Effect of Ca2+ channel blockers on arterial hypertension and heart ischaemic lesions induced by chronic blockade of nitric oxide in the rat.
The effects of the Ca2+ channel blockers diltiazem, nifedipine and amlodipine were investigated on both arterial hypertension and myocardial changes induced by chronic blockade of nitric oxide synthesis. Control male Wistar rats received Nomega-nitro-L-arginine methyl ester (L-NAME; 20 mg rat(-1) day(-1)) in the drinking water for 8 weeks; blood pressure and body weight were monitored weekly. The Ca2+ channel blockers were given concomitantly to L-NAME, as follows: diltiazem (13.5 mg rat(-1) day(-1)) and amlodipine (6.25 mg rat(-1) day(-1)) were administered in the drinking water whereas nifedipine (6.25 mg rat(-1) day(-1)) was given in the chow. Nomega-nitro-L-arginine methyl ester induced a time-dependent increase in blood pressure which was significantly attenuated by diltiazem (154+/-1.6 vs. 139+/-1.6 mm Hg, p < 0.05), nifedipine (166+/-2.7 vs. 150+/-2.1 mm Hg, p < 0.05) and amlodipine (208+/-5.8 vs. 158+/-1.8 mm Hg, p < 0.05) at the last week of the treatment. Rats treated with the L-NAME also developed myocardial ischaemia, as indicated by the increased percentage of fibrous tissue found in the left ventricles of these animals (10.9+/-0.1%, p < 0.01) when compared to control ones (6.3+/-0.1%). Neither diltiazem (14.9+/-1.2%) nor nifedipine (11.1+/-1.5%) prevented this effect whereas amlodipine (6.9+/-1.1%, p < 0.01) virtually abolished the increase in fibrous tissue induced by L-NAME. The plasma concentration of the Ca2+ channel blockers was measured by liquid chromatography coupled to mass spectrometry at two different time points (morning and afternoon). Only amlodipine treatment was able to maintain constant levels (186+/-46 ng ml(-1) in the morning and 110+/-19 ng ml(-1) in the evening) compared to nifedipine (3003+/-578 ng ml(-1) in the morning and 436+/-100 ng ml(-1) in the evening) and diltiazem (77+/-51 ng ml(-1) in the morning and not detectable in the evening). In conclusion, our results indicate that amlodipine (but not diltiazem and nifedipine) can efficiently control myocardial ischaemia in nitric oxide deficient rats, probably due to its intrinsically long half-life.
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas (SP), Brazil.
C F
CF
de Oliveira
L P
LP
Nathan
K
K
Metze
H
H
Moreno
I M
IM
de Luca
M
M
Sucupira
R
R
Zatz
A
A
Zappellini
E
E
Antunes
G
G
de Nucci
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001795:Blood Pressure Determination / Q000379:methods; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000097:blood / Q000494:pharmacology*; D004110:Diltiazem / Q000097:blood / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009543:Nifedipine / Q000097:blood / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D004110:Diltiazem; D009543:Nifedipine; D019331:NG-Nitroarginine Methyl Ester