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PubMed1994

Possible presence of calcium channel blocker(s) in Rubia cordifolia: an indigenous medicinal plant.

Crude extract of Rubia cordifolia (RC) was tested in isolated tissue preparations for its possible calcium channel antagonistic activity. RC suppressed the spontaneous contractions of guinea-pig atria, rabbit jejunum and rat uterus in a concentration dependent manner (0.1-3 mg/ml). In rabbit aorta, it inhibited norepinephrine (10 microM) and KCl (80 mM) induced contractions. Replacement of physiological salt solution with calcium free solution abolished the spontaneous movements of rabbit jejunum. However, addition of calcium (25 micrograms/ml) in the tissue bath restored the spontaneous movements. When the tissues were pretreated with plant extract (1 mg/ml) or verapamil (0.5 microgram/ml), addition of calcium failed to restore spontaneous contractions. These results indicate that the plant extract exhibits spasmolytic activity similar to that of verapamil suggestive of presence of calcium channel blocker like constituent(s) in this plant.

Animals↗
PubMedDate not supplied

Effect of oxodipine, a novel dihydropyridine calcium channel blocker, in neurogenic hypertensive dogs.

The effects of an acute intravenous injection of oxodipine (5, 20 and 50 micrograms/kg), a new dihydropyridine calcium channel blocker, on blood pressure and heart rate were investigated in arterial neurogenic hypertension elicited in anesthetized dogs by acute sinoaortic denervation. This model is associated with disruption of baroreflex pathways and heart denervation, allowing a direct investigation of the effects of the drug on heart rate and blood vessels. The low dose (5 micrograms/kg) of oxodipine remained ineffective, whereas doses of 20 and 50 micrograms/kg of oxodipine elicited a decrease in blood pressure with no change in heart rate. These results suggest that, in contrast to other first generation dihydropyridines, oxodipine exerts a relatively specific action on blood vessels without significant intrinsic negative chronotropic properties in anesthetized sinoaortic-denervated dogs.

Anesthesia↗
PubMed1995

Bone pain that responds to calcium channel blockers. A retrospective and prospective study of transplant recipients.

A severe episodic bone pain syndrome of unknown cause was first described in renal transplant recipients in France and associated with the use of cyclosporine. We have retrospectively and prospectively evaluated this pain syndrome in our transplant patients. This pain is bilateral, of acute onset and episodic, primarily involving the knees and/or ankles. It usually occurs at night or with recumbency, and is often relieved with elevation or walking. Physical examination of the affected areas is unrevealing. Kidney, liver, pancreas, heart, lung and combined organ transplant recipients on cyclosporine were available from the University of Washington Transplant Services and were retrospectively evaluated by chart review (n = 351) or prospective clinical evaluation (n = 38) for evidence of this clinical syndrome. In the retrospective chart review, 19.1% of patients had episodes of bone pain. The highest prevalence occurred in renal transplant recipients (27.7%). The bone pain syndrome was documented in the charts of 14 patients who subsequently developed significant osteonecrosis. Prospectively, 21 of 22 patients with the bone pain syndrome experienced complete relief of this pain upon treatment with calcium channel blockers (95.4% response rate). The pathophysiology of this bone pain syndrome is unknown, although its response to the vasodilatory effects of calcium channel blockers suggests a vascular etiology.

Bone and Bones↗
PubMed1988

The calcium channel blocker nisoldipine delays progression of chronic renal failure in humans (preliminary communication).

Chronic renal failure (CRF) patients with a stable course were asked to participate in a follow-up program in which they were randomized into two groups: 1) the placebo group taking their standard antihypertensive therapy without any calcium ion blocker: and 2) the nisoldipine group, those patients taking the calcium channel blocker nisoldipine as the only antihypertensive drug. The two groups had similar blood pressures on entering the study (151 +/- 21.3/90.7 +/- 7.4 mmHg in the nisoldipine and 146.7 +/- 18/94 +/- 9.4 mmHg in the placebo group). Their protein intake was also similar (daily average throughout the follow-up period: 0.83 +/- 0.18 g protein per kg body weight in the nisoldipine and 0.9 +/- 0.12 g in the placebo group). The patients were checked monthly. The follow-up averaged 11.1 +/- 4.8 months in the nisoldipine group and 13.7 +/- 4.2 months in the placebo group. The rate of progression of CRF, as expressed by the slope of the regression line of 1/serum creatinine versus time, decreased in the nisoldipine group from the initial (-8.03 +/- 4.91) x 10(-3) to (-5.57 +/- 5) x 10(-3) (two-tailed P-test = 0.016) after intervention. The slopes tended to become steeper in the placebo group, with an initial slope of (-4.1 +/- 3.2) x 10(-3) changing to (-7.9 +/- 5) x 10(-3) after intervention. This difference did not reach statistical significance (two-tailed P = 0.072). The rate of progression of CRF decreased in 12 of 14 patients in the nisoldipine-treated group versus 3 of 11 patients in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury.

OBJECT: Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose-response curves in preclinical drug testing. This idea was tested in a model of TBI in rats. METHODS: Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose. CONCLUSIONS: The authors established these time-window profiles and dose-response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose-response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.

Animals↗
PubMedDate not supplied

An open-label, randomized, controlled, 4-week comparative clinical trial of barnidipine hydrochloride, a calcium-channel blocker, and benazepril, an angiotensin-converting enzyme inhibitor, in Chinese patients with renal parenchymal hypertension.

This study compared barnidipine, a calcium-channel blocker, and benazepril, an angiotensin-converting enzyme inhibitor, in 85 Chinese patients with renal parenchymal hypertension (diastolic blood pressure range 95 - 110 mmHg). Patients were randomly assigned to receive either 10 mg barnidipine or 10 mg benazepril orally daily for 4 weeks. In patients with diastolic blood pressure > 90 mmHg after 2 weeks of treatment, the dose of barnidipine or benazepril was increased by 5 or 10 mg, respectively. Both the barnidipine-treated group (n = 43) and the benazepril-treated group (n = 42) showed significant mean reductions from baseline in sitting systolic and diastolic blood pressures. The decrease in diastolic blood pressure with benazepril was significantly greater than with barnidipine treatment. Sitting heart rate was not changed by either drug. There was no significant difference in adverse events between the two groups. Barnidipine is similar to benazepril for the treatment of renal parenchymal hypertension.

Adolescent↗
PubMed1988

(S)-emopamil, a novel calcium channel blocker and serotonin S2 antagonist, markedly reduces infarct size following middle cerebral artery occlusion in the rat.

(S)-Emopamil is a novel calcium channel blocker of the phenylalkylamine class, with superior blood-brain permeability and potent serotonin S2 antagonist activity. In this study, we investigated the effects of (S)-emopamil on the histopathologic consequences of permanent middle cerebral artery (MCA) occlusion in anesthetized Sprague-Dawley rats. In three treatment protocols, intraperitoneal (S)-emopamil therapy was begun either 30 minutes prior to, immediately after, or 1 hour after MCA occlusion. Nontreated and saline-treated control groups were also studied. Cortical infarct volumes in nontreated and saline-treated control rats were 85 +/- 22 and 66 +/- 19 mm3 (mean +/- SD), respectively, and did not differ statistically from one another. Corresponding cortical infarct volume values in (S)-emopamil-pretreated rats, and in rats with post-treatment at 0 hours and 1 hour, were 33 +/- 23, 29 +/- 14, and 27 +/- 16 mm3, respectively; each of these was significantly smaller than control values. In contrast to the neocortex, striatal infarct volume was not altered by (S)-emopamil treatment. The results of this study demonstrate the marked therapeutic efficacy of (S)-emopamil in focal cortical infarction, even when treatment is delayed for 1 hour following MCA occlusion.

Animals↗
PubMed2004

ACE inhibitors and calcium channel blockers: patterns of use and associations with mortality in type 1 diabetes.

OBJECTIVE: To determine the frequency of ACE-I and Calcium channel blockers (CCB) use in type 1 diabetes (T1D), and associations of these medications with mortality. RESEARCH DESIGN AND METHODS: Data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study, a 10-year follow up of childhood onset T1D, were used to document ACE-I and CCB use. Use in subjects who died during follow up was compared to gender, age, duration (+/-5 years), hypertension, and renal status matched living controls. RESULTS: ACE-I use increased from baseline (1986-1988) to 10 years later (1996-1998) for those with hypertension (20.8-65.8%), and microalbuminuria (2.3-31.5%). However, the majority of patients with microalbuminuria were not on ACE-I at 10 years. CCB use was 2.1% at baseline, increased to 10.4% at 8 years, and fell to 9.5% at 10 years. An increased risk of mortality was apparent for those not treated with either ACE-I or CCB when controlling for cardiovascular status and age (hazard ratio (HR) 2.6, 95% CI 1.1-6.3), while ACE-I use alone was protective (HR=0.26, 0.08-0.79). CCB use with or without ACE-I was not related to mortality status. CONCLUSIONS: This data suggests that ACE-I use is not optimal, but more favorably associated with decreased mortality than CCB use.

