359
Keywords
This article is cited by
-
Efficacy and Safety of Azelnidipine as an Antihypertensive Compared to Amlodipine: A Systematic Review and Meta-analysis
High Blood Pressure & Cardiovascular Prevention (2023)