Protective Effect Of Verapamil Research Articles

Verapamil Attenuates the Severity of Tendinopathy by Mitigating Mitochondrial Dysfunction through the Activation of the Nrf2/HO-1 Pathway.

Tendinopathy is a prevalent condition in orthopedics patients, exerting a profound impact on tendon functionality. However, its underlying mechanism remains elusive and the efficacy of pharmacological interventions continues to be suboptimal. Verapamil is a clinically used medicine with anti-inflammation and antioxidant functions. This investigation aimed to elucidate the impact of verapamil in tendinopathy and the underlying mechanisms through which verapamil ameliorates the severity of tendinopathy. In in vitro experiments, primary tenocytes were exposed to interleukin-1 beta (IL-1β) along with verapamil at a concentration of 5 μM. In addition, an in vivo rat tendinopathy model was induced through the localized injection of collagenase into the Achilles tendons of rats, and verapamil was injected into these tendons at a concentration of 5 μM. The in vitro findings highlighted the remarkable ability of verapamil to attenuate extracellular matrix degradation and apoptosis triggered by inflammation in tenocytes stimulated by IL-1β. Furthermore, verapamil was observed to significantly suppress the inflammation-related MAPK/NFκB pathway. Subsequent investigations revealed that verapamil exerts a remediating effect on mitochondrial dysfunction, which was achieved through activation of the Nrf2/HO-1 pathway. Nevertheless, the protective effect of verapamil was nullified with the utilization of the Nrf2 inhibitor ML385. In summary, the in vivo and in vitro results indicate that the administration of verapamil profoundly mitigates the severity of tendinopathy through suppression of inflammation and activation of the Nrf2/HO-1 pathway. These findings suggest that verapamil is a promising therapeutic agent for the treatment of tendinopathy, deserving further and expanded research.

Verapamil inhibits TXNIP-NLRP3 inflammasome activation and preserves functional recovery after intracerebral hemorrhage in mice

Intracerebral hemorrhage (ICH) is the second most common type of stroke with no satisfactory treatment. Recent studies from our group and others indicated a potential positive effect of verapamil, a commonly prescribed calcium channel blocker, with thioredoxin-interacting protein (TXNIP) inhibitor properties, in ischemic stroke and cognitive disorders. It is unclear whether there would be a beneficial effect of verapamil administration in ICH. Therefore, this study was designed to determine the neuroprotective effects of verapamil in a murine ICH model. ICH was induced by stereotactic injection of collagenase type VII (0.075 U) into the right striatum of adult male C57BL/6 mice. Verapamil (0.15 mg/kg) or saline was administered intravenously at 1 h post-ICH followed by oral (1 mg/kg/d) administration in drinking water for 28 days. Motor and cognitive function were assessed using established tests for motor coordination, spatial learning, short- and long-term memory. A subset of animals was sacrificed at 72 h after ICH for molecular analysis. Verapamil treatment reduced expression of TXNIP and NOD-like receptor pyrin domain-containing-3 inflammasome activation in the perihematomal area. These protective effects of verapamil were associated with decreased proinflammatory mediators, microglial activation, and blood-brain barrier permeability markers and paralleled less phosphorylated nuclear factor kappa B level. Our findings also demonstrate that long-term low-dose verapamil effectively attenuated motor and cognitive impairments. Taken together, these data indicate that verapamil has therapeutic potential in improving acute motor function after ICH. Further investigations are needed to confirm whether verapamil treatment could be a promising candidate for clinical trials.

MP67-07 THE PROTECTIVE EFFECTS OF PROPOLIS ON OXIDATIVE STRESS AND CRYSTAL DEPOSITION WITH HYPEROXALURIA INDUCED TUBULAR CELL INJURY IN RAT MODEL

