非二氢吡啶类钙离子拮抗剂的肾脏保护作用

近十余年肾脏病学者通过动物及I临床试验发现非二氢吡啶类钙离子拮抗剂存在肾脏保护作用,逐渐成为慢性肾脏疾病治疗中继ACEI及ARB之后可选择的肾脏保护药物.尤其对肾脏血流动力学及非血流动力学方面的影响而达到减少尿蛋白、延缓肾功能进展的作用,已有临床报道其单独使用及与AUEI联合应用的肾保护作用.本文对此领域近年的研究进展作一综述.     

Cardiovascular and renal protection in type 2 diabetes mellitus: the role of calcium channel blockers

The most important factor that prevents the progression of renal damage in diabetes mellitus, beside the improvement of blood glucose control, is tight BP control. The tenet of tight BP control may be defined as the lowest BP level one can accomplish using antihypertensive therapy that is at the same time compatible with the absence of untoward side effects. In fact, both the Framingham Heart Study in nondiabetic normal subjects and the United Kingdom Prospective Diabetes Study in type 2 diabetic patients showed that systolic values as low as 108 to 111 mmHg and diastolic values as low as 70 to 71 mmHg are significantly associated with decreased cardiovascular mortality and morbidity. However, 45 to 50% of the patients with type 2 diabetes mellitus and hypertension have systolic BP levels above 140 mmHg during antihypertensive therapy, particularly when using monotherapy. Thus the issue regarding the choice of which drugs one should use to treat hypertension became critical from a clinical point of view. Pharmaceutical compounds, which inhibit the renin-angiotensin system, have become the first-choice treatment in patients with diabetes mellitus and incipient and advanced renal complications. The present brief review analyzes the effects of calcium channel blockers (CCB) on cardiovascular and renal complications in diabetes mellitus. The review discussed those studies that directly and blindly compared CCB with angiotensin-converting enzyme (ACE) inhibitors and with angiotensin II AT(1) receptor blockers (ARB). Furthermore, size of the population recruited in each trial was used as a criterion of priority in the selection of the reports from the available literature. From the point of view of cardiovascular complications, the results of these studies showed a slightly better benefit of CCB on stroke, whereas ACE inhibitors better prevented the occurrence of myocardial infarction and congestive heart failure. On the other hand, recent observations demonstrated that also ACE inhibitors and ARB are effective in the primary and secondary prevention of stroke, although these studies did not directly compare these compounds with CCB. With regard to the outcome of renal complications, both ARB and ACE inhibitors more effectively prevented the progression of renal damage among the patients with overt nephropathy than CCB. On the contrary, both CCB and ACE inhibitors were equally effective on blunting the decay of GFR in diabetic patients who do not have overt proteinuria. However, ACE inhibitors and ARB more markedly decreased the rate of albumin excretion rate in the range of both microalbuminuria and macroalbuminuria. Recent advances in the understanding of the pathogenesis of abnormalities of albumin excretion rate and of atherosclerosis are also discussed. Both mechanical stress, mainly secondary to systolic hypertension, and elevated circulating and tissue levels of angiotensin II, partially independent from each other, cause excessive generation of superoxide compounds. This chain reaction of events in turn leads to disorders of structural components of glomerular filter and to damage of the vascular wall. Systolic BP control (<130 mmHg) is not adequately accomplished in the majority of the patients treated only with ACE inhibitors and ARB, even in association with diuretics. Poor BP control may lead to excessive systemic mechanical stress at the vascular level despite satisfactory inhibition of angiotensin II effects. In conclusion, one can suggest that CCB are useful and often indispensable pharmaceutical compounds, beside ACE inhibitors and ARB, to accomplish tight BP control (<130/85 mmHg), a target that is unlikely to be successfully maintained in the overall population of type 2 diabetic patients only by ACE inhibitors or ARB, as monotherapy. However, ACE inhibitors and ARB might be considered first-choice drugs in the treatment of hypertension in diabetes mellitus, mainly because of a better renoprotection.     

Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications

It is no a secret that we are confronted by an alarmingly increasing number of patients with progressive renal disease. There is ample evidence for the notion that angiotensin II (Ang II) is a major culprit in progression. The vasopeptide Ang II turned out to have also multiple nonhemodynamic pathophysiologic actions on the kidney, including proinflammatory and profibrogenic effects. Diverse complex Ang II generating systems have been identified, including specifically local tissue-specific renin-angiotensin systems (RAS). For example, proximal tubular cells have all components required for a functional RAS capable of synthesizing Ang II. On the other hand, Ang II is not the only effector of the RAS and other peptides generated by the RAS influence renal function and structure as well. Moreover, the discoveries that Ang II can be generated by enzymes other than angiotensin-converting enzyme (ACE) and that Ang II and other RAS derived peptides bind to various receptors with different functional consequences have further added to the complexity of this system. Several major clinical trials have clearly shown that ACE inhibitor treatment slows the progression of renal diseases, including in diabetic nephropathy. Well-controlled studies demonstrated that this effect is in part independent of blood pressure control. More recently, with Ang II type 1 receptor (AT(1)) receptor antagonists a similarly protective effect on renal function was seen in patients with type 2 diabetes. Neither ACE inhibitor treatment nor AT(1) receptor blockade completely abrogate progression of renal disease. A recently introduced novel therapeutic approach is combination treatment comprising both ACE inhibitor and AT(1) receptor antagonists. The rationale for this approach is based on several considerations. Small-scale clinical studies, mainly of crossover design, documented that combination therapy is more potent in reducing proteinuria in patients with different chronic renal diseases. Blood pressure as an important confounder was, however, significantly lower in the majority of this studies in the combination treatment arms compared to the respective monotherapies. In a recent prospective study Japanese authors avoided this confounder and demonstrated that combination therapy reduced hard end-points (end stage renal failure or doubling of serum creatinine concentration) by 50% compared to the respective monotherapies. This effect could not be explained by a more pronounced reduction of blood pressure in the combination therapy group. Although these results are encouraging, administration of combination therapy should be reserved currently to special high risk groups. Further studies are necessary to confirm these promising results. It is possible that combination therapy may increase the risk of hyperkalemia, particularly when with coadministered with medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or spironolactone. In our opinion patients with proteinuria >1 g/day despite optimal blood pressure control under RAS-blocking monotherapy are a high-risk group which will presumably benefit from combination therapy.     

Improved outcome of cadaveric renal transplantation due to calcium channel blockers

Calcium channel blockers (CCB) administered to recipients of cadaveric renal transplants have been shown to improve graft function, decrease the incidence of delayed function, prevent acute cyclosporine toxicity, and lessen the number of rejection episodes in the first several weeks posttransplant. In order to determine whether CCB provide a similar long-term benefit, a retrospective analysis of 83 first cadaveric renal transplants performed in 1987 and 1988 was performed. The clinical course of 17 patients who were discharged and maintained on CCB therapy for 1 year was compared with that of 24 patients who never received CCB during the same 1-year period. The remaining 42 patients were excluded for failing to meet these inclusion criteria. The two groups were similar with respect to age, sex, cold ischemia time, degree of sensitization, HLA matching, DR matching, and DR mismatching. The no CCB group did receive a significantly greater number of pretransplant transfusions. In the 1 year of follow-up, graft loss in the CCB group was less than in the no CCB group (1/17, 5.9% vs. 6/24, 25%). There was a striking decrease in the percentage of first rejection episodes in the CCB group as compared with no CCB therapy (35% vs. 83%, P less than 0.005). In addition, a similar decrease in second rejection episodes was found in the CCB group (18% vs. 33%, P less than 0.05). The two groups also were compared with respect to graft function. Despite similar serum creatinine levels at 1 month (CCB 1.8 mg% vs. no CCB 2.2 mg%, P = 0.37) and 1 year (CCB 1.7 mg% vs. no CCB 2.4 mg%, P = 0.19), the CCB group had a significantly higher glomerular filtration rate at 1 month (53.9 vs. 38.7, P less than 0.05) and 1 year (57.0 vs. 35.0, P less than 0.001) as measured by clearance of radiolabeled iothalamate. These results suggest that the short-term improvements noted in both graft function and rejection episodes with CCB are maintained for the first year posttransplant. More importantly, CCB use results in improved 1-year graft survival.     

