Chronotropic Effects of Azelnidipine, a Slow- and Long-acting Dihydropyridine-type Calcium Channel Blocker, in Anesthetized Dogs: A Comparison With Amlodipine

Abstract

Azelnidipine, a dihydropyridine calcium channel blocker unlike other dihydropyridine calcium channel blockers, does not increase but slightly decreases heart rate (HR) in clinical settings. In the present study, the mechanism for the HR-lowering action characteristic of azelnidipine was investigated in anesthetized dogs. In the in situ perfused sinus node preparation, the negative chronotropic action of azelnidipine was almost 5 times more potent than that of amlodipine. When injected intravenously in intact anesthetized dogs, both drugs produced a long-lasting blood pressure reduction, but the action of azelnidipine developed more slowly than that of amlodipine. Azelnidipine hardly affected HR at lower doses and decreased HR at higher doses. On the other hand, amlodipine consistently induced slight tachycardia. The HR-lowering effect of azelnidipine in autonomically blocked dogs was not much different from that in intact dogs, whereas tachycardia induced by amlodipine was eliminated in autonomically blocked dogs. However, neither drug affected the HR gain of baroreceptor reflex induced by changing carotid sinus pressure. These results suggest that compared with amlodipine, azelnidipine has a greater intrinsic negative chronotropic action and induces a lower level of reflex tachycardia most probably due to a slower development of blood pressure-lowering effects and that these characteristics of azelnidipine underlies its HR-lowering effects when administered systemically.

Acute effects of intravenous nifedipine or azelnidipine on open-loop baroreflex static characteristics in rats

“…This finding suggested that the acute hypotensive effect of intravenous nifedipine or azelnidipine was primarily attributable to peripheral vasodilation. As has been documented [2], the onset of the hypotensive effect of azelnidipine was gradual compared with that of nifedipine (Fig. 1).…”

“…2B and F), suggesting a direct negative chronotropic effect. Although low-dose nifedipine (1 or 10 μg/kg) induced hypotension with reflex tachycardia, high-dose nifedipine (100 μg/kg) induced hypotension with bradycardia in dogs [2]. This finding indicated that the direct negative chronotropic effect can overcome the positive chronotropic effect evoked by reflex sympathoexcitation.…”

“…In contrast, azelnidipine is a thirdgeneration dihydropyridine calcium channel blocker that has gradual onset and long-acting characteristics to minimize reflex tachycardia [2,24]. In addition to gradual pharmacodynamics, azelnidipine possesses a potency to inhibit not only L-type but also T-type (α 1H and α 1G but not α 1I subtype) calcium channels [3,6].…”

“…Among L-type calcium channel blockers, nifedipine is a first-generation dihydropyridine calcium channel blocker. Although a previous study has demonstrated a sympathoinhibitory effect of nifedipine in a regimen of low-rate administration [22], the sympathoinhibitory effect is not usually observed following acute administration because a drop in arterial pressure (AP) yields sympathoexcitation that is mediated by the arterial baroreflex [2]. It would be of interest, from the perspective of the mechanism of action, to determine whether nifedipine when administered acutely can act centrally and inhibit sympathetic outflow under the conditions that the reflex sympathoexcitation is prevented.…”

Differential Effects Between a Calcium Channel Blocker and a Diuretic When Used in Combination With Angiotensin II Receptor Blocker on Central Aortic Pressure in Hypertensive Patients

“…22 Furthermore, an experimental study has confirmed that azelnidipine has a dose-dependent effect on HR reduction. 23 Other studies have reported that atenolol achieved a greater reduction in aortic PWV than RAS inhibitors, despite the similar reductions in MAP. 16,24 This phenomenon can be explained by the reduction in HR by atenolol, 16,24 because HR is an important factor in the intraindividual variation of PWV.…”