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One month oral therapy with calcium channel blockers caused significant (P < 0.001) decrease in serum levels of triiodothyronine and thyroxine and significant increase in serum levels of thyroid stimulating hormone in rabbits. Most probable mechanism of action was block in the synthesis and/or release of thyroid hormones.
Hypertension and high levels of proteinuria are independent risk factors for accelerated progression of renal failure. There is increasing evidence that strict control of both blood pressure (BP) and proteinuria are beneficial in slowing the rate of progression of chronic renal disease in diabetic as well as non-diabetic nephropathy. The angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin 2 receptor blockers (ARB) have clearly demonstrated their beneficial effect on both reduction of BP and proteinuria. The calcium channel blockers (CCB) have individual pharmacological and therapeutic properties that may vary, but as a group they are effective antihypertensive agents in patients with renal disease. Their effects on the kidney may extend beyond BP reduction alone. Current studies suggest that CCB do not worsen the progression of renal disease but may rather provide benefit when systemic BP has been tightly normalised. The non-dihydropyridine calcium channel blockers (NDHP), diltiazem and verapamil, slow the progression of type 2 diabetic nephropathy with overt proteinuria almost to a similar extent as observed with ACE-I. The dihydropyridine calcium channel blockers (DHP) have a variable effect on proteinuria. Pharmaceutical compounds, which inhibit the renin-angiotensin system (RAAS), remain the drugs of first choice in the treatment of hypertension and/or proteinuria in chronic nephropathy. However, a combination of two or more drugs is almost always required to attain sufficient BP reduction. CCB may have an advantage in combination with ACE-I and/or ARB.
BACKGROUND: The aetiology of perforated colonic diverticular disease (PCDD) remains largely unknown. Perforation may result from a combination of high intracolonic pressures, secondary to excessive colonic segmentation, and impairment of the mucosal barrier. Calcium channel blockers and antimuscarinic drugs, which reduce colonic contractility and tone, could potentially protect against perforation. The aim of this study was to test this hypothesis using a case control design. METHODS: All cases of acute PCDD were identified over a five year period in two hospitals in Norfolk, UK. Each case was matched for age, sex, and date of admission to two controls groups: (1) patients undergoing cataract surgery and (2) patients with basal cell carcinoma. Data on drug use prior to hospital admission were obtained from medical and nursing records and compared between cases and controls. RESULTS: A total of 120 cases of PCDD were identified and matched to 240 controls in each group. A statistically significant protective association was seen between calcium channel blocker use and PCDD using both control groups. The odds ratios were 0.41 (95% confidence interval (CI) 0.18-0.93) using the ophthalmology control group and 0.36 (95% CI 0.16-0.82) using the dermatology control group. CONCLUSIONS: This study has shown for the first time that a protective association exists between calcium channel blockers and PCDD. The validity of this association is supported by the consistent finding in both control groups and the plausible biological mechanisms. Further studies are required to confirm this association but calcium channel blockers may represent a potential preventive therapy in PCDD.
The effects of the calcium channel blocker nisoldipine on renal function after 60 min. normothermic ischemia and contralateral nephrectomy were studied in male Wistar rats. Nisoldipine (300 ppm) was given in a standard diet as well as one hour prior to ischemia (10 mg./kg. orally). Survival, serum urea, serum creatinine, urine volume and creatinine clearance were used to test the effectiveness of the drug. Nisoldipine treatment resulted in the survival of all animals (compared to 66.6 per cent in the untreated group) and improved immediate and long term (14 days) renal function. The drug given post ischemia only was not effective, suggesting that nisoldipine must be present in the kidney during ischemia. The beneficial effects of the drug in postischemic acute renal failure may be attributed in part to effects on postischemic renal hemodynamics. Additional direct effects on ischemic renal epithelial cells, presumably by inhibiting transmembrane calcium fluxes, cannot be excluded.
