dihydropyridines and Ischemia

Calcium antagonists have been shown to be superior over other antihypertensive drugs to prevent stroke. Because this cannot be fully attributed to blood pressure lowering effects, other mechanisms seem to play a role. Previously we found in patients with subarachnoid hemorrhage that nimodipine enhances fibrinolytic activity. The purpose of this systematic review was to investigate the fibrinolytic effect of calcium antagonists in general, especially in patients with hypertension. We systematically studied the entire PUBMED and EMBASE database with the search terms 'calcium antagonist' combined with 'fibrinolysis', '(euglobulin) clot lysis time' (ECLT), 'tissue plasminogen activator' (tPA), or 'plasminogen activator inhibitor' (PAI). Twenty-six prospective studies were identified and 22 manuscripts were included (802 investigated individuals). The results show that calcium antagonists significantly increase fibrinolysis as shown by a reduction of the ECLT standardized mean differences (SMD) -0.58 (95% confidence interval (CI) -1.05 to -0.11)) and an increase of tPA activity (SMD 0.73 (95% CI 0.25 to 1.21)). This increase of fibrinolysis is apparently caused by an increase of the tPA antigen level (SMD 0.16 (95% CI -0.05 to 0.37)) and a decrease of the plasminogen activator inhibitor-1 antigen antigen (SMD -0.36 (95% CI -0.74 to 0.02)). A sensitivity analysis showed that dihydropyridines, but not phenylalkylamines, exert a fibrinolytic effect. This fibrinolytic effect is not only seen in patients with subarachnoid hemorrhage but also in hypertensive patients. In conclusions, calcium antagonists increase fibrinolytic activity. This may add to the beneficial pharmacological effect of calcium antagonists to prevent ischemic events in patients with hypertension and subarachnoid hemorrhage.

Topics: Calcium Channel Blockers; Dihydropyridines; Fibrinolysis; Humans; Hypertension; Ischemia; Subarachnoid Hemorrhage

Blockade of the T-type calcium channel (TCC), which is expressed in the renal efferent arterioles of the juxtamedullary nephron and vasa recta, has been shown to protect against renal injury. Studies were designed to determine the effects of a specific TCC blocker, R(-) efonidipine [R(-)EFO], on the regulation of renal circulation.. Renal medullary blood flux (MBF) and cortical blood flux (CBF) were simultaneously monitored using laser-Doppler flowmetry in Sprague-Dawley rats. Responses were also determined in rats with angiotensin II (AngII) induced renal ischemia. Intravenous (i.v.) or renal interstitial (r.i.) infusion of R(-)EFO (0.25 mg/h, i.v. or r.i.) significantly increased MBF by 24.0 ± 7.0 and 21.0 ± 4.4%, respectively, but without changing CBF or mean arterial pressure. The nitric oxide (NO) synthase inhibitor NG-nitro-L-argininemethylester (L-NAME, 1 μg/kg per min, i.v. or r.i.) significantly attenuated R(-)EFO-induced increase in MBF. R(-)EFO inhibited the AngII-mediated (50 ng/kg per min, i.v.) reduction of MBF (28.4 ± 1.7%), which was associated with increased urinary NO(2) + NO(3) excretion and decreased urinary hydrogen peroxide (H(2)O(2)) excretion. Intracellular H(2)O(2) fluorescence (real-time fluorescence imaging) in the epithelial cells of isolated medullary thick ascending limb (mTAL) significantly increased following AngII stimulation (1 μmol/L, 235 ± 52 units), which was significantly inhibited by pre and coincubation with R(-)EFO. R(-)EFO stimulation also increased the intracellular NO concentration in the epithelial cells of mTAL (220 ± 62 units).. These results suggest that TCC blockade with R(-)EFO selectively increases MBF, an effect that appears to be mediated by changes in renal NO and oxidative stress balance, which may protect against ischemic renal injury in the renal medullary region.

Topics: Angiotensin II; Animals; Blood Flow Velocity; Calcium Channel Blockers; Calcium Channels, T-Type; Dihydropyridines; Disease Models, Animal; Drug Antagonism; Infusions, Intravenous; Ischemia; Kidney Medulla; Laser-Doppler Flowmetry; NG-Nitroarginine Methyl Ester; Nitrogen Dioxide; Nitrogen Oxides; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Renal Circulation; Vasoconstrictor Agents