You have accessJournal of UrologyStone Disease: Basic Research & Pathophysiology II1 Apr 2016MP67-07 THE PROTECTIVE EFFECTS OF PROPOLIS ON OXIDATIVE STRESS AND CRYSTAL DEPOSITION WITH HYPEROXALURIA INDUCED TUBULAR CELL INJURY IN RAT MODEL Kamil Fehmi Narter, Alper Kafkasli, Oguz Ozturk, Ozgur Yazici, Bilal Hamarat, Sukran Sarikaya, and Kemal Sarica Kamil Fehmi NarterKamil Fehmi Narter More articles by this author , Alper KafkasliAlper Kafkasli More articles by this author , Oguz OzturkOguz Ozturk More articles by this author , Ozgur YaziciOzgur Yazici More articles by this author , Bilal HamaratBilal Hamarat More articles by this author , Sukran SarikayaSukran Sarikaya More articles by this author , and Kemal SaricaKemal Sarica More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1323AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Oxidative stress (OS) can be effective in the kidney stone formation. We aimed to evaluate the degree of crystalization (CaOx) as well as oxidant (ROS)/antioxidant status in the kidney tissues, serum samples and possible protective effect of verapamil (V) or propolis (P)(honey-bee antioxidant product) on hyperoxaluric rat model. METHODS A total of 60 SD rats (350 g) were divided into the 6 study groups contained 8 rats during early (7 days) and late (28 days) follow-up. Control group;12 rats. Ethylene glycol (EG) group (0.75%, drinking water) Verapamil group (EG+1 mg/kg V, feeding tube) Propolis group (EG+50 mg/kg P, feeding tube) Histopathological evaluations of crystalization in kidney tissue;Light microscopy 10% formalin/24 h, paraffin,4-lm- section, stain HE). After the homogenization tissue samples were equilibrated to 1 mg tissue/1 ml Phosphate Buffered Saline. Blood samples were centrifuged in 3000 rpm/5 min. ELISA tests of catalase (CAT), superoxide dismutase (SOD), total glutathione (GSH), nitric oxide (NO), malonil dialdehid (MDA), total anti-oxidant capacity (TAOC) have been used to evaluate oxidant/antioxidant status of tissue and serum samples (YH-Biosearch). The statistical analyses;GraphPad Prism 6.0 software, multiple t-tests and statistical significance the Sidak-Bonferroni method, α=1.000%. RESULTS Statistically significant results were indicated on graphs. ELISA tissue and serum levels (Fig.1) of all parameters were shown. Crystalization (CaOx) in V group (mild), in P group (Limited) and in without any protective agent (EG group)(extensive, dense) at late phase (Fig 2). Although, both V and P did tend to limit the degree of crystaliazation, it was significantly lower in P group than V group. CONCLUSIONS As a result of our study, the limitation of both crystalization and OS might be instituted by propolis. As clinical application of propolis in the prophylaxis of stone disease might limit the formation, especially in recurrent stone formers. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e883 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Kamil Fehmi Narter More articles by this author Alper Kafkasli More articles by this author Oguz Ozturk More articles by this author Ozgur Yazici More articles by this author Bilal Hamarat More articles by this author Sukran Sarikaya More articles by this author Kemal Sarica More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Protective Effects of Verapamil against H2O2-Induced Apoptosis in Human Lens Epithelial Cells.

Verapamil is used in the treatment of hypertension, angina pectoris, and atrial fibrillation. Recently, several studies have demonstrated that verapamil increased the optic nerve head blood flow and improved the retrobulbar circulation. All these show that verapamil is potentially useful for ophthalmic treatment. Thus, the aim of this study is to investigate whether verapamil could protect human lens epithelial cell (HLEC) from oxidative stress induced by H2O2 and the cellular mechanism underlying this protective function. The viability of HLEC was determined by the MTT assay and apoptotic cell death was analyzed by Hoechst 33258 staining. Moreover, Caspase-3 expression was detected by immunocytochemistry and flow cytometry analysis. We also detected Caspase-3 mRNA expression by reverse-transcription-polymerase chain reaction and the GSH content in cell culture. The results showed that oxidative stress produced significant cell apoptotic death and it was reduced by previous treatment with the verapamil. Verapamil was effective in reducing HLEC death mainly through reducing the expression level of apoptosis-related proteins, caspase-3, and increasing glutathione content. Therefore, it was suggested that verapamil was effective in reducing HLEC apoptosis induced by H2O2.

