Efficacy Of Calcium Channel Blockers Research Articles

Impaired CaV1.2 inactivation reduces the efficacy of calcium channel blockers in the treatment of LQT8

Mutations in the CaV1.2 L-type calcium channel can cause a profound form of long-QT syndrome known as long-QT type 8 (LQT8), which results in cardiac arrhythmias that are often fatal in early childhood. A growing number of such pathogenic mutations in CaV1.2 have been identified, increasing the need for targeted therapies. As many of these mutations reduce channel inactivation; resulting in excess Ca2+ entry during the action potential, calcium channel blockers (CCBs) would seem to represent a promising treatment option. Yet CCBs have been unsuccessful in the treatment of LQT8. Here, we demonstrate that this lack of efficacy likely stems from the impact of the mutations on CaV1.2 channel inactivation. As CCBs are known to preferentially bind to the inactivated state of the channel, mutation-dependent deficits in inactivation result in a decrease in use-dependent block of the mutant channel. Further, application of the CCB verapamil to induced pluripotent stem cell (iPSC) derived cardiomyocytes from an LQT8 patient demonstrates that this loss of use-dependent block translates to a lack of efficacy in correcting the LQT phenotype. As a growing number of channelopathic mutations demonstrate effects on channel inactivation, reliance on state-dependent blockers may leave a growing population of patients without a viable treatment option. This biophysical understanding of the interplay between inactivation deficits and state-dependent block may provide a new avenue to guide the development of improved therapies.

Evaluating the efficacy and safety of calcium channel blockers as adjunctive analgesics to opioid therapy: a literature review

AbstractCalcium channel blockers have been postulated as opioid adjuncts, due to their complementary mechanism of action, which may reduce pain signal transduction. The purpose of this study was to conduct a literature review regarding the safety and efficacy of calcium channel blockers alongside opioids in pain management. From August 2020 to January 2021, PubMed, Scopus, and ProQuest were searched using the following terminology: calcium channel blocker OR verapamil OR diltiazem OR amlodipine OR nicardipine OR nimodipine OR nifedipine AND analgesia. Studies included were those with adult human subjects that had reported efficacy and safety outcomes for calcium channel blocker use as opioid adjuncts. Exclusion criteria for the analysis were articles including pregnant patients, those not readily translatable to English and those detailing the use of calcium channel blockers for an alternative diagnosis or indication. Ten studies were included in this review. Five were randomised controlled trials, one involving verapamil, one addressing diltiazem, one including nifedipine and three examining nimodipine. A sixth clinical trial involving verapamil, diltiazem and nimodipine was reviewed. The seventh and final clinical trial included nimodipine or nifedipine use during aorto‐coronary bypass surgery. One conclusive study addressed nimodipine’s use in cancer patients treated with morphine and the other nifedipine’s morphine adjunct potential postoperatively. Currently, there is insufficient data to support the use of calcium channel blockers as adjuncts to opioid therapy in pain management. When compared, the studies came to varying conclusions and demonstrated conflicting data indicating the need for more research regarding this topic.

Abstract 16787: Calcium Channel Blockers and Nitrates in 5-FU Vasospasm

Introduction: Coronary vasospasm is a side effect of 5-FU (fluorouracil). Beyond switching chemotherapy regimens, there are no established treatments for vasospasm. Limited data exist regarding the efficacy of calcium channel blockers (CCBs) and/or nitrates with 5-FU vasospasm. Methods: We conducted a retrospective analysis of all patients at Massachusetts General Hospital who were diagnosed with 5-FU coronary vasospasm. As part of institutional practice, those referred to cardio-oncology receive pre-treatment with vasospasm therapies (either combination [nitrates and CCBs] or single agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcomes were the safety and effectiveness of this cardiac pre-treatment approach. Results: Among 7,711 patients who received 5-FU from Jan 2001 to Jul 2017, 86 (1.11%) developed coronary vasospasm. Overall 64 patients continued to receive subsequent 5-FU, while 22 stopped. Of the 64 who continued, 60 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU. Of these 60, 52% (31/60) received both nitrates and CCBs, 20% (12/60) received CCBs alone, and 28% (17/60) received nitrates alone, while 4 continued 5-FU without cardiac pre-treatment. Chest pain (without a myocardial infarct) recurred in 11.7% (7/60) among those who received cardiac pre-treatment vs. 50% (2/4) among those who did not (P=0.033). When those who stopped were compared to those who continued 5-FU (with cardiac pre-treatment), the cardiovascular profile, stage and type of cancer were similar. As compared to patients who stopped 5-FU, those who continued after nitrates/CCBs had improved progression free (HR 0.56, P=0.076 [95% CI 0.30-1.06]) and overall (HR 0.29, P<0.001 [95% CI 0.15-0.57]) survival. Conclusion: In the largest report of 5-FU associated vasospasm, re-challenge after pre-treatment with CCBs and nitrates was safe and effective, thus allowing patients to receive additional 5-FU.

The Effect of Calcium Channel Blockers on Moderate or Severe Albuminuria in Diabetic, Hypertensive Patients

ObjectivesInhibitors of the renin-angiotensin system are recommended for the management of albuminuria in patients with hypertension and diabetes mellitus, but there is little consensus about alternative therapies. Calcium channel blockers are recommended for the management of hypertension, but the data are controversial regarding their role in patients with albuminuria. This review was designed to assess the efficacy of calcium channel blockers compared with inhibitors of the renin-angiotensin system in decreasing albuminuria in diabetic, hypertensive patients with nephropathy. MethodsWe searched MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov for records that compared calcium channel blockers to inhibitors of the renin-angiotensin system and reported pre- and postintervention albuminuria measurements. Two reviewers independently screened abstracts for randomized, controlled trials in adults. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to select 29 trials from 855 records. We synthesized the data through a random-effects model. ResultsWe analyzed data from 2113 trial participants with hypertension and diabetes mellitus who had the equivalent of ≥30 mg/day of urinary albumin excretion. Inhibitors of the renin-angiotensin system were more effective than calcium channel blockers in decreasing albuminuria (standardized difference in means −0.442; confidence interval, −0.660 to −0.225; P < .001). This finding was independent of the blood pressure response to treatment. There was no difference between the 2 drug classes regarding markers of renal function. ConclusionsInhibitors of the renin-angiotensin system are superior to calcium channel blockers for the reduction of albuminuria in nephropathy due to hypertension and diabetes mellitus. The net clinical benefit, however, is small.

Safety and Efficacy of Tocolytics for the Treatment of Spontaneous Preterm Labour.

Preterm birth is the major cause of perinatal mortality and morbidity worldwide. Attempts to reduce the burden may be proactive using biochemical or biophysical prediction and preventative measures. If these efforts fail, then the approach may have to be reactive using tocolytics to inhibit spontaneous preterm labour. We have reviewed the evidence concerning the safety and efficacy of various classes of tocolytic agents. The evidence to support the use of magnesium sulfate or nitric oxide donors as a tocolytic is poor. Compared to placebo or no treatment, there is evidence to support the efficacy of calcium channel blockers (mainly nifedipine), prostaglandin synthetase inhibitors (mainly indomethacin and sulindac), oxytocin receptor antagonists (mainly atosiban) and β2-agonists (mainly ritodrine, terbutaline, salbutamol and fenoterol). Maternal safety concerns have reduced the use of β2-agonists. Fetal safety and gestational age restrictions have largely condemned prostaglandin synthetase inhibitors to second-line therapy. First-line therapy in Europe and other parts of the world outside the USA and Australia is limited to calcium channel blockers and oxytocin receptor antagonists. With respect to efficacy, atosiban and nifedipine are similar, but the robustness of the evidence favours atosiban. With respect to safety, atosiban is clearly the safest tocolytic as there are fetomaternal concerns with nifedipine, particularly in high daily doses. The perfect tocolytic that is uniformly effective and safe does not exist. Cost, licensing and informed consent are considerations involved in the choice. Efforts continue to develop and introduce other or better agents, including novel compounds such as progesterone, PGF2α antagonists and statins.

