Azelnidipine Attenuates Cardiovascular and Sympathetic Responses to Air-Jet Stress in Genetically Hypertensive Rats

Department of Cardiovascular Medicine, Nephrology and Neurology, School of Medicine, University of the Ryukyus, Okinawa, Japan.
Hypertension Research (Impact Factor: 2.66). 05/2007; 30(4):359-66. DOI: 10.1291/hypres.30.359
Source: PubMed


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.

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    • "Konno et al. reported that azelnidipine decreases an indicator of sympathetic nerve activity by an antioxidant effect mediated through inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity and activation of superoxide dismutase [23]. Azelnidipine could significantly attenuate increases of systemic blood pressure without increasing the heart rate during IMO stress [24]. Reduction of afterload by azelnidipine administration might be one mechanism of prevention. "
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    ABSTRACT: We have reported that α and β adrenergic blockers could protect against emotional stress-induced cardiac dysfunction. Azelnidipine is a unique calcium blocker which does not increase heart rate. The purpose of this study is to evaluate the effect of azelnidipine to prevent stress-induced cardiac dysfunction. Rats premedicated with azelnidipine (0.3 mg/kg), labetalol (3 mg/kg), or vehicle, were restrained for 30 min (immobilization stress: IMO) to reproduce emotional stress, and anesthetized to release stress. We measured the fractional area change (FAC) by echocardiography, blood pressure, and heart rate at the end of IMO and every 10 min for 60 min after IMO. During IMO, FAC in the labetalol group was significantly lower than that in the other two groups. At 20 min after IMO, FAC in the azelnidipine or labetalol group was significantly higher than that in the vehicle group (86 ± 9%, 73 ± 5% vs. 56 ± 11%, p<0.05). During IMO, mean blood pressure in the azelnidipine or labetalol group was significantly lower than that in the vehicle group (107 ± 5 mmHg, 106 ± 17 mmHg vs. 124 ± 5 mmHg, p<0.05). Acute administration of azelnidipine could prevent a sudden drop of cardiac function after acute stress like IMO. Azelnidipine might have a protective effect on stress-induced cardiac dysfunction like α and β adrenergic blockers.
    Preview · Article · Mar 2012 · Journal of Cardiology
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    • "Thus, azelnidipine improves the BRS, and this might result in a reduction of the heart rate mediated by the parasympathetic-dominant state. Azelnidipine is a lipophilic drug and is thought to exert effects on the central nervous system after crossing the blood—brain barrier [6] [9]. In addition, some experimental studies have demonstrated that azelnidpine might have antioxidant Figure 1 Blood pressure and heart rate determined by the oscillometric method after treatment with the two drugs. "
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    ABSTRACT: The present study was conducted to clarify whether azelnidipine might have beneficial effects on autonomic functions, and whether such beneficial effects might affect the vascular functions (i.e., arterial stiffness and endothelial function). This study with a cross-over design was conducted in 21 hypertensive patients (65 +/- 9 years old) being treated with calcium channel blockers (CCBs) other than azelnidipine or benidipine (i.e., during the study period, the CCB was switched to either azelnidipine 16 mg/day or benidipine 4 mg/day, administered alternately for 8 weeks each). Blood examinations were conducted and the heart rate variability, baro-receptor sensitivity (BRS), brachial-ankle pulse wave velocity (baPWV) and flow-mediated vasodilatation (FMD) in the brachial artery were measured after treatment with each of the two drugs. While the blood pressure levels decreased to a similar degree after both treatments, the BRS (8.8 +/- 5.5 ms/mmHg vs. 6.4 +/- 2.9 ms/mmHg, p < 0.01) and high-frequency power component (HF: 139 +/- 152 ms2/Hz vs. 88 +/- 97 ms2/Hz) were higher after treatment with azelnidipine than after treatment with benidipine (p < 0.05). However, the baPWV, FMD and plasma levels of malonyldialdehyde low-density lipoprotein cholesterol and nitric oxides were similar after treatment with both drugs. Azelnidipine has greater beneficial effects on the autonomic functions than benidipine although the degree of reduction of blood pressure induced by the two drugs was similar. However, this greater beneficial effect of azelnidipine on the autonomic functions did not produce any distinguishable differences in effects of azelnidipine and benidipine on the arterial stiffness and endothelial functions.
    Preview · Article · Apr 2008 · Journal of Cardiology
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    ABSTRACT: We examined the effects of antihypertensive drugs, exercise training, and combinations thereof on insulin sensitivity (IS), and the association between this relation and sympathetic activity, muscle fiber composition, and capillary density in spontaneously hypertensive rats (SHR). Six-week-old male SHR were allocated to 7 groups: a control group (C), and groups treated with azelnidipine (Aze) (a calcium channel blocker), olmesartan (Olm) (an angiotensin II type 1 receptor blocker), exercise training (Exe), and combinations of drugs and exercise training (Aze+Exe, Olm+Exe, and Olm+Aze+Exe). At age 18 weeks, IS and sympathetic activity were evaluated by an euglycemic hyperinsulinemic glucose clamp technique and power spectral analysis of systolic blood pressure, respectively. After the experiments, capillary density and muscle fiber composition in soleus muscle were examined. Aze or Exe alone significantly increased IS associated with a significant reduction in sympathetic activity. Olm alone tended to increase IS with little change in sympathetic activity. Aze, Olm, or Exe significantly increased the capillary density and percentage of insulin-sensitive type I fiber. A combination of Aze and Exe or a combination of Olm and Exe tended to increase IS compared with each drug therapy alone. There were significant correlations between IS and sympathetic activity, capillary density, and the percentage of type I fiber in all the rats. We found that Aze improved IS more substantially compared with Olm in SHR. We also found that Aze, Olm, Exe, and combinations thereof improved IS, probably through the modulation of sympathetic activity or capillarity and muscle fiber type in skeletal muscles.
    Full-text · Article · Apr 2008 · Hypertension Research
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