In electrophysiologic studies we have previously shown that the calcium-channel blockers nifedipine, verapamil, and diltiazem have different actions on the atrioventricular node: nifedipine has no evident effect at a dose of 7.5 micrograms/kg of body weight intravenously, whereas verapamil (0.15 mg/kg) and diltiazem (0.25 mg/kg) both prolong the AH interval significantly and terminate or slow reciprocating atrioventricular tachycardia involving the atrioventricular node alone or in association with an accessory pathway. None of the calcium-channel blockers tested influenced intraventricular conduction, but all increased the sinus rate. Since these properties suggested that it would be safer to combine nifedipine, rather than verapamil and diltiazem, with beta-adrenergic blockers in the treatment of ischemic heart disease, we tested this combination for efficacy and safety. Our previous results have now been reviewed, and they show that according to both subjective and objective criteria, nifedipine adds benefits to the action of propranolol in the management of chronic stable angina pectoris. No adverse effects were seen in our series, and beneficial influences were noted in patients with elevation of blood pressure. Side effects reported by others and said to arise from the interaction between nifedipine and beta blockers are analyzed, and prudence is suggested before the combination, or indeed any negative inotropic agent, is given to patients with impaired left ventricular function. The previous reports cannot be taken to indicate that nifedipine has a greater tendency to produce adverse effects in this combination than does the beta-adrenergic blocker.
OBJECTIVES: This study investigates the effect of a range of potential risk factors on the severity of gingival overgrowth in transplant patients medicated with ciclosporin in the absence of any calcium channel blockers. MATERIALS AND METHODS: One hundred dentate solid organ transplants medicated with ciclosporin (but not calcium channel blockers or phenytoin) were recruited for the study. Demographic, pharmacological and periodontal data were recorded and gingival overgrowth assessed from stone models. RESULTS: Univariate analysis identified the duration of transplant, papilla bleeding index, creatinine serum concentration, azathioprine and prednisolone dosage as risk factors for overgrowth severity. Multivariate modelling, excluding the periodontal parameters, gave a predictive model that included dosages of ciclosporin, azathioprine, prednisolone and weight (p<0.0001, adjusted-R2=19%). Adding the periodontal variables strengthened the model (p<0.0001, adjusted-R2=34.5%). CONCLUSION: The explanatory models in this study contain a number of variables that moderate inflammation (azathioprine and prednisolone) or are markers of it (papilla bleeding index). Dosage of each of the three immunosuppressants was identified as a risk factor for the severity of gingival change. This observation appears to have been masked by the effects of the calcium channel blockers in earlier studies.
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KB-2796, a novel calcium channel blocker, is under development as an anti-migraine drug. We examined its effects on spreading depression (SD) in rat hippocampal slices as compared with those of flunarizine, dimetotiazine and sumatriptan. Extracellular recording was made from the CA1 subfield. An SD, followed by a series of spontaneous SDs, was induced by a brief period of hypoxia (40-60 sec). The latency of initiated SD and the interval between the initiated and subsequent spontaneous SDs were examined. KB-2796 significantly prolonged both latency and interval in a concentration-dependent manner (10(-10)-10(-8) M). KB-2796 was about 1,000 and 10 times more potent than flunarizine in prolonging the latency and interval, respectively. However, dimetotiazine and sumatriptan did not show any activity at 10(-7) and 10(-6) M. the effect of KB-2796 on SD may be due to their calcium channel blocking effects.
