Effects of Calcium Channel Blockade on Angiotensin II-Induced Peritubular Ischemia in Rats

Abstract

Recent studies have indicated that derangement of peritubular capillary (PTC) circulation with consequent tubulointerstitial hypoxia plays a pivotal role in the pathogenesis of renal injury. The present study was performed to determine whether azelnidipine, a new dihydropyridine calcium channel blocker, attenuates angiotensin II (AngII)-induced peritubular ischemia in anesthetized rats. The superficial PTCs were visualized directly using an intravital fluorescence videomicroscope system, and the PTC blood flow was evaluated by analyzing the velocity of fluorescein isothiocyanate-labeled erythrocytes. Intravenous infusion of AngII (50 ng/kg/min, 10 min) significantly increased mean arterial pressure (MAP) and renal vascular resistance (RVR) (by 35 Ϯ 3% and 110 Ϯ 32%, respectively), and decreased total renal blood flow (RBF) and PTC erythrocyte velocity (by Ϫ34 Ϯ 4 and Ϫ37 Ϯ 1%, respectively). Treatment with azelnidipine (5 g/kg/min i.v., 10 min) had no effect on basal MAP, RBF, RVR, or PTC erythrocyte velocity. However, azelnidipine markedly attenuated the AngII-induced increases in MAP (7 Ϯ 3%) and RVR (40 Ϯ 4%) and decreases in RBF (Ϫ24 Ϯ 1%) and PTC erythrocyte velocity (Ϫ22 Ϯ 1%). Similar attenuation in the AngII-induced responses of MAP, RBF, RVR, and PTC erythrocyte velocity were observed in rats treated with a higher dose of azelnidipine (20 g/kg/min i.v., 10 min), which significantly decreased basal MAP and RVR and increased RBF and PTC erythrocyte velocity. These data suggest that calcium channel blockade attenuates AngII-induced peritubular ischemia, which may be involved in its beneficial effects on renal injury.

Combination Therapy with Renin-Angiotensin System Inhibitors and the Calcium Channel Blocker Azelnidipine Decreases Plasma Inflammatory Markers and Urinary Oxidative Stress Markers in Patients with Diabetic Nephropathy

“…Recent studies have indicated that derangement of peritubular capillary circulation with consequent tubulointerstitial hypoxia plays a pivotal role in the pathogenesis of renal injury (37). It has been reported that AZ attenuates Ang II-induced peritubular ischemia, mitochondrial injury and apoptosis in hypoxic renal tubular cells (37,38). In the study of Nakamura et al (7), however, only a few subjects were treated with RAS inhibitors.…”

Additive antioxidative effects of azelnidipine on angiotensin receptor blocker olmesartan treatment for type 2 diabetic patients with albuminuria

“…Azelnidipine attenuates angiotensin IIinduced peritubular ischemia and has antioxidative properties that may be involved in its beneficial effect on renal injury. 14 Although it has been reported that azelnidipine decreases not only urinary albumin excretion but also urinary 8-OHdG and L-FABP levels in diabetic nephropathy, 15,16 the dosage and kinds of RAS inhibitors were not fixed and the relationship between the changes in those urinary markers and the changes in plasma aldosterone levels are not well known. Therefore, the objective of this study was to determine the effects of additional therapy from the CCBs azelnidipine or amlodipine using the maximum recommended dose of ARB, 40 mg olmesartan, on BP control and renoprotection in hypertensive diabetic patients with CKD.…”

Activation of the Renin-Angiotensin System and Chronic Hypoxia of the Kidney

“…2). Nishiyama's group recently provided direct evidence of the angiotensin II-induced reduction in blood flow by visualizing the superficial peritubular capillaries directly through an intravital fluorescence videomicroscope system (45). Evaluation of peritubular capillary blood flow by analyzing the velocity of fluoresceinlabeled erythrocytes showed a marked decrease in peritubular capillary blood flow in rats following the intravenous administration of angiotensin II.…”