Protective effect of verapamil administered at different time points on myocardial ischemia-reperfusion injury in rats

Objective To investigate the effect of verapamil administered at different time points on myocardial ischemia-reperfusion injury in rats, and explore the mechanism of myocardial protection.Methods The model of myocardial ischemia reperfusion in rats was established and 18 male SD rats were randomly divided into 3 groups,n =6 each. Verapamil dilution (0. 25 mg/kg) was pumped into verapamil1 group 10 min before ischemia, and verapamil dilution (0. 25 mg/kg) was pumped into verapamil-2 group 10 min before reperfusion. Normal saline (2 ml/kg) was pumped into IR group 10 min before ischemia.Rats were killed 60 min after reperfusion. The levels of serum cardiac Troponin T (cTnT) and the expression of myocardial Caspase-3 were evaluated. Histomorphological methods were used to analyze the extent of myocardial injury. Results The levels of serum cTnT and the expression of myocardial Caspase-3 in verapamil-1 group (4.60 ± 1.12) ng/L, (39.51 ±5.01)% were significantly lower than those in IR group (7. 70 ± 1.31 ) ng/L, (51.10 ±5. 30)% and verapamil-2 group (7. 23 ± 1.03) ng/L, (49. 35 ±4. 95 ) % ( P ＜ 0. 05 ). The levels of serum cTnT and the expression of myocardial Caspase-3 had no significant difference between verapamil-2 group and IR group (P ＞ 0. 05 ). The extent of myocardial injury in verapamil-1 group was significantly lower than that in IR group and verapamil-2 group (P ＜ 0. 05 ). The extent of myocardial injury had no significant difference between verapamil-2 group and IR group (P ＞0. 05). Conclusion Starting from 10 min before ischemia, verapamil has protective effects on myocardial ischemia/reperfusion injury. Starting from 10 min before reperfusion, verapamil does not provide protection on myocardial ischemia reperfusion injury. Key words: Verapamil; Myocardial ischemia; Reperfusion injury

Proteome analysis of differential protein expression in infarcted rat heart after verapamil treatment

To explore the protein-level mechanism of action verapamil in acute myocardial infarcted rats, the myocardial proteome was analyzed by two-dimensional electrophoresis (2-DE). Compared with the sham-operated group and the infarcted group, the result shows that 8 protein expressions in the verapamil treated group were up-regulated, and 7 protein expressions in this group were down-regulated significantly. Using MALDI-TOF-MS, 15 proteins with significant changes were identified through a database search. These proteins can be divided into 4 groups by their biological function: (1) Energy metabolism and mitochondrial function related proteins; (2) oxidative stress-induced proteins; (3) cytoskeletal Proteins; (4) other proteins. The findings show that the myocardial protective effects of verapamil in the myocardial damage process are related to the recovery of energy supply as well as anti-oxidative stress property.

Assessment of Hemorheological Deformability of Human Red Cells Exposed totert-Butyl Hydroperoxide, Verapamil and Ascorbate by Ektacytometer

Normal erythrocyte is deformable and this facilitates blood flow in the capillaries. Oxidative stress reduces the deformability of erythrocytes, and influences on blood flow in microcirculation. The objective of this study was to investigate the deformability of erythrocytes exposed to oxidative stress, the protective effects of verapamil and ascorbic acid against oxidative damages in erythrocytes, and the value of the microfluidic ektacytometer, RheoScan-D (RheoMeditech, Korea) in clinical application. Effects of oxidative stress on erythrocytes were investigated using tert-butyl hydroperoxide (tBHP). Before exposure to tBHP, the erythrocytes were pretreated with verapamil and ascorbic acid to examine their protective effect against oxidative damages. The deformability of erythrocytes was measured by the microfluidic ektacytometer, RheoScan-D. When treated with tBHP, the deformability of erythrocytes was decreased (P<0.01) and methemoglobin (metHb) formation and mean corpuscular volume (MCV) of erythrocytes were increased (P<0.01, P<0.05) compared to those of the untreated control cells. Compared to the tBHP treated cells, pretreatment with verapamil increased the deformability of erythrocytes (P<0.01) and decreased metHb formation (P<0.01) and MCV (P<0.05). Likewise, pretreatment with ascorbic acid increased the deformability of erythrocytes (P<0.01) and decreased metHb formation (P<0.01). Oxidative stress reduces the deformability of erythrocytes and the deformability could be one of markers for oxidative damage. Verapamil and ascorbic acid have protective role against tBHP induced oxidative stress. The ektacytometer, RheoScan-D used in this study is convenient for clinical measurement and could be used in various fields of clinical medicine.

