Benidipine stimulates nitric oxide synthase and improves coronary circulation in hypertensive rats.
We evaluated the effects of long-term treatment with benidipine, a long-acting calcium antagonist, on endothelial cell-type nitric oxide synthase (eNOS) activity and eNOS mRNA expression in the left ventricle (LV) and its relation to coronary flow reserve, and microvascular remodeling in renovascular hypertensive rats (RHR: 2K-1C Goldblatt). Benidipine (5 mg/kg/day) was given to RHR (B-RHR, n = 11) for 6 weeks. Vehicle-treated RHR (U-RHR, n = 11) and age-matched sham-operated rats (ShC, n = 11) served as control group. Coronary flow reserve was measured in conscious rats using colored microspheres. Fifty-micrometer slices of the LV were incubated with L-arginine to measure nitrite production using the Griess method and eNOS mRNA expression was determined by reverse transcription-polymerase chain reaction. An increased blood pressure in RHR was significantly decreased by benidipine. Nitrite production and eNOS mRNA expression in the LV of U-RHR was significantly lower than that of ShC. This suppression of nitrite production and eNOS mRNA expression was significantly reversed in B-RHR. U-RHR demonstrated a significant decrease in coronary flow reserve and capillary density, and a significant increase in wall-to-lumen ratio, perivascular fibrosis, myocardial fibrosis, and myocyte cross-sectional area. These impaired factors were improved significantly by benidipine. These findings suggest that benidipine therapy may increase nitrite production and eNOS mRNA expression not only by lessening the endothelial damage by the reduction of blood pressure levels, but also by the stimulation of NOS activity and eNOS mRNA, and this increased NOS activity and eNOS mRNA expression may play a role in the amelioration of coronary flow reserve and microvascular remodeling.
Kobayashi
N
N
Department of Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
Kobayashi
K
K
Hara
K
K
Higashi
T
T
Yanaka
H
H
Yagi
S
S
Matsuoka
H
H
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002302:Cardiac Output; D003326:Coronary Circulation / Q000187:drug effects*; D017931:DNA Primers / Q000737:chemistry; D004095:Dihydropyridines / Q000627:therapeutic use*; D006352:Heart Ventricles / Q000201:enzymology* / Q000503:physiopathology; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002121:Calcium Channel Blockers; D017931:DNA Primers; D004095:Dihydropyridines; D009573:Nitrites; D012333:RNA, Messenger; C061004:benidipine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat