(1) Background: Recently, influences of antihypertensive treatment on the renin-angiotensin-aldosterone system (RAAS) has gained attention, regarding a possible influence on inflammatory and anti-inflammatory pathways. We aimed to study the effects of newly initiated antihypertensive drugs on angiotensin (Ang) II and Ang (1-7) as representers of two counter-regulatory axes. (2) Methods: In this randomized, open-label trial investigating RAAS peptides after the initiation of perindopril, olmesartan, amlodipine, or hydrochlorothiazide, Ang II and Ang (1-7) equilibrium concentrations were measured at 8 a.m. and 12 a.m. at baseline and after four weeks of treatment. Eighty patients were randomized (1:1:1:1 fashion). (3) Results: Between the four substances, we found significant differences regarding the concentrations of Ang II (p < 0.0005 for 8 a.m., 12 a.m.) and Ang (1-7) (p = 0.019 for 8 a.m., <0.0005 for 12 a.m.) four weeks after treatment start. Ang II was decreased by perindopril (p = 0.002), and increased by olmesartan (p < 0.0005), amlodipine (p = 0.012), and hydrochlorothiazide (p = 0.001). Ang (1-7) was increased by perindopril and olmesartan (p = 0.008/0.002), but not measurably altered by amlodipine and hydrochlorothiazide (p = 0.317/ 0.109). (4) Conclusion: The initiation of all first line antihypertensive treatments causes early and distinct alterations of equilibrium angiotensin levels. Given the additional AT1R blocking action of olmesartan, RAAS peptides shift upon initiation of perindopril and olmesartan appear to work in favor of the anti-inflammatory axis compared to amlodipine and hydrochlorothiazide.

High salt intake has been shown to induce hypertrophy and fibrosis in the atria and ventricles, which could result in the development of atrial fibrillation (AF). Whereas the development of AF is suggested to be prevented by renin-angiotensin system (RAS) inhibitors, recent findings have indicated that this prevention is closely associated with their antihypertensive effects. In this study, we investigated whether the L/N-type Ca2+ channel blocker cilnidipine counteracts salt-induced atrial and ventricular remodelling and the inducibility of AF. Cilnidipine was orally administered to Dahl salt-sensitive rats fed with an 8% NaCl diet at 10 mg/kg for 5 weeks, and then electrophysiological evaluation and histological analyses were performed. The effects were compared with those of the L-type Ca2+ channel blocker amlodipine at 3 mg/kg. Following the intake of the 8% NaCl diet, the blood pressure (BP) increased, and fibrosis was induced in the atria and ventricles. Cilnidipine decreased BP, and the extent of the decrease in the cilnidipine group was similar to those in the amlodipine group. Cilnidipine produced a greater decrease in the fibrotic area in the atria and ventricles than amlodipine. The cilnidipine group shortened the AF duration from 7.43 ± 3.16 to 2.95 ± 1.73 s, which had been increased by NaCl intake. Plasma noradrenaline levels in the cilnidipine group were lower than those in the amlodipine group. Thus, the suppressive effects of cilnidipine on the salt-induced atrial and ventricular remodelling, fibrosis, and AF sustainability might be closely associated with its N-type Ca2+ channel-blocking actions.