Protective effect of verapamil on multiple hepatotoxic factors-induced liver fibrosis in rats

The purpose of the present work was to investigate the effect of verapamil on liver fibrosis induced by multiple hepatotoxic factors in rats. Male Wistar rats were divided into a normal control group, a liver fibrosis model control group, and verapamil groups with different dosages. Multiple hepatotoxic factors including carbon tetrachloride (CCl 4), ethanol and high cholesterol were used to make the animal model of liver fibrosis. The parameters of serum l-alanine aminotransferase (ALT), liver malondialdehyde and hydroxyproline contents were measured. Samples of the liver obtained by biopsy were subjected to histological and immunohistochemical studies for the expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-β 1 (TGF-β 1). Results showed that verapamil induced a dose-dependent decrease of serum ALT, liver malondialdehyde and hydroxyproline compared with liver fibrosis model control. Verapamil reduced hepatocyte degeneration and necrosis, and delayed the formation of liver fibrosis. The levels of expression of α-SMA and TGF-β 1 in the hepatic tissue of three of the verapamil-treated groups were significantly less than those of the liver fibrosis model control group. The results showed that verapamil acts against the formation of liver fibrosis, the mechanism might be due to a protective effect for hepatocytes and through decreasing TGF-β 1 to block the activation of hepatic stellate cells (HSCs) and collagen gene expression.

Dose-Dependent Effects of Verapamil on Ethanol-Induced Gastric Lesions in Rats

The effects of graded doses of verapamil on ethanol-induced stomach mucosal damage were studied in rats. Gastric lesions were induced in vivo by oral administration of 80% ethanol and evaluated with regard to ulcer index, gastric mucus content, free and total acidity, lipid peroxidation and nonprotein sulfhydryl groups. Orally administered ethanol markedly increased the ulcer index and lipid peroxidation. Pretreatment of rats with verapamil (1, 5, and 25 mg/kg i.p.) was carried out 1 h before the administration of ethanol. Verapamil showed a protective effect against ethanol-induced mucosal damage only at high dose (25 mg/kg). Verapamil dose dependently decreased the total acidity, lipid peroxidation, and nonprotein sulfhydryl content. Verapamil 25 mg/kg also increased significantly the gastric mucus secretion. L-arginine (100 mg/kg) or L-nitroarginine (100 mg/kg) with verapamil were also administered to the animals to determine the role of nitric oxide in the mechanism of the gastroprotective activity of verapamil (25 mg/kg). The results indicate that reduced acidity and lipid peroxidation and increased mucus secretion participate in the protective effects of verapamil against ethanol damage. On the other hand, a decrease in the nonprotein sulfhydryl content was observed with decreased gastroprotective effects of verapamil.

Protective effect of calcium channel blocker verapamil on morphological and functional state of hair cells of the organ of corti in experimental kanamycin-induced ototoxicity.

The protective effect of verapamil against acute ototoxic sensorineural damage produced by intraperitoneal injections of kanamycin (50 mg/kg daily for 14 day) was studied on rats. The functional (otoacoustic emission), histological, and physiological methods proved the protective effect of daily injections of calcium channel blocker verapamil (2 mg/kg) on the state of hair cells of the organ of Corti.

IN VIVO ASSESSMENT OF FREE RADICAL ACTIVITY DURING SHOCK WAVE LITHOTRIPSY USING A MICRODIALYSIS SYSTEM: THE RENOPROTECTIVE ACTION OF ALLOPURINOL