OBJECTIVE: Recent reports have linked calcium channel blockers (CCBs) with an increased risk of acute myocardial infarction (AMI). We sought to determine to what extent physicians relinquished CCBs following these adverse reports and if there were differences in the use of CCBs and other AMI therapies across 3 levels of specialist involvement: generalist attendings, collaborative care (generalist with cardiologist consultation), and cardiologist attendings. DESIGN: We measured use of CCBs during hospitalization for AMI before (1992--1993) and after (1995--1996) the adverse CCB reports, controlling for hospital-, physician-, and patient-level variables. We also examined use of effective medications (aspirin, beta-blockers, thrombolytic therapy) and ineffective AMI treatments (lidocaine). SETTING: Thirty-seven community-based hospitals in Minnesota. PATIENTS: Population-based sample of 5,347 patients admitted with AMI. MEASUREMENTS: The primary outcome was prescription of a CCB at the time of discharge from hospital. Secondary outcomes included use of other effective and ineffective AMI therapies during hospitalization and at discharge. MAIN RESULTS: Compared with cardiologists, generalist attendings were less likely to use aspirin (37% vs 68%; adjusted odds ratio [OR], 0.58; 95% confidence interval [95% CI], 0.42 to 0.80) and thrombolytics (29% vs 64%; adjusted OR, 0.18; 95% CI, 0.13 to 0.25), but not beta-blockers (20% vs 46%; adjusted OR, 0.93; 95% CI, 0.66 to 1.31). From 1992--1993 to 1995--1996, the use of CCBs in patients with AMI decreased from 24% to 10%, the net result of physicians starting CCBs less often and discontinuing them more often. In multivariate models, the odds of CCB relinquishment after the adverse reports (adjusted OR, 0.33; 95% CI, 0.27 to 0.39) were independent of, and not modified by, the involvement of a cardiologist. CONCLUSIONS: Compared with cardiologists, generalist physicians were less likely to adopt some effective AMI therapies, particularly those associated with risk such as thrombolytic therapy. However, generalists were as likely as cardiologists to relinquish CCBs after the adverse reports. This pattern of practice may be the generalist physicians' response to an expanding, but increasingly risky and uncertain, pharmacopoeia.
The development of a group of calcium channel blockers that prolong the QT interval has raised interest in their possible proarrhythmic potential. In animal experiments lidoflazine has no observed arrhythmogenic potential and no antiarrhythmic potential in a model sensitive to the antiarrhythmic properties of both conventional and investigational agents. This lack of antiarrhythmic potential reduces the possible proarrhythmic potential even further, since it has been my observation that many of the more potent antiarrhythmic agents may facilitate arrhythmias in a considerable percentage of the most severely ill patients. Bepridil has both slow channel blocking properties and fast channel blocking effects and thus possesses an antiarrhythmic effect beyond the prolongation of repolarization. Even though early studies with humans showed the drug to be no more effective than the conventional reference agent procainamide, its potential cannot be fully assessed by these preliminary studies. The assessment of arrhythmogenicity is determined by use of the technique of PES. This technique has been shown effective in identifying patients with electrical instability and in identifying the effectiveness of antiarrhythmic agents in preventing VT and sudden death. Thus it seems probable that PES studies may be effective in predicting which drug or agent would facilitate arrhythmias. Alcohol, caffeine, cigarette smoke, and catecholamines facilitate PES induction of VT, lending support to the hypothesis that PES studies can be used to identify proarrhythmic drugs. In fact, patients who experience cardiac arrest on a class I agent can have VT provoked on that agent but not on antiarrhythmic drug therapy. PES thus identifies the proarrhythmic effect of the drug in that particular patient.(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVE: To analyze the effect of the long-acting calcium channel blocker lacidipine on cardiovascular remodeling induced by salt loading in a genetic model of hypertension. DESIGN: We examined the influence of threshold doses of lacidipine, with little blood-pressure lowering effect, on cardiac weight and gene expression in stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: SHRSPs (8-week-old) were randomly allocated to four groups: control, salt-loaded SHRSP and salt-loaded SHRSP treated with lacidipine at 0.3 and 1 mg/kg per day. Systolic blood pressure was measured by the tail-cuff method. At the end of 6 weeks of treatment, ventricles were collected and weighed. Ventricular messenger RNA was extracted and subjected to Northern blot analysis. RESULTS: Lacidipine (0.3 mg/kg per day) not only prevented the salt-dependent cardiac hypertrophy and the slight increase in systolic blood pressure induced by salt, but also prevented, largely or completely, salt-dependent increases in ventricular levels of several gene products: skeletal and cardiac alpha-actin, beta-myosin heavy chain (beta-MHC), type I collagen, long-lasting (L)-type calcium channel and preproendothelin-1. At a higher dose of 1 mg/kg per day, lacidipine further decreased systolic blood pressure below the level of control SHRSP, completely prevented salt-dependent overexpression of the beta-MHC gene and markedly attenuated salt-dependent overexpression of the transforming growth factor-beta1 gene. CONCLUSIONS: Lacidipine prevents the cardiac remodeling and enhanced gene expression induced by salt loading in SHRSP at doses that only minimally affect the high systolic blood pressure.