Role of the fixed-dose combination lercanidipine-enalapril in renal protection

Even with the availability of novel and efficacious antihypertensive agents, an insufficient number of hypertensive patients achieve their desired blood pressure (BP) target. This failure is partly due to the fact that many patients do not strictly adhere to their drug therapy and/or they report the presence of adverse effects. Traditionally, monotherapy is used as first-line treatment to achieve BP targets; however, when this fails, combination therapy is then required. In light of the need to attain BP goals, combination therapy (especially fixed-dose) is currently recommended. The main advantages of combination therapy over monotherapy are not only that of reduced dose, improved efficacy and reduced adverse effects, but also of target protection and reduced cardiovascular (CV) risk. Therefore, the development of single-administration drug combinations should also improve patient adherence to therapy and therefore help in achieving BP control. Among the various combinations available, calcium channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors have been proven to be extremely effective, while also displaying good tolerability. Individually, both the third-generation CCB lercanidipine and the ACE inhibitor enalapril are effective antihypertensive agents. In addition, both of these agents also show other beneficial effects when administered as monotherapy. Of particular importance is the fact that when lercanidipine plus enalapril are administered in combination, they show synergism, thus providing added efficacy with reduced side effects. The present report provides an overview of the main clinical studies examining lercanidipine and enalapril administered as monotherapy, with particular focus on the potential renoprotective effects afforded by the fixed-dose combination lercanidipine-enalapril.     

Gingival overgrowth in renal transplant subjects medicated with tacrolimus in the absence of calcium channel blockers

BACKGROUND: The results from reports analyzing the occurrence of gingival overgrowth (GO) induced by tacrolimus are controversial. In addition, the role of pharmacological and periodontal variables on the development and severity of GO have not been well-established. Therefore, the aim of the present study was to determine the effect of potential risk variables for GO in a Brazilian population comprising renal transplant recipients medicated with tacrolimus in the absence of calcium channel blockers. MATERIALS AND METHODS: Demographic, pharmacological, and periodontal data, recorded from 125 subjects selected to participate in the study, was analyzed with the use of the independent sample t test, the chi-squared statistic, or Mann-Whitney test. The effects of risk variables on GO scores were subsequently examined using multivariate regression analysis and general linear model. RESULTS: The prevalence of clinically significant GO (> or =30%) in the study population was of 7.25%. These subjects showed greater averages of plaque scores (P=0.0043) as well as papillary bleeding index (P=0.0026) when compared to subjects with GO <30%. Papillary bleeding index, time since transplant and azathioprine dosage were significant in the univariate and multivariate models (adjusted R=43.8%), whereas plaque index was significant only in the univariate model. CONCLUSIONS: This study revealed that, in the absence of calcium channel blockers, gingival inflammation, represented by the papillary bleeding index, was a variable associated with Tcr-induced GO, indicating the importance of periodontal maintenance of subjects under Tcr immunosuppressive regimens.     

Anaesthetic implications of calcium channel blockers

Clinical uses of calcium channel blockers are expanding. In addition to the established uses in patients with arrhythmias, angina pectoris or hypertension, newer and to some extent investigational uses indicate widespread application. For instance, their use has been reported in hypertrophic cardiomyopathy and cold cardioplegia, as well as in pulmonary hypertension, antiplatelet therapy, asthma, achalasia and oesophageal spasm, increased intraocular pressure and in cerebral vasospasm. Their use in obstetrical practice has been proposed. Thus, the presentation of a patient who is treated with calcium channel blockers and who requires anaesthesia will become more common. Calcium channel blockers may, under certain circumstances, potentiate haemodynamic and MAC depressive effects of inhalation agents. There is also evidence that the effects of neuromuscular blocking agents may be potentiated. The anaesthetist should be aware that the potential for interactions exists with digoxin, propranolol, quinidine, theophylline or dantrolene. Of interest and some significance are the anaesthetic implications of pathophysiological alterations that can be induced by calcium channel blockers, by affecting lower oesophageal tone, intracranial hypertension, bronchomotor tone (asthma), muscular dystrophy, neuromuscular function, hypoxic pulmonary vasoconstriction, malignant hyperthermia, inhibition of platelet aggregation and hyperkalemia. Despite these significant potential anaesthetic implications and because, at this time, in some instances withdrawal has clearly demonstrated increase in the signs of myocardial ischaemia, it would not seem necessary to recommend preoperative discontinuation of calcium channel blocker medication in patients presenting for anaesthesia. It is, however, appropriate that there is a high index of awareness of potential problems, unless there is some modification in inhalation anaesthetic concentrations and neuromuscular blocker dosage. Monitoring of cardiovascular and neuromuscular functions is essential. Calcium channel blockers would appear to be currently the drugs of choice for angina pectoris, arrhythmias or hypertension in patients with associated chronic obstructive pulmonary disease.     