Adult↗
PubMed1998

Continuous calcium channel blocker infusion in experimentally induced acute pancreatitis: effects on pancreas and liver function.

In this study we examined the effects of continuous calcium channel blocker (CCB) infusion on pancreatic duct-ligated acute pancreatitis (AP) in rabbits. Thirty rabbits were used for this study. Animals in group 1 (n = 10), which served as a control group, underwent dummy operations and received 0.5 microliter/h normal saline via the internal jugular vein. Animals in group 2 (n = 10) with artificially-induced pancreatitis received the same dosage of saline in the same manner. Animals in group 3 (n = 10) with artificially-induced pancreatitis received 180 micrograms/kg/h CCB (Verapamil) via the jugular vein starting from just before pancreatic duct ligation. AP histology score, plasma amylase levels and liver function tests were measured after 48 h. Verapamil infusion did not prevent the rise in plasma amylase levels, nor did it prevent pancreatic inflammation and damage. Serum levels of serum glutamate pyruvate transaminase, serum glutamate oxalacetate transaminase and alkaline phosphatase were significantly elevated in group 2 and significant reductions were seen in the Verapamil treated animals (group 3). The findings in this study imply that a continuous 180 micrograms/kg/h dose Verapamil infusion does not ameliorate the pathogenesis of pancreatitis induced by ligation of pancreatic duct but do not rule out a dose-dependent protective effect. Meanwhile, the lowering of liver function test scores should be considered the beneficial effect of CCBs, and this should be investigated in further studies.

Acute Disease↗
PubMed1993

Influence of calmodulin antagonists and calcium channel blockers on triiodothyronine uptake by rat hepatoma and myoblast cell lines.

The influence of calcium-related mechanisms on cellular uptake of triiodothyronine (T3) has not yet been defined, although it is known that T3 can stimulate cellular entry of calcium. We therefore investigated the saturable uptake of [125I]-T3 (10(-11) mol/L) from serum-free medium in vitro by hepatoma (H4) cells and skeletal myoblast (L6) cells to establish the calcium-dependency of this process. We studied the effects of the following three structurally distinct types of calmodulin antagonists in H4 cells: the naphthalene sulfonamides W7, W12, and W13, calmidazolium, and trifluoperazine. Uptake of [125I]-T3 as a percentage of control values (n = 4, 10(-4) mol/L antagonist) was as follows: W7, 42.0% +/- 3.3% (P < .001); W12, 87.5% +/- 4.5% (NS); W13, 79.5% +/- 2.5% (P < .05); calmidazolium (10(-6) mol/L, n = 8), 55.1% +/- 2.2% (P < .001); and trifluoperazine (10(-5) mol/L, n = 6), 65.7% +/- 4.1% (P < .001). To investigate whether the calmodulin sensitivity of uptake was mediated via transmembrane calcium flux, we also studied the effects of three structurally distinct types of organic calcium channel blockers in both H4 and L6 cells. [125I]-T3 uptake as a percent of control values (10(-4) mol/L blocker, n = 4) was as follows: nifedipine, 8.6% +/- 0.9% (H4) and 16.7% +/- 7.2% (L6); verapamil, 24.6% +/- 3.2% (H4) and 61.9% +/- 4.2% (L6); diltiazem, 62.7% +/- 3.6% (H4) and 36.1% +/- 5.4% (L6); all P < .001. Eadie-Hofstee analysis indicated competitive inhibition of T3 uptake for both calmidazolium and nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed2004

Efficacy of calcium channel blocker in the secondary prevention of myocardial infarction--retrospective analysis of the 10-year prognosis or coronary thrombolysis-treated patients.