The membrane voltage was measured in cultured bovine trabecular meshwork cells. External barium (Ba2+; 10 mM) evoked repetitive overshooting action potentials which were reversibly inhibited by 10(-6) M nifedipine but insensitive to tetrodotoxin (10(-5) M). In contrast, no action potentials could be induced in bovine corneal endothelial cells. The vasoactive peptide endothelin (10(-9)-10(-6) M) induced dose-dependent depolarizations. The intracellular calcium concentration measured by the fura-2 method increased after endothelin application. An initial peak was followed by a sustained plateau. The effect of endothelin on the membrane potential and intracellular calcium value is typical for smooth muscle cells showing a contractile response to the peptide. Recent studies have shown the contractility of bovine trabecular meshwork. We conclude that calcium-channel antagonists and endothelin may alter the aqueous humour outflow through the trabecular meshwork.
The efficacy of the calcium channel blocker nitrendipine in preventing early renal and glomerular hypertrophy and increased urinary albumin excretion (UAE) was studied in experimental diabetes in rats, starting treatment at the onset of diabetes. Female Wistar rats were randomised into four groups: diabetic and non-diabetic rats were given either placebo or nitrendipine (250 mg/kg) in the diet for 8 weeks. After 8 weeks the kidneys in the diabetic animals had increased significantly compared to the non-diabetic controls. In the diabetic nitrendipine-treated animals renal and glomerular hypertrophy was significantly smaller than in the diabetic placebo-treated group (p < 0.05). After an initial increment within the first week, the UAE remained constant throughout the study period in the diabetic nitrendipine-treated animals, while a steady increase was seen in the diabetic placebo-treated group (p < 0.05). No differences were seen in systemic blood pressure between calcium- channel-blocker-treated groups and placebo-treated groups. In conclusion, administration of nitrendipine to diabetic rats for 8 weeks had a significant inhibitory effect on renal and glomerular hypertrophy, and showed a tendency towards a reduction in UAE (p = 0. 06) without affecting metabolic control or systemic blood pressure.
The present study was designed to investigate the pharmacokinetic interaction of morphine with three classes of L-type calcium channel blockers (CCB) and its relationship to morphine-induced mechanical antinociception in mice. The CCB classes were benzothiazepine (diltiazem), dihydropyridine (nimodipine), and phenylalkylamine (verapamil). Each of the three classes of L-type CCB (diltiazem, 40 and 80 mg/kg; nimodipine, 40 mg/kg; verapamil, 40 mg/kg), when administered prior to morphine (4 mg/kg, s.c.), potentiated the analgesic effect of morphine and markedly increased the level of morphine in serum. Pretreatment with diltiazem (40 and 80 mg/kg) and verapamil (40 mg/kg) also increased morphine level in the brain. However, these drugs produced less increase in morphine level in the brain than they produced in serum (i.e., they decreased the brain-to-serum ratio of morphine). Pretreatment with nimodipine (40 mg/kg) did not affect the morphine level in the brain and also decreased the brain-to-serum ratio of morphine. When morphine (3.2-100 mg/kg, s.c.) was injected alone, the brain-to-serum ratio of morphine was constant, regardless of the morphine dose. These results suggest that increases in morphine concentration in peripheral blood may be, at least in part, involved in the ability of L-type CCBs to potentiate the analgesic effect of morphine.