Are prostaglandins or calcium channel blockers efficient for free flap salvage? A review of the literature

The free flap failure rate is less than 5%. The responsible mechanisms of postoperative secondary ischemia are mostly vascular. The main postoperative complication leading to flap failure is thrombosis. Different strategies have been reported to improve the reliability of flaps and decrease the risk of partial or total necrosis: thus, pharmacologic agents have been studied to reduce the risk of microvascular thrombosis. The aim of this review was to evaluate the effect of calcium channel blockers and prostaglandins on free skin flap survival. A systematic review of the literature was performed to identify articles studying the efficacy of calcium channel blockers and prostaglandins on free flap survival. After full text reading, eleven articles were finally included. Eight articles investigated the role of prostaglandins in free tissue transfers, two in rats subjects, one in rabbits, five in humans. Two articles studied the effect of calcium channel blockers on free flaps, one in rats subjects, one in rabbits. One article studied in different groups the effect of calcium channel blockers and prostaglandins on free flaps in rabbits. Literature regarding the efficacy of calcium channel blockers and prostaglandins to salvage free flap is poor and mainly based on animal models. Nevertheless, studies on prostaglandins showed a slight efficiency of these molecules for free flap salvage. Results are less reliable for calcium channel blockers and dependent on the molecule used. In conclusion, there is a lack of evidence to use them in clinical practice.

Probing the Pathogenic Mechanisms Underlying CaV 1.2 Channelopathies

Voltage gated Ca2+ channels are the main conduit for Ca2+ entry into most excitable cells, and the CaV1.2 L-type channel is among the most widespread, existing in cardiac, neuronal, and smooth muscle cells. These channels are precisely tuned to function within each of these systems, enabling the same channel type to coordinate neuronal excitability, vasoconstriction and cardiac excitation-contraction coupling. This tuning is accomplished in part by the nuances of channel gating and voltage dependence in each channel subtype, and by two major forms of feedback regulation: Ca2+ dependent inactivation (CDI) and voltage dependent inactivation (VDI). A growing number of genetic mutations in CaV1.2 are now recognized as the cause of severe cardiac and neuronal syndromes (channelopathies), which are frequently resistant to conventional treatment options. Biophysical studies have shown that these disease-causing mutations can often impact channel gating properties including CDI and VDI. However, as the number of known channelopathies continues to expand, so do the mechanistic differences among different mutations, resulting in increasing numbers of patients for which standard therapies are inadequate. Here, we aim to connect genetic mutations within CaV1.2 to specific effects on channel gating and regulation, in order to improve our understanding of the pathogenesis of these disorders. Moreover, these biophysical alterations likely underlie the lack of efficacy of calcium channel blockers in the treatment of these channelopathy patients. Thus, characterization of these channel deficits will increase our understanding of disease pathogenesis and redirect treatment strategies.

Discovery and Development of Calcium Channel Blockers.

In the mid 1960s, experimental work on molecules under screening as coronary dilators allowed the discovery of the mechanism of calcium entry blockade by drugs later named calcium channel blockers. This paper summarizes scientific research on these small molecules interacting directly with L-type voltage-operated calcium channels. It also reports on experimental approaches translated into understanding of their therapeutic actions. The importance of calcium in muscle contraction was discovered by Sidney Ringer who reported this fact in 1883. Interest in the intracellular role of calcium arose 60 years later out of Kamada (Japan) and Heibrunn (USA) experiments in the early 1940s. Studies on pharmacology of calcium function were initiated in the mid 1960s and their therapeutic applications globally occurred in the the 1980s. The first part of this report deals with basic pharmacology in the cardiovascular system particularly in isolated arteries. In the section entitled from calcium antagonists to calcium channel blockers, it is recalled that drugs of a series of diphenylpiperazines screened in vivo on coronary bed precontracted by angiotensin were initially named calcium antagonists on the basis of their effect in depolarized arteries contracted by calcium. Studies on arteries contracted by catecholamines showed that the vasorelaxation resulted from blockade of calcium entry. Radiochemical and electrophysiological studies performed with dihydropyridines allowed their cellular targets to be identified with L-type voltage-operated calcium channels. The modulated receptor theory helped the understanding of their variation in affinity dependent on arterial cell membrane potential and promoted the terminology calcium channel blocker (CCB) of which the various chemical families are introduced in the paper. In the section entitled tissue selectivity of CCBs, it is shown that characteristics of the drug, properties of the tissue, and of the stimuli are important factors of their action. The high sensitivity of hypertensive animals is explained by the partial depolarization of their arteries. It is noted that they are arteriolar dilators and that they cannot be simply considered as vasodilators. The second part of this report provides key information about clinical usefulness of CCBs. A section is devoted to the controversy on their safety closed by the Allhat trial (2002). Sections are dedicated to their effect in cardiac ischemia, in cardiac arrhythmias, in atherosclerosis, in hypertension, and its complications. CCBs appear as the most commonly used for the treatment of cardiovascular diseases. As far as hypertension is concerned, globally the prevalence in adults aged 25 years and over was around 40% in 2008. Usefulness of CCBs is discussed on the basis of large clinical trials. At therapeutic dosage, they reduce the elevated blood pressure of hypertensive patients but don't change blood pressure of normotensive subjects, as was observed in animals. Those active on both L- and T-type channels are efficient in nephropathy. Alteration of cognitive function is a complication of hypertension recognized nowadays as eventually leading to dementia. This question is discussed together with the efficacy of CCBs in cognitive pathology. In the section entitled beyond the cardiovascular system, CCBs actions in migraine, neuropathic pain, and subarachnoid hemorrhage are reported. The final conclusions refer to long-term effects discovered in experimental animals that have not yet been clearly reported as being important in human pharmacotherapy.