The author apply concepts and tools from evolutionary medicine to understanding the SARS-CoV-2 pandemic. The pandemic represents a mismatched conflict, with dynamics and pathology apparently driven by three main factors: (i) bat immune systems that rely on low inflammation but high efficacy of interferon-based defenses; (ii) viral tactics that differentially target the human interferon system, leading to substantial asymptomatic and pre-symptomatic transmission; and (ii) high mortality caused by hyper-inflammatory and hyper-coagulatory phenotypes, that represent dysregulated tradeoffs whereby collateral immune-induced damage becomes systemic and severe. This framework can explain the association of mortality with age (which involves immune life-history shifts towards higher inflammation and coagulation and reduced adaptive immunity), and sex (since males senesce faster than females). Genetic-risk factors for COVID-19 mortality can be shown, from a phenome-wide association analysis of the relevant SNPs, to be associated with inflammation and coagulation; the phenome-wide association study also provides evidence, consistent with several previous studies, that the calcium channel blocking drug amlodipine mediates risk of mortality. Lay Summary: SARS-CoV-2 is a bat virus that jumped into humans. The virus is adapted to bat immune systems, where it evolved to suppress the immune defenses (interferons) that mammals use to tell that they are infected. In humans, the virus can apparently spread effectively in the body with a delay in the production of symptoms and the initiation of immune responses. This delay may then promote overactive immune responses, when the virus is detected, that damage the body as a side effect. Older people are more vulnerable to the virus because they are less adapted to novel infectious agents, and invest less in immune defense, compared to younger people. Genes that increase risk of mortality from SARS-CoV-2 are functionally associated with a drug called amlodipine, which may represent a useful treatment.

The 2018 ESH/ESC guidelines indicate that the first-choice therapy in the majority of hypertensive patients should be a fixed combination of a drug that blocks the renin-angiotensin-aldosterone system and a calcium antagonist or a diuretic. Evidence from the meta-analysis of controlled clinical trials, however, indicates that the classes of drugs that block the renin-angiotensin-aldosterone system should not be considered equivalent as ACE inhibitors have been clearly shown to outperform AT-1 antagonists in preventing myocardial infarction and total mortality. Moreover, studies such as ASCOT and ACCOMPLISH demonstrate a superiority of the ACE-inhibitor/calcium antagonist association over beta-blocker/diuretic associations and especially towards the ACE-inhibitor/diuretic combination, whereas there is no scientific evidence of efficacy with respect to cardiovascular events on the part of AT-1 antagonist/calcium antagonist combinations. Drugs such as ramipril and amlodipine are undoubtedly the reference molecules within their respective classes as numerous controlled clinical studies have demonstrated their effectiveness on cardiovascular events. It is therefore obvious that the availability of a fixed combination with both molecules is a great opportunity for the therapy of the hypertensive patient, considering also the availability of studies that demonstrate its effectiveness on intermediate endpoints associated with high tolerability. So, in accordance with the 2018 ESH/ESC guidelines, the fixed combination ramipril/amlodipine represents a first choice therapy for hypertension.

Amlodipine is a classical drug with varied properties extending from control of blood pressure to as an antianginal and anti atherosclerotic agent. Amlodipine is a longer acting dihydropyridine calcium channel blocker, effective for 24 hours BP control and cause no BP variability. It is a powerful, well-tolerated, and safe antihypertensive agents that is widely used either alone or as a key component of combination therapy for hypertension. Its effective BP reduction has shown proven benefits in cardiovascular event reduction that is supported with strong evidences from large randomised controlled trials. Combination therapies of amlodipine with other agents eliciting renin-angiotensin-aldosterone system blockade (angiotensin II receptor blockers or renin inhibitors) have shown effective blood pressure-lowering strategies in CV risk reduction and progression of renal disease. Novel type of calcium channel blockers have been developed which have additional properties of blocking T and N subtypes of calcium channels and apart from their class effects they exerts specific action on heart rate and renin aldosterone system. They are considered to be more renoprotective due to this additional properties. Amlodipine is most potent and longer acting agent compared to the newer CCBs, its effectiveness in BP lowering still makes it the agent of choice among all the CCBs.

