Long-term blockade of L/N-type Ca(2+) channels by cilnidipine ameliorates repolarization abnormality of the canine hypertrophied heart.
OBJECTIVE
The heart of the canine model of chronic atrioventricular block is known to have a ventricular electrical remodelling, which mimics the pathophysiology of long QT syndrome. Using this model, we explored a new pharmacological therapeutic strategy for the prevention of cardiac sudden death.


METHODS
The L-type Ca(2+) channel blocker amlodipine (2.5 mg.day(-1)), L/N-type Ca(2+) channel blocker cilnidipine (5 mg.day(-1)), or the angiotensin II receptor blocker candesartan (12 mg.day(-1)) was administered orally to the dogs with chronic atrioventricular block for 4 weeks. Electropharmacological assessments with the monophasic action potential (MAP) recordings and blood sample analyses were performed before and 4 weeks after the start of drug administration.


RESULTS
Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval, MAP duration and beat-to-beat variability of the ventricular repolarization period were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of adrenaline, angiotensin II and aldosterone decreased in the cilnidipine group. In contrast, plasma concentrations of angiotensin II and aldosterone were elevated in the amlodipine group, whereas in the candesartan group an increase in plasma levels of angiotensin II and a decrease in noradrenaline and adrenaline concentrations were observed.


CONCLUSIONS
Long-term blockade of L/N-type Ca(2+) channels ameliorated the ventricular electrical remodelling in the hypertrophied heart which causes the prolongation of the QT interval. This could provide a novel therapeutic strategy for the treatment of cardiovascular diseases.
Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
A
A
Takahara
Y
Y
Nakamura
H
H
Wagatsuma
S
S
Aritomi
A
A
Nakayama
Y
Y
Satoh
Y
Y
Akie
A
A
Sugiyama
D000200:Action Potentials / Q000187:drug effects; D017311:Amlodipine / Q000097:blood / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000494:pharmacology; D000818:Animals; D054537:Atrioventricular Block / Q000188:drug therapy / Q000503:physiopathology; D001562:Benzimidazoles / Q000097:blood / Q000494:pharmacology; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020864:Calcium Channels, N-Type / Q000502:physiology*; D006332:Cardiomegaly / Q000503:physiopathology*; D002908:Chronic Disease; D004095:Dihydropyridines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004562:Electrocardiography; D004837:Epinephrine / Q000097:blood; D005260:Female; D008297:Male; D018377:Neurotransmitter Agents / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D013777:Tetrazoles / Q000097:blood / Q000494:pharmacology; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D004095:Dihydropyridines; D018377:Neurotransmitter Agents; D013777:Tetrazoles; D000804:Angiotensin II; D017311:Amlodipine; C065927:cilnidipine; C081643:candesartan; D009638:Norepinephrine; D004837:Epinephrine