Comparative Efficacy of Calcium Channel Blocker and ACE Inhibitor in the Treatment of Acute Hypertension in Acute Post Streptococcal glomerulonephritis

1.1.Background: Acute Post Streptococcal Glomerulonephritis (APSGN) refers to the immunologic mechanism which triggers inflammation and proliferation of glomerular tissue, characterized by a relatively abrupt onset of variable degrees of gross haematuria, edema, hypertension and renal insufficiency. Patient may develop encephalopathy and or heart failure due to hypertension or hypervolemia as a complication. 1.2.Objectives:The objective of the study was to find out the better drug for hypertension and/or its complications in terms of effectiveness, side effects and compliance. 1.3.Methods: This randomized clinical trial was conducted among 60 children aged3-12 years, who were suffering from Acute Streptococcal Glomerulonephritis (APSGN) with hypertension and/or its complications. After enrolment, the patients were randomly divided into two groups as group A and group B. Both groups received the standard management of APSGN. In addition, children in group A received captopril (dose 0.5 up to 6mg/kg/day) and children in group-B received Nifedipine (0.25 up to 0.5 mg/kg/day). Their effectiveness in relation to timing of response, duration of therapy, duration of hospital stay, side effects and cost effectiveness of the drugs was assessed and compared statistically, and at p value of <0.05 the result was considered significant. 1.4.Results: Most patients had high systolic and high diastolic blood pressure. In captopril group mean systolic and mean diastolic blood pressure were 134.8±9.3 mm of Hg and 94.97±6.3 mm of Hg respectively. In Nifedipine group mean systolic and mean diastolic blood pressure 131.96±8.1 mm of Hg and 92.8±9.1mm of Hg respectively. The mean time needed to normalize both systolic and diastolic blood pressure (<95th percentile) in group A (Captopril) was 4.98±2.07 days and that of group B (Nifedipine) was 3.09±1.83 days. The difference between two group was statistically significant (p<0.05). Duration of antihypertensive therapy was longer in captopril group than in the Nifedipine group (<0.05). There were no significant side effects. 1.5.Conclusion: It is obvious from the study that Nifedipine controlled BP earlier and reduced the duration of hospital stay compared to captopril. For the control of hypertension in APSGN patients, Nifedipine is a better drug. 1.6.Recommendation: Nifedipine should be used in controlling hypertension in acute post streptococcal glomerulonephritis.

Association between gene polymorphism of calcium/calmodulin-dependent kinase 4 and efficacy of amlodipine in the treatment of hypertension in Chinese Han nationality

To evaluate the association between single nucleotide polymorphisms of calcium/calmodulin-dependent kinase 4 (CAMK4) and the therapeutic effect of amlodipine in essential hypertensive patients in Chinese Han nationality. A total of 108 mild-to-moderate essential hypertension patients in Chinese Han nationality were treated with amlodipine for 8 weeks at a dosage of 5 mg/d. Polymerase chain reaction-restriction fragment length polymorphism was performed to detect the genotypes (rs10491334). Blood pressure was measured and analyzed. The result of rs10491334 polymorphism of CAMK4 was consistent with Hardy-Weinberg equilibrium distribution and the frequencies of C allele and T allele were 88.89% and 11.11%, respectively. The systolic blood pressure and diastolic blood pressure before amlodipine treatment were not statistically different among different genotype carriers (P>0.05). The blood pressure was significantly reduced in all patients after amlodipine treatment (P<0.05). Systolic blood pressure was significantly decreased in patients with rs10491334 CC genotype and CT genotype compared with those patients with rs10491334 TT genotype. Total effective rates of CT and TT carriers were higher than those of the CC genotype carriers (P<0.01). The CAMK4 gene polymorphism might be associated with the efficacy of calcium channel blocker in treating mild-to-moderate essential hypertension patients.