Stroke-prone spontaneously hypertensive rats (SHRSPs) are vulnerable to ischemia and delayed neuronal death (DND) of hippocampus pyramidal cells when bilateral carotid arteries are occluded for only 10 min. Since this occlusion induces just mild ischemia, the resulting DND may be an appropriate animal model for dementia in patient with essential hypertension exposed to small ischemic insults. This study was designed to compare the effects of the antihypertensive drugs lercanidipine, nicardipine, lisinopril, valsartan, and hydralazine on occlusion-induced DND in SHRSPs. Drugs were administered for 2 weeks, from 15 to 17 weeks of age. 0.1% Nicardipine and 0.01 or 0.03% lercanidipine were administered in the SP diet (about 61.3, 5.7, and 18.8 mg/kg/day, respectively), and the remaining drugs were administered at 10 mg/kg/day using the mini-osmotic pump. The animals were operated on at 16 weeks of age, and DND was analyzed by histological examination 1 week later. Systolic blood pressure was measured at 15, 16, and 17 weeks of age. For chronic treatment, Calcium-channel blockers were administered from 8 to 17 weeks of age. All antihypertensive drugs significantly lowered systolic blood pressure at 16 weeks of age. Hydralazine and lisinopril were associated with the greatest reduction; however, lercanidipine, nicardipine, and valsartan effectively reduced systolic blood pressure to within a medium range. DND was significantly inhibited only by 0.03% lercanidipine. Chronic treatment with 0.03% lercanidipine also protected pyramidal neurons. The results of this study demonstrate that the long-acting, lipophilic Calcium-channel blocker lercanidipine inhibits occlusion-induced DND in SHRSPs and that lercanidipine may effectively reduce dementia induced by small ischemic insults in patients with essential hypertension.

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Cell Death; Dihydropyridines; Hippocampus; Ischemia; Neurons; Pyramidal Cells; Rats; Rats, Inbred SHR; Stroke

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 +/- 3% and 110 +/- 32%, respectively), and decreased total renal blood flow (RBF) and PTC erythrocyte velocity (by -34 +/- 4 and -37 +/- 1%, respectively). Treatment with azelnidipine (5 microg/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 +/- 3%) and RVR (40 +/- 4%) and decreases in RBF (-24 +/- 1%) and PTC erythrocyte velocity (-22 +/- 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 microg/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.

Topics: Adenosine Triphosphate; Angiotensin II; Animals; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Ischemia; Kidney Tubules; Male; Rats; Rats, Sprague-Dawley; Vascular Resistance

Topics: Acetylcholine; Adenosine A3 Receptor Antagonists; Animals; Brain; Brain Ischemia; Calcium Channels; Central Nervous System; Dihydropyridines; Dizocilpine Maleate; Electrophysiology; Inosine; Ischemia; Neuroprotective Agents; Rats; Receptors, N-Methyl-D-Aspartate

We have investigated the effects of benidipine (hydrochloride), a calcium antagonist, against ischaemic acute renal failure in rats. Using histological examination, we studied whether the inhibition of apoptosis was associated with the protective effects of benidipine on the ischaemic renal injury. Acute renal failure was induced by the unilateral clamping of the left renal artery for 60 min, followed by reperfusion and contralateral nephrectomy. Drugs were given intravenously 5 min before the unilateral clamping. Prophylactic administrations of benidipine (10 microg kg(-1), i.v.) significantly ameliorated the development of renal failure as estimated by the measurements of serum creatinine and blood urea nitrogen 24 h after the reperfusion. Amlodipine (besilate, 100 and 300 microg kg(-1), i.v.) tended to attenuate renal dysfunction. Lisinopril (300 and 1000 microg kg(-1), i.v.), an angiotensin converting enzyme inhibitor, was ineffective in this acute renal failure model. Histological examination using the terminal transferase-mediated dUTP-biotin nick end-labelling (TUNEL) method to detect apoptotic cells revealed that the TUNEL-positive tubular epithelium was prominent in the renal cortex 24 h after the reperfusion. The TUNEL-positive cells were significantly reduced by pretreatment with benidipine. The results demonstrate that benidipine can ameliorate the ischaemic acute renal failure in rats and suggest that the renoprotective effect of benidipine was at least partly attributable to the reduction of apoptosis in tubular epithelial cells.

