title: 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.
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co, Ltd, Tokyo, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Fujisawa
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Yorikane
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Chiba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koike
mesh_terms: D000759:Adjuvants, Anesthesia / Q000008:administration & dosage; D017311:Amlodipine / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001285:Atropine / Q000008:administration & dosage / Q000494:pharmacology; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002940:Circadian Rhythm / Q000187:drug effects*; D003331:Coronary Vessels; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D010424:Pentobarbital / Q000008:administration & dosage; D010477:Perfusion; D011433:Propranolol / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects; D013997:Time Factors
chemical_list: D000759:Adjuvants, Anesthesia; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D017311:Amlodipine; D001383:Azetidinecarboxylic Acid; D001285:Atropine; D011433:Propranolol; D010424:Pentobarbital; C061679:azelnidipine