Calcium Channel Blockers In Hypertension Research Articles

Calcium channel blockers for hypertension: old, but still useful

Calcium channel blockers (CCBs) constitute a heterogeneous class of drugs that can be divided into dihydropyridines (DHPs) and non-DHPs. DHP-CCBs are subcategorized into four generations based on the duration of activity and pharmacokinetics, while non-DHP-CCBs are subcategorized into phenylethylamine and benzodiazepine derivatives. DHP-CCBs are vascular-selective and function as potent vasodilators, whereas non-DHP-CCBs are cardiac-selective and are useful for treating tachyarrhythmia, but reduce cardiac contractility and heart rate. Traditional DHP-CCBs (nifedipine) mainly block L-type calcium channels, whereas novel CCBs block N-type (amlodipine) and/or T-type channels (efonidipine) in addition to L-type channels, leading to organ-protective effects. DHP-CCBs have a potent blood pressure–lowering effect and suppress atherosclerosis and coronary vasospasm. Diltiazem, a non-DHP-CCB, is highly effective for vasospasm control. CCBs reduce left ventricular hypertrophy and arterial stiffness. Amlodipine, a DHP-CCB, reduces blood pressure variability. L/N- and L/T-type CCBs combined with renin-angiotensin system blockers reduce proteinuria and improve kidney function compared with L-type CCBs. According to large-scale trials, DHP-CCBs reduce cardiovascular events in patients with isolated systolic hypertension, as well as in elderly and high-risk patients. Accordingly, CCBs are indicated for hypertension in elderly patients, isolated systolic hypertension, angina pectoris, and coronary vasospasm. Non-DHP-CCBs are contraindicated in high-grade heart block, bradycardia (<60 beats per minute [bpm]), and heart failure with reduced ejection fraction (HFrEF). DHP-CCBs should be used with caution in patients with tachyarrhythmia, HFrEF, and severe leg edema, and non-DHP-CCBs should be used carefully in those with constipation. Each CCB has distinct pharmacokinetics and side effects, underscoring the need for meticulous consideration in clinical practice.

Synthesis of Ethyl Methyl 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates as Potential Calcium Channel Blockers for Hypertension

Aim: Several new dihydropyridine-based calcium channel blockers have been synthesized and pharmacologically evaluated for the treatment of hypertension Background: Dihydropyridines constitute an important class of calcium channel blockers (CCBs) due to their high potency, wide heterogeneity and tremendous biological usefulness. As a follow-up to our previous studies on 4-aryl-1,4-dihydropyridines as calcium channel blockers for the treatment of hypertension, four new series of methyl ethyl ester substituted 1,4-dihydropyridines are reported. Objectives: The aim of the work was to study the effects of unsymmetrical ester substitutions on calcium channel blocking activity of dihydropyridines (DHPs) while retaining the aminoalkoxy side chain at various positions of the 4-aryl ring. The type and location of the substituents on the 4-aryl ring have been extensively explored to study the structure-activity relationship (SAR) in this series of dihydropyridines as calcium channel blockers. Methodology: The target DHPs were synthesized using modified Hantzsch condensation and further derivatization. The compounds were screened for their inhibitory potential against L-type calcium channels at a single concentration of 10 μM on NG108-15 cells (Neuroblastoma X Glioma). The most potent DHP 12 was also tested for its vasodilatory activity using rat thoracic aortic rings precontracted with KCl (30 mM) and in vivo antihypertensive activity in rats using the tail-cuff method. Results: The newly synthesized DHPs displayed diversified calcium channel blocking activity with compounds 1e, 1h, 2d, 2f, 2h, 6, 9, 11, 12 and 14, producing more than 50% inhibition of veratridine response. 3-imidazolylpropoxy substituted analogue 12 turned out to be the most potent compound of the four series of compounds and produced fairly higher inhibition (78.6%) of veratridine response in comparison to nifedipine (70%) at 10 μM. In addition, compound 12 produced potent vasodilatory and antihypertensive properties. Conclusion: Both location of the side chain and the type of substituent on methyl ethyl ester substituted 4-aryl ring affected the response of dihydropyridine derivatives towards L-type calcium channels.