Calcium channel blockers and renal protection: insights from the latest clinical trials

Calcium channel blockers have been widely used in clinical practice because of their antihypertensive capacity. Prevention of renal damage is a very important aim of antihypertensive therapy. This is particularly so taking into account the high prevalence of chronic kidney disease (CKD) in the general population. Recent data have shown that CKD is related to the absence of adequate BP control and also to the clustering of other cardiovascular risk factors seen in the metabolic syndrome. The knowledge of the capacities of the different antihypertensive drugs or their combinations to simultaneously control BP while protecting the kidney and avoiding the facilitation of metabolic alterations is warranted. Recent data from the Intervention as a Goal in Hypertension Treatment trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and African American Study of Kidney Disease and Hypertension (AASK) allow the conclusion that in hypertensive patients with preserved renal function or with CKD, calcium channel blockers are effective antihypertensive drugs to be considered alone or in combination with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.     

The benefits of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers combined with calcium channel blockers on metabolic,renal, and cardiovascular outcomes in hypertensive patients: a meta-analysis

Background

The prevalence of hypertension and its associated complications are markedly growing. Most patients need more than one drug to achieve blood pressure (BP) target. However, most guidelines only focus on the first-line treatment. We conducted a meta-analysis to explore the benefits of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) combined with calcium channel blockers (CCBs) on metabolic, renal, and cardiovascular outcomes in hypertensive patients.

Methods

A systematic literature search was conducted in MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov (until April 7, 2016) to identify randomized controlled trials (RCTs) comparing the benefits of ACEIs/ARBs combined with CCBs versus other dual or triple combinations on clinical outcomes in hypertensive patients. Random effects models were used to compute the weighted mean difference (WMD) for continuous variables.

Results

Sixty RCTs (48,913 patients) were identified. When compared with other combinations, the combination of ACEIs/ARBs and CCBs had comparable WMD of systolic as well as diastolic BP (73 study arms) but provided better benefits on metabolic parameters, such as HDL, FBS, HbA1C, and serum uric acid; renal functions, including serum creatinine and estimated glomerular filtration rate; and cardiovascular diseases, including reduction of all cardiovascular events, myocardial infarction, and syncope/hypotension. A significant increase of serum potassium was observed.

Conclusion

The combination of ACEIs/ARBs with CCBs has superior benefits on metabolic, renal, and cardiovascular outcomes in hypertensive patients. Therefore, this combination should be considered whenever monotherapy does not achieve the guideline target.

     

Potentiation of vincristine effect in human and murine gliomas by calcium channel blockers or calmodulin inhibitors

The effects of calcium channel blockers and calmodulin inhibitors on vincristine cytotoxicity were studied in vitro with five glioma cell lines: three human glioblastomas, one rat glioma, and one mouse ependymoblastoma. One human glioblastoma and the rat glioma were resistant to vincristine in contrast to other glioma cells. The resistance to vincristine was considerably decreased by nontoxic or marginally toxic concentrations of calcium channel blockers or calmodulin inhibitors, although the former was more effective than the latter. In the presence of verapamil, the vincristine cytotoxicity, as measured by cell doubling times, increased 90- and 84-fold in the vincristine-resistant human glioblastoma and rat glioma, respectively. The decrease in the resistance to vincristine was related to a marked increase in the intracellular level of that drug, probably mediated by inhibiting its outward transport. The in vivo studies showed that verapamil or nicardipine administered daily with vincristine for 10 days significantly enhanced the chemotherapeutic effect of vincristine in an intracranially transplanted rat glioma model. An approximately 32% to 118% increase in life span occurred with 15 mg/kg/day of verapamil, depending on the doses of vincristine.     