Systematic review: antihypertensive drug therapy in patients of African and South Asian ethnicity.

Despite the large differences in the epidemiology of hypertension across Europe, treatment strategies are similar for national populations of white European descent. However, hypertensive patients of African or South Asian ethnicity may require ethnic-specific approaches, as these population subgroups tend to have higher blood pressure at an earlier age that is more difficult to control, a higher occurrence of diabetes, and more target organ damage with earlier cardiovascular mortality. Therefore, we systematically reviewed the evidence on antihypertensive drug treatment in South Asian and African ethnicity patients. We used the Cochrane systematic review methodology to retrieve trials in electronic databases including CENTRAL, PubMed, and Embase from their inception through November 2015; and with handsearch. We retrieved 4596 reports that yielded 35 trials with 7 classes of antihypertensive drugs in 25,540 African ethnicity patients. Aside from the well-known blood pressure efficacy of calcium channel blockers and diuretics, with lesser effect of ACE inhibitors and beta-blockers, nebivolol was not more effective than placebo in reducing systolic blood pressure levels. Trials with morbidity and mortality outcomes indicated that lisinopril and losartan-based therapy were associated with a greater incidence of stroke and sudden death. Furthermore, 1581 reports yielded 16 randomized controlled trials with blood pressure outcomes in 1719 South Asian hypertensive patients. In contrast with the studies in African ethnicity patients, there were no significant differences in blood pressure lowering efficacy between drugs, and no trials available with mortality outcomes. In conclusion, in patients of African ethnicity, treatment initiated with ACE inhibitor or angiotensin II receptor blocker monotherapy was associated with adverse cardiovascular outcomes. We found no evidence of different efficacy of antihypertensive drugs in South Asians, but there is a need for trials with morbidity and mortality outcomes. Screening for cardiovascular risk at a younger age, treating hypertension at lower thresholds, and new delivery models to find, treat and follow hypertensives in the community may help reduce the excess cardiovascular mortality in these high-risk groups.

β-Blockers versus calcium channel blockers for acute rate control of atrial fibrillation with rapid ventricular response: a systematic review.

This is a systematic review of the literature to compare the efficacy of calcium channel blockers to β-blockers for acute rate control of atrial fibrillation with rapid ventricular response in the emergency department setting. PubMed, EMBASE, and the Cochrane Registry were searched. Relative risk (95% confidence interval) was calculated between drugs and methodological quality of included studies was evaluated. Of the 1003 studies yielded by our initial search, two met inclusion criteria and provided sufficient data. These were randomized double-blinded studies (n=92) comparing intravenous diltiazem with intravenous metoprolol. The combined relative risk of acute rate control by diltiazem versus metoprolol was 1.8 (95% confidence interval 1.2-2.6). On the basis of the paucity of available evidence, diltiazem may be more effective than metoprolol in achieving rapid rate control, but high-quality randomized studies are needed.

Calcium Channel Blockers Reduce the Effects of Cigarette Smoking on Peripheral Nerve Ischemia/Reperfusion Injury

The efficacy of calcium channel blockers in reducing the effects of ischemia/reperfusion (I/R) injury in animals subjected to cigarette smoke was examined. In this study, 40 rats were divided into 4 groups. Groups A, B, and C received a controlled cigarette smoke exposure for 14 days, following which all animals underwent a standardized sciatic nerve I/R procedure. One sciatic nerve was isolated, and the femoral artery was occluded for 3 hours followed by reperfusion. Group B received verapamil (20 mg/kg/d). Group C received nifedipine (10 mg/kg/d). Mean sciatic function index (SFI) was significantly higher in nonsmoking than smoking animals, and the sciatic function index of group B (verapamil) and group C (nifedipine) was significantly greater than group A (smoking). Mean malondialdehyde at day 28 in group A was 0.96 ± 0.14 compared with 0.74 ± 0.11 in the nonsmoking group (P = 0.03), and the mean malondialdehyde in the nifedipine group was significantly greater than in group A (P = 0.05). Histologic injury scores were not significantly different among groups exposed to smoke. Smoking was associated with slower recovery following peripheral nerve I/R injury, but calcium channel blockers were shown to ameliorate these effects.