Shock wave lithotripsy is believed to cause renal damage directly through cellular injury from high energy shock waves and indirectly through vascular injury and resultant ischemia, which gives rise to oxygen free radical compounds. The transient and volatile nature of free radicals and derived products makes their detection difficult. Moreover, certain medications may provide a protective effect against shock wave lithotripsy induced renal parenchymal injury. We introduced an innovative microdialysis system for in vivo sampling of interstitial fluids that can be analyzed for free radical mediated lipid peroxidation products after shock wave lithotripsy treatment in the swine model. In addition, this system was used to test the antioxidant or renoprotective action of allopurinol. Ten juvenile swine were assigned to a nonmedicated control group that underwent shock wave lithotripsy or to a group that was premedicated with allopurinol before shock wave lithotripsy. Each group of animals underwent shock wave lithotripsy to the lower pole of the right kidney and received a total of 10,000 shock waves. Dialysate fluid was collected at 1,000-shock wave increments via probes surgically implanted into the lower pole of the right and left kidneys before lithotripsy. Samples were immediately preserved in liquid nitrogen and subsequently analyzed for the presence and concentration of conjugated diene levels, a measure of lipid peroxidation. Five additional juvenile swine were assigned to a sham treated group that did not undergo shock wave lithotripsy. Dialysate fluid was collected from the lower pole of the right and left kidneys to establish baseline or pre-lithotripsy levels of conjugated dienes. After shock wave lithotripsy conjugated diene levels increased almost 100-fold over that in the right kidneys of the nonmedicated control group. The difference was statistically significant compared to levels in the contralateral untreated kidneys (p <0.01). Right kidneys in the group premedicated with allopurinol did not demonstrate an increase in conjugated diene levels during shock wave lithotripsy. The results of this study confirm shock wave lithotripsy induced free radical activity as well the antioxidant and protective nature of allopurinol. The newly described microdialysis system enables real-time sampling of interstitial fluids during shock wave lithotripsy. It represents a unique method for assessing free radical formation and evaluating the protective effects of additional antioxidant medications.

Effect of verapamil on lenticular calcium, magnesium and iron in radiation exposed rats.

To investigate the effect of verapamil on lenticular calcium, magnesium, iron and on radiation-induced cataract in rats. Thirty-seven, female, Wistar Albino rats, weighing 180-230 g were randomly grouped as follows: control group (10 rats), radiation group (13 rats) and radiation-verapamil group (14 rats). Both radiation and radiation-verapamil groups received 5 Gy radiation to the whole body in a single dose, including both eyes within the irradiation volume; in addition the verapamil group received daily subcutaneous injections of 8 mg/kg verapamil starting on the first day of radiation. At the end of an 8-week experimental period, the animals were killed by decapitation. Lenticular calcium, magnesium, and iron levels were studied. The mean lens calcium level for the radiation group was significantly higher than that for the control and radiation-verapamil groups and, there was no significant difference between the control and radiation-verapamil groups. The mean lens magnesium value for the radiation group was significantly higher than that for the control group. In the radiation-verapamil group the mean lens magnesium content was significantly lower than that for the radiation group. The iron level in the radiation group was significantly higher than that for the radiation-verapamil group. The lens calcium, magnesium and iron contents increased after radiation exposure. Verapamil treatment significantly reduced the increase in the lenticular content of calcium, magnesium and iron, indicating a probable protective effect of verapamil in radiation-induced cataract formation.

The effect of verapamil on mitochondrial calcium content in normoxic, hypoxic and reoxygenated rat liver.

Calcium channel blockers protect cells against ischaemia-reperfusion injury. In the present study, the effect of verapamil on mitochondrial calcium content was investigated in situ in normoxic, hypoxic and reoxygenated rat liver. Subcellular distribution of exchangeable calcium ions, which form an electron-dense precipitate with antimonate, was demonstrated with the glutaraldehyde-osmium antimonate technique. Calcium precipitates were quantified morphometrically using automatic image analysis. In normoxic liver, the mitochondrial calcium content formed a gradient decreasing from the periportal to perivenous regions. The low mitochondrial calcium content in perivenous regions remained unaffected in all experimental conditions. In hypoxic and reoxygenated liver, the calcium content in mitochondria of the periportal areas was significantly reduced. Verapamil pretreatment levelled the calcium gradient in normoxic liver by reducing the periportal calcium content. Verapamil had no effect on the mitochondrial calcium content in hypoxic liver. In contrast, in verapamil-pretreated reoxygenated liver, the mitochondrial calcium content in periportal mitochondria increased significantly, thus restoring the zonal calcium gradient. In conclusion, these data suggest that modulations of mitochondrial calcium content in the periportal region of the liver lobule may play an important role in the protective effects of verapamil against ischaemia-reperfusion injury.

Protective effects of calcium channel blockers on acute bromobenzene toxicity to isolated rat hepatocytes. Inhibition of phenylephrine-induced calcium oscillations.