The distribution of calcium in isolated bovine pituitary secretory granules was studied by atomic absorption. The total granule calcium (in 26 preparations) averaged 14.5 nmol/mg protein, or 21.2 +/- 1.6% of the total pituitary homogenate calcium. Incubation of granules with KCl resulted in calcium release (78% at 15 mM and 100% at 50 mM, for example). Calcium release was also pH dependent, with greater release at acidic pH values; it was not influenced by either 500 microM strontium or 500 microM lanthanum. Release was augmented by reduced glutathione (GSH), with significant release observable at thiol levels as low as 10 microM. In addition to GSH, cysteine also stimulated release; mercaptoethanol and dithiothreitol were less potent. Interestingly, the disulfides cystine and oxidized glutathione also stimulated calcium release. Since the latter compounds are known to inhibit hormone release from granules, calcium and protein release appear to be regulated independently. A number of dihydropyridines were tested as potential blockers of calcium release from granules. Nimodipine inhibited basal calcium release at high concentrations and potently inhibited GSH-stimulated calcium release, with an apparent Ki in the 10-20 nM range; it also inhibited K(+)-stimulated release but to a lesser extent. Nimodipine, however, did not significantly influence protein or hormone release. GSH-stimulated calcium release was also inhibited by nifedipine, and this inhibition was qualitatively and quantitatively similar to that by nimodipine. Nisoldipine and nitrendipine, however, displayed no significant inhibition. In summary, it appears that the release of secretory granule calcium in vitro is independent of protein release. Thiols and some disulfides stimulate calcium release, and its inhibition by dihydropyridines suggests that granule membranes may contain specific ion channels. The role of granule calcium in the cell remains to be defined.
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AIMS/HYPOTHESIS: Calcium channel blockers, widely used for the treatment of hypertension and angina, could prevent cardiovascular complications in patients with diabetes. They can improve cardiac remodelling in animal models of a variety of cardiovascular diseases. Here, we examined the therapeutic effect of benidipine, a long-acting calcium channel blocker, on cardiac remodelling in Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a Type II (non-insulin-dependent) diabetes mellitus model. METHODS: The methods for morphometric analysis included double staining for coronary capillaries, dye-binding staining for collagen content and Masson's trichrome staining for perivascular fibrosis. Immunohistochemical and in situ hybridization techniques were used for detecting protein and mRNA expressions for vascular endothelial growth factors (VEGF), basic fibroblast growth factors (bFGF) and TGF-beta(1), endothelial nitric oxide synthase (eNOS), and anti- and pro-apoptotic markers. RESULTS: OLETF rats showed an increased coronary capillary density, a reduced venular capillary proportion, an increased cardiac collagen content and prominent cardiac perivascular fibrosis. In OLETF rat hearts, significant increases in vascular expressions for VEGF, bFGF and TGF- beta(1) were found. Furthermore, the apoptosis signalling pathways, involving eNOS and apoptotic markers, were markedly altered, and coronary endothelial cell apoptosis was lower. These alterations with the exception of eNOS expression were significantly blocked by benidipine treatment. CONCLUSION/INTERPRETATION: The suppressive effect of benidipine on overproduction of angiogenic growth factors could prevent cardiac angiogenesis and fibrosis, resulting in an improvement of cardiac remodelling in diabetes. As VEGF and bFGF potently block endothelial cell apoptosis execution, physiological apoptosis revived by benidipine treatment could also contribute to coronary vessel regression.
BACKGROUND/AIM: Although long-term, intensive blood pressure (BP) control with calcium channel blockers (CCBs) reduced arterial stiffness and renal damage of hypertensive patients, combination therapy with antihypertensive drugs is frequently needed to maintain the intensive BP control. The present study was conducted to examine add-on benefits of candesartan therapy on hypertensive patients treated with CCBs for at least 12 months. METHODS: Pulse wave velocity (PWV), urinary albumin excretion (UAE), intima-media thickness (IMT) of the carotid arteries, and 24-hour ambulatory BP were determined in 50 non-diabetic hypertensive patients treated with CCBs before and 12 months after the start of therapy with candesartan or placebo. RESULTS: Candesartan significantly decreased clinic BP and tended to decrease ambulatory BP, but the decreases were similar to those in the placebo group except nocturnal BP decrease, which was significantly enhanced by candesartan. Add-on candesartan significantly decreased PWV and UAE compared to placebo, but IMT was unchanged with candesartan or placebo. The decrease in clinic BP or nocturnal BP decrease did not contribute to the improvement of PWV or UAE. CONCLUSION: Add-on candesartan functionally improved the stiffened arteries of hypertensive patients treated with CCBs by the end of 12 months of treatment independently of its effects on BPs.