Systemic Delivery of Calcium Channel Blockers for Hypertension through Transdermal Delivery - A Review

Hypertension is a significant public health challenge, responsible for a substantial proportion of deaths and disability globally. Calcium Channel Blockers (CCBs) are an essential class for the treatment of hypertension. However, most of CCBs must be taken more than once daily due to their low oral bioavailability and limited half-life, leading to non-compliance in patients. The development of delivery methods for CCBs is an ongoing effort to overcome the issues related to their delivery via their traditional forms. The administration of the drug through the skin for systemic delivery has been recognised as one of the potential routes in hypertension treatment, especially when drugs suffer from low bioavailability, undesirable side effects and short biological half-life following oral administration. The main limitation of transdermal drug delivery is the resistance barrier of skin layers to penetrant molecules. Remarkable research efforts have been made worldwide to minimise the skin barrier and to create transdermal systems of several CCBs via employing skin-enhancing potential. The persistent progress in this field is promising for development the transdermal dosage forms advance technology in the long term and being commercialised sooner rather than later. This review explores the investigations on the viability and applicability of systemic delivery of numerous CCBs through the skin.

Effects of Long- and Intermediate-Acting Dihydropyridine Calcium Channel Blockers in Hypertension: A Systematic Review and Meta-Analysis of 18 Prospective, Randomized, Actively Controlled Trials.

Dihydropyridine calcium channel blockers are a heterogeneous group of antihypertensive drugs. Long-acting dihydropyridine agent amlodipine is widely used for monotherapy and combination therapy for hypertension in clinical practice, while intermediate-acting dihydropyridine agents have shown inconsistent results in randomized clinical trials (RCTs). A meta-analysis of 18 RCTs enrolling a total of 80,483 patients with hypertension followed for a mean of 51.4 months was performed. Amlodipine therapy was associated with 25% higher risk of heart failure (relative risk [RR]: 1.25, 95% confidence interval [CI], 1.05-1.49, P = .019) but 17% lower risk of stroke (RR: 0.83, [95% CI, 0.72-0.97], P = .009) without statistically significant effect on acute myocardial infarction (AMI) compared to major alternative antihypertensive therapy (MAAT), including β-blocker, diuretic, angiotensin-converting enzyme inhibitor, or angiotensin-receptor blocker. Intermediate-acting dihydropyridine calcium channel blocker therapy was associated with 25% higher risk of heart failure (RR: 1.25, [95% CI, 1.06-1.47], 0.005, P = .005) and 26% higher risk of AMI (RR: 1.26, [95% CI, 1.05-1.51], 0.019, P = .019) compared to MAAT. Results of the subgroup analysis suggested that the intermediate-acting dihydropyridine calcium channel blocker was associated with higher risk of heart failure (RR: 1.30, [95% CI, 1.08-1.56], P = .005) and AMI (RR: 1.50, [95% CI, 1.01-2.22], P = .043) compared to renin-angiotensin system blockers and a trend toward higher risk of AMI (RR: 1.17, [95% CI, 0.99-1.38], P = .064) compared to conventional therapy, including β-blockers and diuretics. Meta-regression analyses suggested that long-acting dihydropyridine calcium channel blocker is associated with lower risk of AMI ( B: -0.327, [95% CI, -0.530 to -0.123], P = .002) with a trend toward lower risk of stroke ( B: -0.203, [95% CI, -0.410 to 0.003] P = .054). This study suggests that Amlodipine offers greater protection against major complications of hypertension compared to intermediate-acting dihydropyridine calcium channel blockers.

How to Improve Effectiveness and Adherence to Antihypertensive Drug Therapy: Central Role of Dihydropyridinic Calcium Channel Blockers in Hypertension.