Protective effects of verapamil, nifedipine, diltiazem, and ethylene glycol tetraacetic acid (EGTA) on acute bromobenzene (BB) toxicity to rat hepatocytes were evaluated, and cytosolic [Ca2+]i was monitored in single BB-exposed rat hepatocytes. Additionally, the effect of nifedipine on phenylephrine-stimulated calcium oscillations was investigated. BB at 0.8-2.4 mM increased the lactate dehydrogenase (LDH) leakage rate dose-dependently. Pretreatment with verapamil (25-35 microM), nifedipine (35-45 microM), diltiazem (25 microM), or EGTA (1.5-5 mM) markedly attenuated the BB-induced (1.6 mM) LDH leakage rate during 2 h of incubations. BB did not cause any detectable acute change in [Ca2+]i. BB interfered with phenylephrine-stimulated calcium oscillations, by blocking the oscillations in 58% of the cells and reducing the oscillation frequency in the rest. Nifedipine (100 and 200 microM) blocked the phenylephrine-induced calcium oscillations completely in 55% and 88% of the cells, respectively. The findings demonstrate that verapamil, nifedipine, diltiazem, and EGTA significantly protect rat hepatocytes against BB toxicity. BB interferes with phenylephrine-stimulated calcium oscillations. Nifedipine inhibits the oscillations at doses higher than those exerting a protective effect.

Cardiotoxicity of Doxorubicin: Effects of Drugs Inhibiting the Release of Vasoactive Substances

The therapeutic usefulness of doxorubicin, an antineoplastic drug, is limited by its cardiotoxicity whose mechanism is as yet unknown. Several hypotheses have been postulated including also the release of vasoactive substances, so the aim of the present investigations was to study the relationship between the release of vasoactive substances and the development of doxorubicin-induced cardiotoxicity. The effects of the following drugs on doxorubicin-induced (cumulative dose of 20 mg/kg intraperitoneally) cardiotoxicity in rats have been evaluated: verapamil (1 and 10 mg/kg orally), that inhibits the slow channel influx of calcium and catecholamine release, acetylsalicylic acid (50 and 100 mg/kg orally), that inhibits the prostaglandin biosynthesis and release, and cromolyn sodium (cromolyn; 1 and 10 mg/kg orally), that inhibits the secretion of histamine. Our results showed that verapamil reduced and delayed doxorubicin-induced mortality, and limited doxorubicin-induced body weight decrease and ECG changes. Acetylsalicylic acid and cromolyn did not protect against doxorubicin-induced cardiotoxicity. These findings suggest that the release of vasoactive substances does not play a prevalent role in the development of doxorubicin-induced cardiotoxicity. The protective effect of verapamil is probably due to the inhibition of doxorubicin-induced intracellular calcium overload.

Protective effects of verapamil and adenosine treatment on high energy phosphate metabolism in ischemic and reperfused myocardium.

Isolated rat hearts were subjected to retrograde perfusion to investigate the protective effects of adenosine and verapamil on the myocardium. In group 1, the perfusate was standard Krebs-Henseleit buffer solution. The perfusate was changed to Krebs-Henseleit buffer containing verapamil (100 nM) in group 2, adenosine (100 microM) in group 3 and both drugs in combination in group 4 for 30 min before ischemia and during 20 min of reperfusion. Group 2 displayed a recovery of creatine phosphate but not of ATP at the end of reperfusion. In group 4, the recovery of both ATP and creatine phosphate was significantly greater than in group 1. The coronary flow of group 4 was significantly higher than that of the other groups. Treatment with both verapamil and adenosine before and after global ischemia may protect the ischemic myocardium by improving high energy phosphate metabolism and coronary circulation.

Functional, Histologic, and Ultrastructural Study of the Protective Effects of Verapamil in Experimental Ischemic Acute Renal Failure in the Rabbit

