Benidipine stimulates nitric oxide synthase and improves coronary circulation in hypertensive rats

Abstract

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.

Benidipine improves oxidized LDL-dependent monocyte and endothelial dysfunction in hypertensive patients with type 2 diabetes mellitus

“…12 The ability of benidipine to inhibit MDMP generation provides additional evidence of the antiatherosclerotic action of this drug. 22,34,35 The reduction in circulating levels of chemokines and adhesion molecules following benidipine administration provides confirmatory data and is consistent with the observed improvement in endothelial infarction. 22,23 In particular, it suggests that benidipine is effective for vascular disorders that involve oxLDL, since the effect of this drug was significant in diabetes patients with high levels of anti-oxLDL antibody.…”

“…Therefore, the effect of benidipine on monocytes and endothelial cells described above might be independent of the antihypertensive effect. 22,23,25,[34][35][36] Various factors are involved in diabetic vascular change, one of which is monocyte/macrophage migration. 16,[37][38][39][40] Migration of monocytes into the vascular subendothelium occurs during the inflammatory response and plays a key role in the development of atherosclerosis.…”

Influence of the Combination Drug Prestans (Perindopril A, Amlodipine) on Morpho-Functional Parameters of Arterial Bed in Essential Hypertension

“…Таким образом, данная группа препаратов эффек-тивно ингибирует вызванную эндотелином вазокон-стрикцию именно на этом уровне. Показано, что лечение нифедипином приводит к увеличению плот-ности капиллярной сети в миокарде, а терапия блока-торами кальциевых каналов длительного действия (бенидипин), кроме того, способствует нормализа-ции отношения просвет/стенка в артериолах мио-карда левого желудочка [14].…”

Differential Effects of Calcium-Channel Blockers on Vascular Endothelial Function in Patients With Coronary Spastic Angina

“…Previous studies using animal models have demonstrated that benidipine increases endothelial NO synthase gene expression and enhances NO production. [26][27][28] A recent study has shown that benidipine improves decreases in tetrahydrobiopterin, an essential cofactor of NO synthase, in the plasma and kidneys, leading to reduction of proteinuria in a rat model of type II diabetes. 28 Preservation of tetrahydrobiopterin levels by benidipine may be partly involved in enhancement of NO production.…”