The role of mitochondrial calcium uniporter in neuroprotection in traumatic brain injury

The alteration in cellular Ca2+ homeostasis is one of the key mechanisms contributing to secondary neuronal damage and altered physiology during the process of traumatic brain injury (TBI). However, there is considerable uncertainty about the efficacy of calcium channel blockers in randomized, controlled, clinical trials. In the physiological condition, cellular Ca2+ homeostasis occurs through repetitive bursts of rising intracellular Ca2+ that, sometimes are referred to as Ca2+ oscillations. Mitochondria are intimately involved in the spatiotemporal tuning of cellular Ca2+ signaling mainly through mitochondrial Ca2+ uniporter (MCU). Excessive Ca2+ uptake by the mitochondria through MCU is a key event in mitochondrial dysfunction and cell death in TBI. Selective inhibition of MCU has showed a promising cardioprotection and neuroprotection effect in many preclinical studies. Based on these preclinical results, the selective inhibition of MCU may be a new strategy for neuroprotection in TBI patients.

Comparison of Four Single-Drug Regimens on Ventricular Rate and Arrhythmia-Related Symptoms in Patients With Permanent Atrial Fibrillation

Rate control of atrial fibrillation (AF) is a main treatment modality. However, data are scarce on the relative efficacy of calcium channel blockers and β blockers or between drugs within each class. The purpose of the present study was to compare the effect of 4 rate-reducing, once-daily drug regimens on the ventricular heart rate and arrhythmia-related symptoms in patients with permanent AF. We included 60 patients (mean age 71 ± 9 years, 18 women) with permanent AF in an investigator-blind cross-over study. Diltiazem 360 mg/day, verapamil 240 mg/day, metoprolol 100 mg/day, and carvedilol 25 mg/day were administered for 3 weeks in a randomized sequence. The 24-hour heart rate was measured using Holter monitoring, and arrhythmia-related symptoms were assessed using the Symptom Checklist questionnaire before randomization and on the last day of each treatment period. The 24-hour mean heart rate was 96 ± 12 beats/min at baseline (no treatment), 75 ± 10 beats/min with diltiazem, 81 ± 11 beats/min with verapamil, 82 ± 11 beats/min with metoprolol, and 84 ± 11 beats/min with carvedilol. All drugs reduced the heart rate compared to baseline (p <0.001 for all). The 24-hour heart rate was significantly lower with diltiazem than with any other drug tested (p <0.001 for all). Compared to baseline, diltiazem significantly reduced both the frequency (p <0.001) and the severity (p= 0.005) of symptoms. In contrast, verapamil reduced symptom frequency only (p=0.012). In conclusion, diltiazem 360 mg/day was the most effective drug regimen for reducing the heart rate in patients with permanent AF. Arrhythmia-related symptoms were reduced by treatment with the calcium channel blockers diltiazem and verapamil, but not by the β blockers.

Microvascular Coronary Artery Spasm Presents Distinctive Clinical Features With Endothelial Dysfunction as Nonobstructive Coronary Artery Disease