The present study was performed in vivo in rabbits to evaluate the functional and morphologic effects of verapamil in a model of ischemic acute renal failure (ARF). Particularly impressive was the ultrastructural integrity of renal tubules in the animals exposed to both ischemia and verapamil. Three groups were studied: Group A: no ischemia; Group B: renal ischemia alone; and Group C: renal ischemia with verapamil. Creatinine clearance was higher in Group C (0.77 mL/min/kg) compared to Group B (0.13 mL/min/kg) at 24 h of reperfusion (p < .005) as well as at 48 and 72 h (0.73 mL/min/kg) vs. 0.35 mL/min/kg; p < .05 and 0.90 mL/min/kg vs. 0.46 mL/min/kg; p < 0.05, respectively). Light microscopic evaluation of Group C rabbits revealed significantly better preservation of proximal tubule (PT) brush border (p < .0005) and less desquamation of PT (p < .05) compared to Group B. Ultrastructural examination of in vivo perfused kidneys also demonstrated decreased loss of microvilli of PT (p < .0005) as well as less cellular edema (p < .005), fewer cells with apical PT membrane rupture (p < .01), better preservation of mitochondria (p < .005), less flattening of the PT basolateral labyrinth (p < .05), and fewer hypertrophic actin bands at the basal surface of PT epithelial cells (p < .05). These results suggest that verapamil markedly attenuates PT morphologic injury in a rabbit model of reversible ischemic ARF. The functional protection observed in these studies may be related, in part, to the improved structural integrity of the renal tubules. Renal transplantation and anticipated renal ischemia (i.e., surgical interventions) are two important situations where treatment with verapamil or other calcium channel blockers may prove to be clinically beneficial.

Protective Effect of Verapamil on Shock Wave Induced Renal Tubular Dysfunction

In a prospective randomized study, the effects of the calcium entry blocker verapamil on shock wave induced tubular impairment were examined. A total of 24 patients with renal pelvis or caliceal stones undergoing anesthesia-free extracorporeal shock wave lithotripsy (ESWL**Dornier Medical Systems, Inc., Marietta, Georgia.) without auxiliary measures was randomly assigned to the verapamil group (12) or the control group (12). Four doses of verapamil (80mg. each) were given orally starting the night before ESWL. Controls received no medication. To assess renal tubular function the urinary excretion of α1-microglobulin, N-acetyl-β5-glucosaminidase and Tamm-Horsfall protein were determined before, immediately, and 12 and 24hours after ESWL. After ESWL there was an increase in urinary α1-microglobulin and N-acetyl-β5-glucosaminidase, which was significantly higher in the control than in the verapamil group. Tamm-Horsfall protein, a glycoprotein synthesized by the distal tubules, decreased significantly less in the verapamil group compared to the controls. Our results indicate that verapamil exhibits a protective effect on shock wave induced tubular damage. The underlying mechanisms are not elucidated yet, and direct actions on tubular cells and interference with renal hemodynamics are to be discussed.

Role of calcium channel blockers in protection against experimental renal injury

The available evidence indicates that the first generation calcium channel blocker verapamil has a protective effect against both acute and chronic renal failure. At the cell membrane, verapamil helps minimize the effects of excess calcium influx after ischemic injury, evidenced by reduced uptake of 45Ca, thus lessening tubular injury from both calcium-activated phospholipases and mitochondrial calcium overload. In experimental chronic renal failure, the long-term administration of verapamil protects against renal dysfunction and damage, independent of any effect on systemic mean arterial pressure. Protective effects of verapamil are delineated in several models, supporting the presented hypothesis of the pathogenesis of renal failure.

Protective Effects of Calcium Antagonists on Energy and Substrate Metabolism During Ischemia and Reperfusion in Hypertensive Myocardial Hypertrophy

The aim of the present study was to define the protective effects of verapamil and nifedipine on mechanical performance and energy and substrate metabolism of the postischemically reperfused myocardium in a chronic pressure overload cardiac hypertrophy model. The isolated beating rat heart preparation was used and left ventricular pressures and high-energy phosphates were continuously monitored during 30 min of global ischemia and reperfusion, respectively. Recovery of mechanical performance and high-energy phosphate and sugar monophosphate metabolism was significantly impaired in untreated hypertrophied hearts compared with normal control hearts and hypertrophied hearts treated with calcium antagonists. In hypertrophied hearts with chronic verapamil treatment, recovery was significantly improved compared to acute verapamil treatment, nifedipine treatment, and normal control hearts. Thus, verapamil and nifedipine exerted a protective effect on the postischemic recovery of the hypertrophied myocardium that was most prominent following long-term pretreatment with verapamil. Prolonged maintenance of adequate plasma levels and tissue distribution of calcium antagonists before an ischemic event may improve the postischemic prognosis in the presence of pressure-induced myocardial hypertrophy.