Topics: Acute Kidney Injury; Animals; Apoptosis; Blood Urea Nitrogen; Calcium Channel Blockers; Creatinine; Dihydropyridines; In Situ Nick-End Labeling; Ischemia; Kidney Cortex; Kidney Tubules; Male; Rats; Rats, Wistar

1. We investigated the effect of efonidipine hydrochloride (NZ-105) against acute renal failure (ARF) in male Wistar rats. ARF was produced by ischemia or glycerol. 2. Ischemia-induced ARF was produced by right nephrectomy and clamping of the left renal artery for 60 min, followed by reperfusion. NZ-105 (20 mg/kg) was orally administered twice a day for 3 days before ARF. The plasma creatinine and urea nitrogen concentrations were markedly elevated in the ischemia ARF group on the 1st day, but the elevation was significantly suppressed by NZ-105 treatment. 3. Glycerol-induced ARF was produced by intramuscular injection of 50% (v/v) glycerol (10 ml/kg) in rats which were restricted to drinking water for 24 hr. NZ-105 (20 mg/kg) was orally administered twice a day for 3 days before ARF. NZ-105 significantly attenuated the severe impairment of creatinine and urea nitrogen clearances and the elevated fractional sodium excretion (FENa) caused by ARF. 4. In the kidney homogenate, NZ-105 (10(-6)-10(-4) M) inhibited lipid peroxidation induced by ascorbic acid and Fe or by NADPH and the inhibitory effect of NZ-105 was stronger than alpha-tocopherol, an antioxidant agent. NZ-105 (10(-5)-10(-3) M) showed radical scavenging action against diphenyl-p-picrylhydrazyl and galvinoxyl induced radicals. 5. These findings suggest that NZ-105 prevents the renal damage caused by the two kinds of ARF. Moreover, the inhibitory effects of NZ-105 against lipid peroxidation and radical formation may be one of the mechanisms involved in the prevention of ARF.

Topics: Acute Kidney Injury; Animals; Calcium Channel Blockers; Dihydropyridines; Diuretics; Free Radical Scavengers; Free Radicals; Glycerol; Ischemia; Kidney; Lipid Peroxidation; Male; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Rats, Wistar

Splanchnic artery occlusion (SAO) with subsequent reperfusion elicits a severe form of circulatory shock. To study the possible involvement of Ca2+ overload in this shock state, we have examined the effects of benidipine, a novel long-acting calcium antagonist, in a rat model of SAO shock, focusing on endothelial damage. Pentobarbital-anesthetized rats were subjected to 90-min occlusion of both the celiac and superior mesenteric arteries, followed by reperfusion. Rats given only the vehicle for benidipine developed hypotension following reperfusion, and only 7 of 16 rats (44%) survived 2 hr of reperfusion. In isolated superior mesenteric rings from SAO-shock rats, the EDRF-dependent dilator response to acetylcholine (ACh) (100 mM) was severely depressed (9% vs. 97% in control artery rings, P less than 0.001), whereas the EDRF-independent dilator response to acidified NaNO2 (100 microM) was unchanged. By contrast, 90% (9 of 10, P less than 0.05) rats treated with benidipine 45 min postocclusion (3 micrograms/kg, i.v.) survived 2 hr, and the dilator response to ACh was markedly improved (49% of initial, P less than 0.001). SAO-shock rats treated with benidipine also exhibited significantly attenuated accumulation of free amino-nitrogenous compounds (5.5 vs. 7.9 U/ml, P less than 0.05) and myocardial depressant factor (34 vs. 62 U/ml, P less than 0.001). These results suggest that endothelial damage plays a role in the pathogenesis of shock following bowel ischemia and reperfusion and that Ca(2+)-entry blockade improves endothelial function, which is involved in the amelioration of the shock state.

Topics: Acetylcholine; Animals; Blood Pressure; Calcium Channel Blockers; Celiac Artery; Constriction; Dihydropyridines; Endothelium, Vascular; Ischemia; Kinetics; Male; Mesenteric Arteries; Myocardial Depressant Factor; Rats; Rats, Inbred Strains; Shock; Vasodilation

The effect of the calcium blocker S-(+)-methyl 4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitro-phenyl)thieno[2,3-b]pyridine- 5-carboxylate (S-312-d) on ischemic acute renal failure (ARF) was studied in rats. Ischemic ARF was induced by temporary (30-60 min) clamping of the left kidney 2 weeks after contralateral right nephrectomy. Plasma creatinine, creatinine clearance, urinary osmolality and fractional excretion of sodium were used to test the effectiveness of the drug. S-312-d (0.01-0.1 mg/kg b.wt. i.v.) administration before ischemia offered dose-dependent protection against the functional impairment induced by ischemia. This effect was accompanied by an increase in the survival rate of ischemic rats. S-312-d given after ischemia was not effective. The renal cortical edema induced by ischemia was significantly reduced by pretreatment with S-312-d. The increase in renal tissue calcium content observed after ischemia was also suppressed by S-312-d. Comparison with other established calcium blockers indicated S-312-d to be a good candidate for protection against ischemic ARF. These findings indicate that S-312-d may be clinically useful against renal ischemia.

Topics: Acute Kidney Injury; Animals; Calcium; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Ischemia; Kidney; Male; Rats; Rats, Inbred Strains