Continuous blockade of L-type Ca2+ channels suppresses activation of calcineurin and development of cardiac hypertrophy in spontaneously hypertensive rats.
We examined whether Ca2+ channel blockers inhibit the activation of the Ca2+-dependent phosphatase calcineurin and the development of cardiac hypertrophy in spontaneously hypertensive rats (SHR). We randomly divided 12-week-old SHR into three groups, one each receiving vehicle, bolus injection or continuous infusion of nifedipine (10 mg/kg/day) from 12 to 24 weeks of age. Systolic blood pressure (BP) and heart rate were measured every week after the treatment using the tail-cuff plethysmography method. After 4, 8 and 12 weeks of treatment, 6 rats of each group were subjected to examinations that included an assay for calcineurin activity in the heart, magnetic resonance imaging (MRI), histology and Northern blot analysis. Continuous infusion of nifedipine consistently reduced BP, whereas bolus injection resulted in a fluctuation of BP. Continuous infusion of nifedipine not only reduced left ventricular mass but also decreased the transverse diameter of cardiomyocytes, interstitial fibrosis and the expression of the atrial natriuretic peptide and brain natriuretic peptide genes in the heart, while bolus injection of nifedipine did not significantly attenuate any of these hypertrophic responses in SHR. The activity of calcineurin in the heart was strongly suppressed by continuous but not bolus infusion of nifedipine in SHR. The results indicate that continuous blockade of Ca2+ channels with nifedipine effectively suppresses the development of cardiac hypertrophy in SHR, possibly through inhibition of the calcineurin activity.
Zou
Yunzeng
Y
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Japan.
Yamazaki
Tsutomu
T
Nakagawa
Keiichi
K
Yamada
Haruyasu
H
Iriguchi
Norio
N
Toko
Haruhiro
H
Takano
Hiroyuki
H
Akazawa
Hiroshi
H
Nagai
Ryozo
R
Komuro
Issei
I
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects; D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D006332:Cardiomegaly / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D005355:Fibrosis / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D009543:Nifedipine / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*
D065095:Calcineurin Inhibitors; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D009543:Nifedipine