The aim of this study was to examine and compare the effects of the acute administration of verapamil or amlodipine as representatives of the calcium channel blockers or nicorandil as a representative of the mitochondrial ATP-dependent potassium (KATP) channel opener to cardiac contractility, coronary flow, and oxidative stress markers on ischemia/reperfusion injury in the isolated rat heart. The hearts of adult male Wistar albino rats (n = 60 total, 12 per group) were divided into five groups, two controls (preconditioning with Krebs-Henseleit solution) and three experimental depending on acute administrated pharmacological agents (0,63 µmol/L of verapamil, 0,1 µmol/L of amlodipine, and 200 µmol/L of nicorandil). After stabilization and 5 min of preconditioning in experimental groups, hearts from I/R control and all experimental groups underwent global ischemia (20 min) and reperfusion (30 min). Hearts from sham group were continuously followed for 50 min, after stabilization period. Cardiodynamic parameters and coronary flow were recorded at the end of stabilization (S), at the last minute of pharmacological preconditioning (P) and at intervals of 5 min after global ischemia, during reperfusion, or in case of sham group during 20-50 min after stabilization. At the same intervals, we collected coronary venous effluent from which we spectrophotometrically measured the parameters of oxidative stress: the index of lipid peroxidation, superoxide anion radical, hydrogen peroxide, and nitrite. In summary, our findings clearly indicate that the blocking of the calcium channel or the activation of KATP may mediate the protective effect of myocardial preconditioning. The ex vivo results showed that all examined drugs after ischemia and reperfusion have beneficial cardioprotective properties associated with lower values of major pro-oxidative molecules. Obtained effects seem to be the most convincible in case of nicorandil.

This study investigated the modulatory and chemopreventive benefit of amlodipine (AML), a dihydropyridine calcium channel antagonist, against neurobehavioural abnormalities (NAs) associated with chlorpromazine (CPZ) toxicity in mice. Adult mice were divided into five groups of six animals/group. Group 1 (control) was administered saline (10 mL/kg i.p.). Group 2 received CPZ (2 mg/kg i.p.). Groups 3 and 4 received bromocriptine (BMC, 2.5 mg/kg s.c.) and AML (1 mg/kg s.c.), respectively, while group 5 received their combination. Groups 3-5 later received CPZ 30 min after initial treatments. Animals were subjected to neurobehavioural tests and euthanized 18 h later. CPZ-induced NAs were characterized by significant increase (P < 0.001) in cataleptic behaviour and lowered (P < 0.05) spontaneous activity reaction time in mice. There were also significant (P < 0.001) increases in malondialdehyde levels and decreased locomotion plus learning and memory parameters (P < 0.05-0.001). AML pretreatment alone did not alleviate CPZ-induced motor deficits in the mice. While pretreatment with BMC alone attenuated CPZ-associated catalepsy, its combination with AML further protected mice against NAs. Furthermore, BMC pretreatment did not affect CPZ-induced increase in malondialdehyde level, but AML or BMC+AML significantly (P < 0.05) decreased malondialdehyde in the CPZ-treated rats. Reduced glutathione levels and activities of superoxide dismutase and catalase remained elevated in all treatment groups. In conclusion, data from this study suggest possible chemopreventive benefit of AML alone or in combination with BMC against CPZ-associated neurobehavioural deficits. The ameliorative effect of AML may be related to its antioxidant and/or calcium channel blocking property.