BACKGROUND: Calcium channel blockers (CCBs) may have a positive influence on the long-term prognosis of Japanese patients with ischemic heart disease. METHODS AND RESULTS: The effect of nifedipine-retard (NR) (n=202) compared with that of non-CCB treatment (n=92) on the secondary prevention of myocardial infarction (MI) was retrospectively investigated in patients who had survived acute MI between 1987 and 1996. The primary endpoint was the occurrence of cardiac death or non-fatal MI. The median follow-up was 6.3+/-2.4 years. The incidence of cardiac events was 8.9% in the NR group and 14.1% in the non-CCBs group (p=0.14, odds ratio (OR): 0.584, 95% confidence interval (CI): 0.286-1,193). However, subanalysis revealed that NR significantly reduced the incidence of cardiac events in patients aged less than 55 years (4.2 vs 18.2%, p=0.016, OR: 0.180, 95%CI: 0.045-0.721) and those who did not smoke (8.6 vs 16.4%, p=0.048, OR: 0.462, 95%CI: 0.203-0.999). CONCLUSION: Although this was a retrospective analysis, it showed that NR did not cause an increase in the incidence of cardiac events in post-MI patients; it even prevented cardiac events, especially in those who were less than 55 years of age and in non-smokers, suggesting the potential usefulness of CCBs in the secondary prevention of MI in Japan.

Aged↗
PubMed2005

Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension.

BACKGROUND: Characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH) who benefit from long-term calcium channel blockers (CCB) are unknown. METHODS AND RESULTS: Acute pulmonary vasodilator testing with epoprostenol or nitric oxide was performed in 557 IPAH patients. Acute responders, defined by a fall in both mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) >20%, received long-term oral CCB. Patients who benefit from long-term CCB were defined as those being in New York Heart Association (NYHA) functional class I or II after at least 1 year on CCB monotherapy. Among the 70 patients who displayed acute pulmonary vasoreactivity (12.6%; 95% CI, 9.8% to 15.3%) and received CCB therapy, only 38 showed long-term improvement (6.8%; 95% CI, 4.7% to 8.9%). Long-term CCB responders had less severe disease at baseline than patients who failed. During acute vasodilator testing, long-term CCB responders displayed a more pronounced fall in mean PAP (-39+/-11% versus -26+/-7%; P<0.0001), reaching an absolute value of mean PAP lower than that measured in patients who failed (33+/-8 versus 46+/-10 mm Hg; P<0.0001). After 7.0+/-4.1 years, all but 1 long-term CCB responders were alive in NYHA class I or II, with a sustained hemodynamic improvement. In the group of patients who failed on CCB, the 5-year survival rate was 48%. CONCLUSIONS: Long-term CCB responders represent <10% of IPAH patients evaluated in a pulmonary vascular referral center. During acute vasodilator testing, these patients showed significantly lower levels of both mean PAP and PVR, which reached near-normal values.

Adult↗
PubMed2000

Benidipine, a long-acting calcium-channel blocker, prevents the progression to end-stage renal failure in a rat mesangioproliferative glomerulonephritis.

BACKGROUND: Although the renoprotective effect of calcium-channel blockers (CCBs) has been examined in several models of hypertensive nephropathy, it remains unclear. It also remains to be clarified whether CCBs prevent the progression to end-stage renal failure in chronic progressive glomerulonephritis (GN). A new rat model of progressive mesangioproliferative GN was used to study the effect of benidipine hydrochloride, a long-acting dihydropyridine CCB, on the clinical features and morphological lesions. METHODS: This animal model of progressive GN was induced by a single intravenous injection of anti-Thy-1 monoclonal antibody (MoAb 1-22-3) two weeks after unilateral nephrectomy. After 10 weeks of treatment with benidipine (1, 3, and 5 mg/kg body weight, p.o.) or hydralazine (5 mg/kg body weight, p.o.), systolic blood pressure (SBP), urinary protein excretion, creatinine clearance, glomerulosclerosis index, tubulointerstitial lesion index, glomerular cross-sectional area, and glomerular expression of transforming growth factor-beta (TGF-beta) and alpha-smooth muscle actin (alpha-SMA) were measured. RESULTS: Untreated rats developed hypertension, massive proteinuria, renal dysfunction, severe glomerular and tubulointerstitial injury, higher glomerular size, and marked glomerular staining for TGF-beta and alpha-SMA, while uninephrectomized control rats did not. Each dose of benidipine and hydralazine equally reduced SBP to uninephrectomized control levels. Three and five mg/kg/day of benidipine increased creatinine clearance, ameliorated glomerular and tubulointerstitial injury, and reduced glomerular staining for TGF-beta and alpha-SMA, but 1 mg/kg/day of benidipine and hydralazine failed. Only a dose of 5 mg/kg/day of benidipine reduced glomerular size, although it did not reduce the size to control levels. CONCLUSION: These results indicate that in a rat model of progressive mesangioproliferative GN, benidipine prevents the progression to end-stage renal failure in a dose-dependent manner. This renoprotective action is associated with the suppression of glomerular expression of TGF-beta and alpha-SMA.