Essential hypertension is a complex clinical condition, characterized by multiple and concomitant abnormal activation of different regulatory and contra-regulatory pathophysiological mechanisms, leading to sustained increase of blood pressure (BP) levels. Asymptomatic rise of BP may, indeed, promote development and progression of hypertension-related organ damage, which in turn, increases the risk of major cardiovascular and cerebrovascular events. A progressive and independent relationship has been demonstrated between high BP levels and increased cardiovascular risk, even in the high-to-normal range. Conversely, evidence from randomized controlled clinical trials have independently shown that lowering BP to the recommended targets reduces individual cardiovascular risk, thus improving event-free survival and reducing the incidence of hypertension-related cardiovascular events. Despite these benefits, overall rates of BP control remain poor, worldwide. Currently available guidelines support a substantial equivalence amongst various antihypertensive drug classes. However, several studies have also reported clinically relevant differences among antihypertensive drugs, in terms of both BP lowering efficacy and tolerability/safety profile. These differences should be taken into account not only when adopting first-line antihypertensive therapy, but also when titrating or modulating combination therapies, with the aim of achieving effective and sustained BP control. This review will briefly describe evidence supporting the use of dihydropyridinic calcium channel blockers for the clinical management of hypertension, with a particular focus on barnidipine. Indeed, this drug has been demonstrated to be effective, safe and well tolerated in lowering BP levels and in reducing hypertension-related organ damage, thus showing a potential key role for improving the clinical management of hypertension.

The inherent susceptibility of dorsal motor nucleus cholinergic neurons to the neurodegenerative process in Parkinson's Disease

The inherent susceptibility of dorsal motor nucleus cholinergic neurons to the neurodegenerative process in Parkinson's Disease

Crossover study of amlodipine versus nifedipine CR with home blood pressure monitoring via cellular phone: internet-mediated open-label crossover trial of calcium channel blockers for hypertension (i-TECHO trial)

We developed a new data collection system named i-converter that could transmit data to a website via cellular phone. Using the system, we compared the effects of two calcium channel blockers on the home blood pressure. Amlodipine and nifedipine CR were administered to 41 patients with essential hypertension for more than 6 weeks each in a randomized open-label crossover study. The dose of each drug was increased until the home blood pressure reached the target level of under 135/85 mmHg. The morning home systolic and diastolic blood pressures were significantly lower during nifedipine CR treatment: 133 +/- 10/81 +/- 8 mmHg with amlodipine versus 131 +/- 8/80 +/- 8 mmHg with nifedipine CR, P < 0.05. The morning pulse rate was significantly higher during nifedipine CR treatment (69 +/- 9 beats/min with amlodipine versus 70 +/- 9 beats/min with nifedipine CR, P < 0.05). The evening home blood pressure and pulse rate, however, showed no significant differences between the two drugs (128 +/- 11/74 +/- 7 mmHg and 74 +/- 10 beats/min with amlodipine versus 128 +/- 10/75 +/- 7 mmHg and 74 +/- 9 beats/min with nifedipine CR, all not significant). Nifedipine CR had a stronger antihypertensive effect than amlodipine during the critical morning period, but the morning pulse rate was higher. Our new data transmission system was effective for collecting precise data on the blood pressure and pulse rate via the internet.

Does hormone replacement therapy affect the use of prescription medicines in postmenopausal women: experience from the Estonian Postmenopausal Hormone Therapy Trial [ISRCTN35338757

To determine how postmenopausal hormone therapy (HRT) is related to the use of other prescription medication. Follow up of a randomised controlled trial with a blind subtrial of hormone therapy versus placebo and a nonblind subtrial of open label hormone therapy versus nontreatment. A total of 1823 postmenopausal women aged 50-64 at the time of sampling participated in the trial from 1999 to 2004. Use of prescription medication was identified by records in the central computerised database of the Estonian Health Insurance Fund. The use of 21 classes of prescription medication was compared in the hormone therapy arms and placebo or nontreatment trial arms. The influence of women's socio-economic characteristics on the intensity of concomitant medication use was also examined. The proportion of women using any prescription medication besides hormone therapy did not differ between the arms. However, the type of prescribed drugs varied between the arms. After combining data from both hormone therapy arms, for women using HRT the combined hazard ratio was 1.26 (95% CI: 1.05-1.53) for the use of calcium channel blockers, 1.48 (95% CI: 1.10-1.99) for local vaginal treatment, 0.70 (95% CI: 0.50-0.99) for hypnotics and sedatives and 0.77 (95% CI: 0.60-0.99) for selective serotonin reuptake inhibitors (SSRIs). Women who were older, who had a higher body mass index, who were unemployed and who lived outside the capital used more prescription drugs in comparison with others. Hormone therapy did not increase the overall use of prescription medication other than hormone therapy, but the types of drugs used in hormone therapy and nontherapy arms varied, with increased use of calcium channel blockers for hypertension and local vaginal treatments for vaginal candidiasis and decreased use of hypnotics, sedatives and SSRIs in the HRT arms.