The calcium channel blockers act by blocking the influx of calcium ions into vascular smooth muscle and cardiac muscle cells during membrane depolarization. Because muscle contraction is largely dependent upon influx of calcium, its inhibition causes relaxation, particularly in arterial beds. Thus, the major effects of the calcium channel blockers are relaxation of vascular and arterial smooth muscle cells resulting in arterial vasodilation. The major use of the calcium channel blockers is for hypertension and angina pectoris (variant, exertional, and unstable). Some calcium channel blockers are also used for supraventricular arrhythmias and heart failure. Off label uses include migraine headaches. The major calcium channel blockers used in the United States include amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, and verapamil. While all affect the L type voltage gated calcium channel, the structure and site of interaction within the channel varies among the agents. Verapamil blocks the phenylalkylamine site and diltiazem the benzothiazepine site, while the remaining agents (exemplified by amlopidine and nifedipine) bind to the 1,4 dihydropyridine site. These agents are also commonly referred to as being first generation (verapamil, diltiazem, nifedipine) or second generation (amlopine, felodipine, isradipine, nicardipine, nimodipine and others) calcium channel blockers. Several of the calcium channel blockers are now available in generic forms and some are available as combinations with diuretics and lipid lowering agents. Many of the calcium channel blockers have been linked to rare instances of idiosyncratic drug induced liver disease. Hepatic injury from calcium channel blockers is usually mild and reversible, but rare symptomatic and severe instances have been reported. Agents most clearly linked to liver injury are verapamil, diltiazem, amlodipine and nifedipine, probably because these agents have been most widely used. The pattern of injury varies somewhat among the different agents, so that the hepatic injury appears not to be a class effect or the result of inhibition of calcium channels, but rather due to hypersensitivity (verapamil) or metabolic injury that usually results in a mixed hepatocellular-cholestatic pattern (diltiazem, amlopidine, nifedipine). These four agents have different chemical structures and interact with different sites or different calcium channels, so that different patterns of idiosyncratic adverse events and different hepatic reactions might be expected. However, repeated instances of liver injury from different calcium channel blockers have been reported, so that switching from one calcium channel blocker that has caused liver injury to another in this class should be done with caution. Several of these agents can also cause minor elevations in serum aminotransferase levels that are often transient and resolve even with continuation of the agent or can be persistent, resolving only once the agent(s) are discontinued. Common, minor class specific side effects of the calcium channel blockers include headache, dizziness, flushing, nausea, fatigue, diarrhea, peripheral edema, palpitations, bradycardia and rash. Each calcium channel blocker is discussed separately with individual clinical cases and references. The following are links to each drug record.

While the diagnosis of migraine in children is generally straightforward, treatment can seem complex with a number of medication choices, many of which are used "off label." Patients with intermittent migraines can often be managed with ibuprofen or naproxen taken as needed. Unfortunately, by the time that children present to our practice, they have often tried these medications without improvement. Triptans are frequently prescribed to these patients with good success. It is important to make the patient aware of the possible associated serotonergic reactions. If the patient is having more than one headache per week or the headaches are prolonged, prophylactic treatment is indicated. In our practice, the overwhelming majority of these patients will be treated with amitriptyline or topiramate. We generally allow side effect tolerability to guide our choice of medication. Cyproheptadine is often used in younger patients as it comes in a liquid form. There is evidence supporting the use of propranolol, though the potential worsening of underlying asthma symptoms may limit its use, and sodium valproate, which must be used with caution in female patients of childbearing age due to significant teratogenicity risks. Other prophylactic treatments with less robust evidence include the antiepileptic drugs gabapentin, zonisamide, and levetiracetam; calcium channel blockers such as verapamil and amlodipine; and the angiotensin receptor blocking agent candasartin (not available in the USA). Almost all patients in our practice are advised to take magnesium supplementation. Magnesium is a supplement with relatively few adverse effects and good evidence for improvement of migraine symptoms. We evaluate lifestyle issues and comorbidities in all our patients. Ignoring these will make successful treatment near impossible. Good sleep, adequate hydration, appropriate diet, and exercise are vitally important. Finally, most of our patients benefit from a psychology evaluation with cognitive behavioral therapy. Stress management and biofeedback are tremendously helpful in improving quality of life in migraineurs.

Vascular dementia is the second most common cause of dementia affecting over seven million people worldwide, yet there are no licensed treatments. There is an urgent need for a clinical trial in this patient group. Subcortical ischaemic vascular dementia is the most common variant of vascular dementia. This randomised trial will investigate whether use of calcium channel blockade with amlodipine, a commonly used agent, can provide the first evidence-based pharmacological treatment for subcortical ischaemic vascular dementia.