BackgroundAngina without significant stenosis, or nonobstructive coronary artery disease, attracts clinical attention. Microvascular coronary artery spasm (microvascular CAS) can cause nonobstructive coronary artery disease. We investigated the clinical features of microvascular CAS and the therapeutic efficacy of calcium channel blockers.Methods and ResultsThree hundred seventy consecutive, stable patients with suspected angina presenting nonobstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test, with simultaneous measurements of transcardiac lactate production and of changes in the quantitative coronary blood flow. We diagnosed microvascular CAS according to lactate production and a decrease in coronary blood flow without epicardial vasospasm during the acetylcholine provocation test. We prospectively followed up the patients with calcium channel blockers for microvascular coronary artery disease. We identified 50 patients with microvascular CAS who demonstrated significant impairment of the endothelium-dependent vascular response, which was assessed by coronary blood flow during the acetylcholine provocation test. Administration of isosorbide dinitrate normalized the abnormal coronary flow pattern in the patients with microvascular CAS. Multivariate logistic regression analysis indicated that female sex, a lower body mass index, minor–borderline ischemic electrocardiogram findings at rest, limited–baseline diastolic-to-systolic velocity ratio, and attenuated adenosine triphosphate–induced coronary flow reserve were independently correlated with the presence of microvascular CAS. Receiver-operating characteristics curve analysis revealed that the aforementioned 5-variable model showed good correlation with the presence of microvascular CAS (area under the curve: 0.820). No patients with microvascular CAS treated with calcium channel blockers developed cardiovascular events over 47.8±27.5 months.ConclusionsMicrovascular CAS causes distinctive clinical features and endothelial dysfunction that are important to recognize as nonobstructive coronary artery disease so that optimal care with calcium channel blockers can be provided.Clinical Trial RegistrationURL: www.umin.ac.jp/ctr. Unique identifier: UMIN000003839.

Protective effects of the calcium-channel blocker flunarizine on crush injury of sciatic nerves in a rat model

Neural damage can be mitigated by calcium-channel blockers (CCBs). However, the mechanism of action of CCBs is not yet fully understood. Objective : To investigate the mechanism of action and efficacy of CCB, flunarizine in restoring neural function after crush injury to the nerves. The sciatic nerves of rats were crushed using pincers to establish the model for crush injury. Two hundred and eighty-eight Sprague-Dawley (SD) rats were randomly divided into sham-operated, saline, and low-dose flunarizine and high-dose flunarizine (FI and FII) groups. The expression of the protein c-fos in the dorsal root ganglia (DRG) after crush injury to the sciatic nerves was investigated by using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. The effect of flunarizine on c-fos expression and its efficacy in restoring neural function was evaluated. The c-fos messenger ribonucleic acid (mRNA) and protein expression in FI and FII groups was significantly lower than in the saline group and was the least in the FII group. Nerve-conduction velocity was increased in the order of: saline < FI< FII< sham-operated. There was no significant difference in the nerve-conduction velocity in the sham-operated and FII groups (P>.05). When administered after crush injury to peripheral nerves, flunarizine may protect neurons with lesions from further damage and improve neural function by downregulating c-fos expression.

Three paediatric patients with reversible cerebral vasoconstriction syndromes

Reversible cerebral vasoconstriction syndromes (RCVS) occur predominantly in middle-aged women. Only one child with RCVS has ever been reported. We report three boys (aged 10, 16 and 10 years) who had multiple thunderclap headaches, including one boy with bath-related attacks. None of them had secondary causes. All their magnetic resonance angiography demonstrated reversible cerebral vasoconstrictions of the major arteries with increased cerebral blood flow velocities on transcranial colour-coded sonography studies. Two of the three had hypertensive surges during headache attacks. None of the three boys had seizure, stroke or other neurological deficits. However, a left occipital subcortical lesion of unknown nature was noted in one boy. The efficacy of calcium channel blockers was variable in these three boys. This report suggests that, although rare, RCVS should be considered in paediatric patients if they present with a history of multiple attacks of thunderclap headache.

Blood pressure lowering efficacy of calcium-channel blockers as second-line therapy for primary hypertension

Blood pressure lowering efficacy of calcium-channel blockers as second-line therapy for primary hypertension

Calcium channel blockers in the spectrum of antihypertensive agents

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. Through blood pressure reduction, and possibly other mechanisms such as antioxidative effects, they may play a role in diminishing the risk for a variety of cardiovascular outcomes. The combination of CCBs with other newer antihypertensive agents such, as ACE inhibitors and angiotensin receptor blockers, may provide complementary effects on risk reduction in cardiovascular adverse events and renal disease. Although the efficacy of CCBs as antihypertensive agents has been adequately demonstrated, there have been concerns regarding the use of short acting dihydropyridines after acute myocardial infarction. There have also been questions about the role of CCBs with regards to other antihypertensive agents in renal disease. For example, differential effects of dihydropyridine and non-dihydropyridine CCBs may affect progression of renal disease and risk for diabetes. Certain precautions involving drug interactions are needed because of the effects of CCBs on the CYP450 enzyme systems.