Actins↗
PubMed2004

Design, synthesis, and preliminary pharmacological evaluation of 4-aminopiperidine derivatives as N-type calcium channel blockers active on pain and neuropathic pain.

Several compounds with a 4-aminopiperidine scaffold decorated on both nitrogen atoms by alkyl or acyl moieties containing the structural motifs of verapamil and of flunarizine, as well as those that are more frequent in known N-type calcium channel antagonists, have been synthesized. Antinociceptive activity on the mouse hot-plate test was used to select molecules to be submitted to further studies. Active compounds were tested in vitro on a PC12 rat pheochromocytoma clonal cell line, to evaluate their action on N-type calcium channels, and on a rat model of neuropathic pain. Two compounds that show N-type calcium channel antagonism and are endowed with potent action on pain and neuropathic pain (3 and 18) have been selected for further studies.

Analgesics↗
PubMed1991

Volatile anesthetics depress calcium channel blocker binding to bovine cardiac sarcolemma.

Volatile anesthetics produce their negative inotropic effect on the heart mainly by interference with calcium homeostasis in the myocardial cell. In order to elucidate the mechanism of the depression, we have evaluated the effect of the volatile anesthetics on the binding of the calcium channel blocker [3H]nitrendipine to purified bovine cardiac sarcolemma. The radioligand binding studies were carried out at 25 degrees C, with increasing concentrations of [3H]nitrendipine (0.01-1 nM), in the presence or absence of unlabeled nitrendipine to determine specific binding, and with or without 1.9% halothane, 2.3% isoflurane, and 4.8% enflurane. Separately, [3H]nitrendipine was measured in the presence of increasing doses of halothane (0.78, 1.33, 1.90, and 2.57%). Kinetic studies of association and dissociation rate were performed with 1.90% halothane and 1 nM [3H]nitrendipine at different time intervals. All three volatile anesthetics produced depression of [3H]nitrendipine binding to the isolated cardiac sarcolemma. Only halothane produced a significant depression in binding, ranging between 59 and 66% (P less than 0.05), depending on the concentration of [3H]nitrendipine used. Isoflurane produced 29-38% depression, and enflurane produced 5-22% depression. Halothane also produced a significant (P less than 0.01) dose-dependent decrease in [3H]nitrendipine-specific binding. The kinetic binding experiments demonstrated that the time course for halothane's effect on association and dissociation of [3H]nitrendipine was 5 min for the half-maximum effect; the maximal reduction in binding capacity was at 15-30 min (P less than 0.05). Scatchard analysis revealed that all three volatile anesthetics produced reduction in the maximal number of binding sites; however, they varied in their effect on binding affinity. Only halothane produced a homogenous increase in the dissociation constant, signifying reduced affinity of the Ca2+ blocker to the channel. We suggest that the volatile anesthetics produce conformational changes in these channels consistent with their ability to depress channel-mediated Ca2+ influx into myocytes.

Anesthetics↗
PubMed1998

Possible mechanism for the anti-atherosclerotic action of the calcium channel blocker AE0047 in cholesterol-fed rabbits.