Renin-angiotensin system inhibitors should be considered as the first-line therapy in the treatment of patients with hypertension and diabetes. However, most of the diabetic subjects with hypertension require at least two drugs to achieve blood pressure targets. The ACCOMPLISH trial suggested that the best combination in the treatment of high-risk hypertensive patients should include a renin-angiotensin system inhibitor and a dihydropyridine. However, not all dihydropyridines block the same receptors. Those dihydropyridines that block T-type calcium channel blockers may provide additional advantages. A number of studies suggest that compared with amlodipine, manidipine have the same antihypertensive efficacy, but with a lesser risk of ankle edema. In addition, manidipine, but not amlodipine, significantly reduces urinary albumin excretion rates.

Sideroblastic cardiomyopathy secondary to repeated blood transfusions is a feared complication in thalassaemia. Control of myocardial iron is thus becoming the cornerstone of thalassaemia management. Recent evidence suggests a role for L-type Ca(2+) channels in mediating iron uptake by the heart. Blocking the cellular iron uptake through these channels may add to the benefit of therapy to standard chelation in reducing myocardial iron. We aim to determine the efficacy of amlodipine (a calcium channel blocker) as an adjunct to standard aggressive chelation in retarding myocardial iron deposition in thalassaemics with or without cardiomyopathy.

ACT-280778 is an oral, non-dihydropyridine, dual L-/T-type calcium channel blocker. This phase 2a, double-blind, randomized, placebo- and active-controlled study investigated the efficacy and safety of 10 mg ACT-280778. Patients with mild-to-moderate essential hypertension received once-daily placebo (n=53), ACT-280778 10 mg (n=52) or amlodipine 10 mg (n=54) for 4 weeks. The primary end point was the change from baseline to week 4 in placebo-adjusted mean trough sitting diastolic blood pressure (SiDBP) with ACT-280778. Tolerability was assessed by recording treatment-emergent adverse events (TEAEs). Baseline clinical characteristics were similar across groups. No significant difference was observed at week 4 in mean trough SiDBP between placebo (-9.9 (95% confidence limit (CL) -12.7, -7.0) mm Hg) and ACT-280778 (-9.5 (-12.4, -6.5) mm Hg; P=0.86); amlodipine reduced mean trough SiDBP by -16.8 (-19.0, -14.5) mm Hg, confirming assay validity. Change in mean PR interval at week 4 (pre-dose) differed between placebo (-1.0 (95% CL -4.4, 2.3) ms) and ACT-280778 (6.5 (3.5, 9.6) ms); amlodipine did not increase PR interval (1.1 (-1.6, 3.9) ms).Treatment-emergent adverse events (TEAE) frequency was 32.1% (placebo), 32.7% (ACT-280778) and 33.3% (amlodipine). The most common TEAEs were headache, peripheral edema, hypertension and second-degree atrioventricular block. ACT-280778 (10 mg) did not lower blood pressure in mild-to-moderate hypertension.

In recent years, treatment strategies for hypertension have often focused on combination therapies that include diuretics and renin angiotensin aldosterone system blockers such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. However, in clinical practice, a significant number of patients do not respond completely to these combination treatments, and long-term reduction of cardiovascular risk remains insufficient. The particularly high residual cardiovascular risk of hypertensive patients, even when adequately treated with strategies based on renin angiotensin aldosterone system blockers, speaks in favor of new, innovative strategies. Thus, it has become relevant to consider whether it is always necessary to block plasma renin activation and whether other guideline-approved combinations should be considered routinely. Diuretic/calcium channel blocker combinations, which are supported by significant long-term evidence, are put forth as a preferred combination in the main guidelines, but are still underused by physicians who do not yet have easy access to such treatments. Fixed-dose indapamide sustained release/amlodipine is the first such single-pill combination to become available. Complementary mechanisms of action of these two molecules are expected to lead to greater and longer-term reductions in systolic blood pressure and pulse pressure and potentially to the reduction of cardiovascular risk.

