Effects of two calcium channel blockers on messenger RNA expression of endothelin-1 and nitric oxide synthase in cardiovascular tissue of hypertensive rats.
OBJECTIVE
The aim of this study was to investigate the effects of calcium channel blockers on messenger RNA expression of endothelin-1 and endothelial-type nitric oxide synthase in the cardiovascular tissue of stroke-prone spontaneously hypertensive rats (SHRSP).


METHODS
The calcium channel blocker nilvadipine (1.0 or 3.2 mg/kg per day) was subcutaneously administered to two groups of SHRSP, from 4 or 8 weeks of age, for 8 weeks and 4 weeks, respectively. For comparison, nifedipine (3.2 mg/kg per day) was similarly administered to SHRSP from 4 weeks of age for 8 weeks. Kidney, heart, aorta and brain tissue samples were obtained when the rats were 12 weeks old. Messenger RNA expression of endothelin-1 and endothelial-type nitric oxide synthase was determined by reverse transcription-polymerase chain reaction followed by Southern blotting and a ribonuclease protection assay, respectively. Results were compared with those in untreated SHRSP and Wistar-Kyoto rats at 12 weeks of age.


RESULTS
Both nilvadipine and nifedipine significantly decreased blood pressure in SHRSP. Although there were no changes in the weights of the kidney and brain, there was a significant decrease in the weight of the left ventricle of the groups treated with nilvadipine (1.0 mg/kg per day: mean +/- SEM 0.282 +/- 0.003 g; 3.2 mg/kg per day: 0.269 +/- 0.005 g) and nifedipine (1 mg/kg/day: 0.281 +/- 0.012 g) for 8 weeks compared with untreated SHRSP (0.301 +/- 0.004 g). Endothelin-1 messenger RNA expression, which was significantly increased by about twofold in the kidney, heart and brain of SHRSP compared with Wistar-Kyoto rats, was normalized by both calcium blockers. Endothelin-1 messenger RNA expression, which was decreased in the aorta of SHRSP, was further decreased by both calcium blockers. While there was no significant difference in endothelial-type nitric oxide synthase messenger RNA expression in the kidney, heart and aorta between the untreated SHRSP and Wistar-Kyoto rats, expression in the aorta was significantly increased in the group treated with these calcium blockers for 8 weeks from 4 weeks of age.


CONCLUSIONS
These results suggest that, in addition to their potent antihypertensive effects, calcium channel blockers may exhibit cardiovasculoprotective and renoprotective effects by modifying mRNA expression of endothelin-1 and endothelial-type nitric oxide synthase in tissue.
Naruse
M
M
Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical University, Japan. RXK00525@niftyserve.or.jp
Tanabe
A
A
Seki
T
T
Adachi
C
C
Yoshimoto
T
T
Mishina
N
N
Imaki
T
T
Naruse
K
K
Demura
R
R
Demura
H
H
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015139:Blotting, Southern; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D005500:Follow-Up Studies; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D009929:Organ Size; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002121:Calcium Channel Blockers; D019332:Endothelin-1; D012333:RNA, Messenger; C035100:nilvadipine; D019001:Nitric Oxide Synthase; D009543:Nifedipine