两种钙离子拮抗剂对ESWL时保护肾功能的初探

为了避免和减小ＥＳＷＬ对肾功能的损伤，应用两种钙离子拮抗剂（络活喜、硝苯地平）进行研究对照。６０例肾盂及输尿管上段结石进行ＥＳＷＬ治疗，随机分为络活喜组，硝苯地平组和对照组，各２０例。ＥＳＷＬ前３天分别口服络活喜，硝苯地平；对照组不服用任何药物。采用放射免疫法测定ＥＳＷＬ前后２４小时尿α微球蛋白（α１ＭＧ）、β２－微球蛋白（β２ＭＧ）、白蛋白（Ａｌｂ）、ＴＨ糖蛋白（ＴＨＰ）及尿免疫球蛋白（ＩｇＧ）的变化。ＥＳＷＬ后对照组尿α１ＭＧ、β２ＭＧ、Ａｌｂ及ＩｇＧ分泌量明显高于ＥＳＷＬ前水平（Ｐ＜０００１）；尿ＴＨＰ明显低于ＥＳＷＬ前水平（Ｐ＜０００１）。络活喜组尿Ａｌｂ、ＩｇＧ比ＥＳＷＬ前增加（Ｐ＜００１，Ｐ＜００５）。硝苯地平组仅尿Ａｌｂ比ＥＳＷＬ前增加（Ｐ＜００５）。认为两种钙离子拮抗剂对ＥＳＷＬ时肾功能损害均有保护作用，硝苯地平的疗效优于络活喜。     

Effects of intracavernous calcium channel blockers in dogs

Intracavernous injection of smooth muscle relaxing agents can induce penile erection. In this experimental study, we compared the effects of intracavernously injected calcium channel blockers (CCBs) and papaverine in dogs, and investigated their clinical applicabilities. We administered 30 mg papaverine, 10 mg nifedipine, 10 mg nitrendipine and 2.5 mg verapamil to 10 adult male dogs intracavernously, each at different times. Intracavernous pressure values, systemic arterial pressure values and heart rate values were recorded for 45 minutes after the intracavernous injections. We used the paired Studentt-test for statistical analysis. Papaverine induced full erection in all of the 10 dogs. Nifedipine induced full erection in 4, nitrendipine in 5, and verapamil in 6 of the 10 dogs. Nifedipine and nitrendipine caused significant decreases in blood pressure and increases in heart rate. In conclusion, the effects of intracavernous CCBs are not superior to those of papaverine. We cannot recommend nifedipine and nitrendipine for intracavernous injection, but verapamil may be included in intracavernous pharmacotherapeutic combinations.     

Benefits of candesartan on arterial and renal damage of non-diabetic hypertensive patients treated with calcium channel blockers

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.     

The interaction of the calcium channel blockers verapamil and nifedipine with cyclosporin A in pediatric renal transplant patients

The elimination of cyclosporin A was assessed in eight pediatric renal transplant patients who received calcium channel blockers concomitantly with their immunosuppressive therapy. In three children, verapamil decreased the rate of elimination of cyclosporin A. In five children who received nifedipine, cyclosporin A elimination was also impaired, which contrasts with the reports in adult patients indicating that this calcium channel blocker has no effect on cyclosporin A elimination. When both calcium channel blockers were used on separate occasions in the same patient, nifedipine was less potent than verapamil in depressing cyclosporin A elimination. Although the number of subjects studied is small, these results likely indicate that nifedipine, as well as other calcium channel blocking drugs, must be used with caution in pediatric renal transplant patients.     

Role of calcium channel blockers in the future,in view of the INSIGHT Study

The data from The International Nifedipine Intervention as a Goal in Hypertension Treatment (INSIGHT) Study indicate that effectively reducing blood pressure can decrease the incidence of cardiovascular events in high risk patients with concomitant pathology, including diabetes and hypercholesterolemia, as well as in smokers and those with poor family history. Old and new antihypertensive drugs were similar in preventing cardiovascular mortality as major events. The glomerular filtration rate of patients on co-amilozide went down compared to those on nifedipine. Metabolic parameters, as expected, were not disturbed during treatment with calcium channel blockers, in contrast to the high-dose diuretic-treated population. Ankle edema induced by nifedipine was very disturbing. It can be concluded that overall calcium channel blockers are neither better nor worse than conventional therapy, allowing for possible small differences in stroke (advantage to calcium channel blockers) and myocardial infarction (advantage to diuretics). Thus, calcium channel blockers should be included in the future among the first choice drugs.