Hypertension is associated with oxidative stress. Amlodipine besylate (AB) and benidipine hydrochloride (BH), which are Ca(2+) antagonists, have been reported to reduce oxidative stress. In this study, we examined the neuroprotective effects of AB and BH on oxidative stress-injured neural stem cells (NSCs), with a focus on the phosphatidylinositol 3-kinase (PI3K) pathway and the extracellular signal-regulated kinase (ERK) pathway. After treatment with H2O2, the viability of NSCs decreased in a concentration-dependent manner; however, co-treatment with AB or BH restored the viability of H2O2-injured NSCs. H2O2 increased free radical production and apoptosis in NSCs, whereas co-treatment with AB or BH attenuated these effects. To evaluate the effects of AB or BH on the H2O2-inhibited proliferation of NSCs, we performed BrdU labeling and colony formation assays and found that NSC proliferation decreased upon H2O2 treatment but that combined treatment with AB or BH restored this proliferation. Western blot analysis showed that AB and BH increased the expression of cell survival-related proteins that were linked with the PI3K and ERK pathways but decreased the expression of cell death-related proteins. To investigate whether the PI3K and ERK pathways were directly involved in the neuroprotective effects of AB and BH on H2O2-treated NSCs, NSCs were pretreated with the PI3K inhibitor, LY294002, or the ERK inhibitor, FR180204, which significantly blocked the effects of AB and BH. Together, our results suggest that AB and BH restore the H2O2-inhibited viability and proliferation of NSCs by inhibiting oxidative stress and by activating the PI3K and ERK pathways.

The effects of clinically available drugs targeting muscarinic cholinergic, adrenergic, dopaminergic, and serotonergic receptors; intracellular calcium levels and/or the function of calcium-dependent biochemical pathways; ion channels; and cellular pumps were tested against a keratitis isolate of Acanthamoeba castellanii belonging to the T4 genotype. In vitro growth inhibition (amoebistatic) assays were performed by incubating A. castellanii with various concentrations of drugs in the growth medium for 48 h at 30°C. To determine amoebicidal effects, amoebae were incubated with drugs in phosphate-buffered saline for 24 h, and viability was determined using trypan blue exclusion staining. For controls, amoebae were incubated with the solvent alone. Of the eight drugs tested, amlodipine, prochlorperazine, and loperamide showed potent amoebicidal effects, as no viable trophozoites were observed (>95% kill rate), while amiodarone, procyclidine, digoxin, and apomorphine exhibited up to 50% amoebicidal effects. In contrast, haloperidol did not affect viability, but all the drugs tested inhibited A. castellanii growth. Importantly, amlodipine, prochlorperazine, and loperamide showed compelling cysticidal effects. The cysticidal effects were irreversible, as cysts treated with the aforementioned drugs did not reemerge as viable amoebae upon inoculation in the growth medium. Except for apomorphine and haloperidol, all the tested drugs blocked trophozoite differentiation into cysts in encystation assays. Given the limited availability of effective drugs to treat amoebal infections, the clinically available drugs tested in this study represent potential agents for managing keratitis and granulomatous amoebic encephalitis caused by Acanthamoeba spp. and possibly against other meningoencephalitis-causing amoebae, such as Balamuthia mandrillaris and Naegleria fowleri.

The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that initial antihypertensive therapy with benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing progression of chronic kidney disease as well as cardiovascular morbidity and mortality in renal patients. The renal results of the ACCOMPLISH trial strongly support the recommendation of using calcium channel blockers as second antihypertensive agent added to renin-angiotensin axis-blocking drugs. This review discusses the validity of these data and their relationship with the cumulative evidence on the effects of calcium antagonists on renal disease progression.