1. The present study was designed to investigate the anti-atherosclerotic effect of AE0047, a calcium channel blocker, and to compare it with that of nilvadipine in cholesterol-fed rabbits. Furthermore, the effects of AE0047 on low-density lipoprotein (LDL) oxidation were studied in vitro. 2. A 7 week treatment period with AE0047 (3 and 10 mg/kg, p.o.) led to a dose-dependent reduction in the lipid deposition area by Oil Red-O staining (surface index) without affecting serum lipid levels. There was no reduction in the surface index following treatment with the same dose of nilvadipine (10 mg/kg). 3. In a vehicle-administered high-fat diet group of rabbits, levels of total cholesterol (TC) and esterified cholesterol (EC) and calcium content in the aorta were increased approximately two- to three-fold over those of the normal diet group. Increased levels of TC and EC and calcium content were reduced to the same levels as the normal diet group by AE0047 treatment, whereas nilvadipine did not affect TC and EC levels. 4. In an in vitro study, AE0047 (10 micromol/L) inhibited LDL oxidation and the aggregation of apolipoprotein (Apo) B-100 induced by Cu2+. Furthermore, AE0047 inhibited the degradation of oxidized LDL by macrophages. In contrast, the same dose of nilvadipine (10 micromol/L) did not inhibit either LDL oxidation or the aggregation of ApoB-100. 5. In summary, AE0047 inhibited LDL oxidation, resulting in a decrease of its uptake into macrophages and an inhibition of cholesterol esterification. This leads to an anti-atherosclerotic effect of AE0047. Thus, AE0047 may have therapeutic potential in preventing cardiovascular disease in hypertensive patients.

Animals↗
PubMed2000

Neurobehavioral protection by the neuronal calcium channel blocker ziconotide in a model of traumatic diffuse brain injury in rats.

OBJECT: Abnormal accumulation of intracellular calcium following traumatic brain injury (TBI) is thought to contribute to a cascade of cellular events that lead to neuropathological conditions. Therefore, the possibility that specific calcium channel antagonists might exert neuroprotective effects in TBI has been of interest. The focus of this study was to examine whether Ziconotide produces such neuroprotective effects. METHODS: The authors report that the acceleration-deceleration model of TBI developed by Marmarou, et al., induces a long-lasting deficit of neuromotor and behavioral function. The voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) exerts neuroprotective effects in this model of diffuse brain injury (DBI) in rats. The dose and time of injection of Ziconotide chosen for the present study was based on the authors' previous biochemical studies of mitochondria. Rats were trained in a series of motor and memory tasks, following which they were subjected to DBI using the Marmarou, et al., model. At 3, 5, and 24 hours, all rats were injected with 2 mg/kg Ziconotide for a total cumulative dose of 6 mg/kg Ziconotide. Control brain-injured animals were injected with an equal volume of saline vehicle at each of these time points. The rats were tested for motor and cognitive performance at 1, 3, 7,14, 21, 28, 35, and 42 days postinjury. Saline-treated rats displayed severe motor and cognitive deficits after DBI. Compared with saline-treated control animals, rats treated with Ziconotide displayed better motor performance during inclined plane, beam balance, and beam walk tests; improved memory while in the radial arm maze; and improved learning while in the Morris water maze. CONCLUSIONS: These results demonstrated that the acceleration-deceleration model, which had been developed by Marmarou, et al., induces severe motor and cognitive deficits. We also demonstrated that Ziconotide exhibits substantial neuroprotective activity in this model of TBI. Improvement was observed in both motor and cognitive tasks, even though treatment was not initiated until 3 hours after injury. These findings support the development of neuronal N-type calcium channel antagonists as useful therapeutic agents in the treatment of TBI.

Animals↗
PubMed1997

Preservation of renal function: the spectrum of effects by calcium-channel blockers.

The vast majority of animal data derived from models of either remnant kidney or diabetes demonstrate that dihydropyridine (nifedipine-like) calcium-channel blockers (DHPCCBs) effectively reduce arterial pressure but do not significantly affect proteinuria nor prevent development of glomerular scarring. Conversely, the non-DHPCCBs such as diltiazem and verapamil blunt both the rise in proteinuria as well as mesangial matrix expansion and subsequent glomerular scarring in diabetes. Additionally, the non-DHPCCBs markedly attenuate development of glomerular scarring in the remnant kidney model. The primary reasons for these differences between subclasses of CCBs relates to a lack of the following attributes by DHPCCBs: (1) they fail to reduce glomerular membrane permeability which is increased in these models; (2) they fail to affect the synthesis of certain key matrix proteins that perpetuate development of glomerular scarring (this effect may be due to the differential expression of calcium channels within the glomerular mesangium); and (3) the DHPCCBs totally abolish renal autoregulation in these models, an effect not observed with non-DHPCCBs. Taken together with long-term (> 3 year) clinical studies, primarily in diabetic nephropathy, it is clear that the non-DHPCCBs seem to offer protection to the kidney not available with DHPCCBs alone, unless systolic arterial pressure is reduced to levels of < or = 110 mmHg.

Animals↗