Type II diabetes was shown to prolong the QT interval on the ECG and to promote cardiac arrhythmias. This is not so clear for metabolic syndrome, a precursor state of type II diabetes. The objectives of the present study were to generate a guinea pig model of metabolic syndrome by long-term exposure to diabetogenic diets, and to evaluate the monophasic action potential duration (MAPD)-modulating effects of drugs in these animals. Male Hartley guinea pigs were fed with either the control, the High Fat High Sucrose (HFHS) or the High Fat High Fructose (HFHF) diet for 150 days. Evolution of weight, blood cholesterol, triglycerides, urea and glucose tolerance were regularly monitored. Histopathological evolution was also evaluated in target organs such as pancreas, heart, liver and kidneys. Ex vivo experiments using the Langendorff retroperfusion technique, isolated hearts from guinea pigs either fed with the control, the HFHS or the HFHF diet were exposed to dofetilide 20 nM (D), chromanol 293B 10 μM (C) and amlodipine 100 nM (A) in different drug combinations and monophasic action potential duration was measured at 90% repolarization (MAPD₉₀). Our data show that it is possible to generate a guinea pig model of metabolic syndrome by chronic exposure to diabetogenic diets. Minor histopathological abnormalities were observed, mainly in the pancreas and the liver. Metabolic syndrome potentiates the MAPD-prolonging actions of I(Kr)-blocking (dofetilide) and I(Ks)-blocking (chromanol 293B) drugs, an effect that is reversible upon administration of the calcium channel blocker amlodipine.

The xCELLigence real time cell analyzer Cardio system offers a new system for real-time cell analysis that measures impedance-based signals in a label-free noninvasive manner. The aim of this study was to test whether impedance readings are a useful tool to detect compound effects on beating frequency (beats per minute, bpm) and arrhythmias of human induced pluripotent stem cell- and a mouse embryonic stem cell-derived cardiomyocyte line (hiPSC-CM and mESC-CM, respectively). Baseline values for control wells were 45±3 and 179±6 bpm, respectively (n=6). Correspondingly, isoproterenol increased beating frequency by 77% and 71%, whereas carbachol decreased frequency by 11% and 100% (stopped in 5/6 mESC-CM wells). E-4031 decreased beating rate and caused arrhythmias in both cell types, however, more pronounced in the human iPSC-CMs. Amlodipine inhibited contractions in both models, and T-type calcium channel block strongly reduced beating rate and eventually stopped beating in mESC-CM but caused a smaller effect in hiPSC-CM. The results of this initial study show that, under the right conditions, the beating frequency of a monolayer of cells can be stably recorded over several days. Additionally, the system detects changes in beating frequency and amplitude caused by added reference compounds. This assay system has the potential to enable medium-throughput screening, but for implementation into routine daily work, extended validation, testing of additional batches of cardiomyocytes, and further assay optimization (e.g., frequency of media exchange, growth matrix, seeding density, age of cells after plating, and temperature control) will be needed.

The majority of hypertensive patients, especially those with target organ damage, are likely to require multiple-drug therapy in order to reach blood pressure (BP) targets and reduce their risk of adverse vascular outcomes. The rationale for combination therapy with agents that block the renin-angiotensin system (RAS) and a calcium channel blocker (CCB) or diuretic is well founded in growing evidence. Recent published trials have shown that the combination of an RAS suppressor and a dihydropiridinic CCB would offer additional benefits independently of BP reduction. A telmisartan-amlodipine combination has demonstrated significantly greater BP reductions compared with each monotherapy component in the overall population, and in particular in patients with moderate to severe hypertension and high-risk patients. This combination is well tolerated with a safety profile similar to placebo and is consistent with the known safety profile of its monotherapy components.

While it may seem at first that antihypertensive drug combinations run counter to the desire to 'personalize' the management of hypertension, the best combinations have predictable efficacy in different individuals and subpopulations. Race is probably not a valid surrogate for clinically meaningful genetic variation or guide to therapy. Most guidelines suggest similar blood pressure goals for different races but drug treatment recommendations have diverged. In the United States, race is not considered to be a major factor in drug choice, but in England and other countries, initial therapy with renin-angiotensin system blocking drugs is not recommended in Blacks. In this review we: (1) examine new trends in race-based research; (2) emphasize the weaknesses of race-based treatment recommendations; and (3) explore the effects of a new combination, renin inhibition (aliskiren) and amlodipine, in African Americans.