Antioxidant effects and the therapeutic mode of action of calcium channel blockers in hypertension and atherosclerosis

Drugs currently known as calcium channel blockers (CCB) were initially called calcium antagonists because of their ability to inhibit calcium-evoked contractions in depolarized smooth muscles. Blocking the entry of calcium reduces the active tone of vascular smooth muscle and produces vasodilatation. This pharmacological property has been the basis for the use of CCBs in the management of hypertension and coronary heart disease. A major question is whether drugs reducing blood pressure have other effects that help prevent the main complications of hypertension, such as atherosclerosis, stroke, peripheral arterial disease, heart failure and end-state renal disease. Experimental studies that focus on this question are reviewed in the present paper.

Evidence-based evaluation of calcium channel blockers for hypertension: Equality of mortality and cardiovascular risk relative to conventional therapy

ObjectivesWe present a meta-analysis based on three recent, substantial, randomized outcome trials and several smaller trials that compared calcium channel blockers (CCBs) with conventional therapy (diuretics or beta-blockers) or with angiotensin-converting enzyme (ACE) inhibitors BackgroundThere is continuing uncertainty about the safety and efficacy of CCBs in the treatment of hypertension. Previous meta-analyses conflict and suggest that CCBs increase myocardial infarction (MI) or protect from stroke. MethodsStandard procedures for meta-analysis were used to analyze three major trials on 21,611 patients and another three lesser studies to a total of 24,322 patients. ResultsCalcium channel blockers have a strikingly similar risk of total and cardiovascular mortality and of major cardiovascular events to conventional therapy. Calcium channel blockers give a lower risk of nonfatal stroke (−25%, p = 0.001) and a higher risk of total MI (18%, p = 0.013), chiefly nonfatal (18%). After performing the Bonferroni correction for multiplicity, these p values become 0.004 and 0.052, respectively. When compared with ACE inhibitors in 1,318 diabetic patients, CCBs had a substantially higher risk of nonfatal (relative risk [RR] = 2.259) and total MI (RR = 2.204, confidence interval 1.501 to 3.238; p = 0.001 or 0.004 with Bonferroni correction). Total and cardiovascular mortality rates are similar. To confirm the hypothesis that ACE inhibitors are superior to CCBs in diabetic patients requires more trial data, especially with renal end points. ConclusionsMortality (total and cardiovascular) and major cardiovascular events with CCBs were apparently similar to those events seen with conventional first-line therapy (diuretics or beta-blockers). Stroke reduction more than balanced increased MI. In diabetics, CCBs may be less safe than ACE inhibitors.

Tolerability of antihypertensive drugs in a community-based setting

Background: Outside the experimental environment of clinical trials, the tolerability of angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and the angiotensin II antagonist losartan has not been compared. Objectives: The purpose of this study was to estimate, in current clinical practice, the 3-month cumulative incidence of side effects among first-time users of losartan, ACEIs, and CCBs for hypertension. Methods: We conducted a prospective cohort study through a network of 173 pharmacies across Canada to identify patients with hypertension who were newly prescribed monotherapy with losartan, an ACEI, or a CCB. Individuals were interviewed by telephone 3 times over a 3-month period to determine perceived side effects of the antihypertensive medication prescribed. Data were analyzed using a multivariate logistic regression model. Results: Among the 663 eligible individuals, the 3-month cumulative incidence of perceived side effects was 52.5% ( 42 80 ), 60.2% ( 222 369 ), and 69.6% ( 149 214 ) for those treated with losartan, an ACEI, and a CCB, respectively. After adjustment for sex, age, level of education, number of symptoms perceived the week before entering the study, prior use of antihypertensive drugs, current use of any other drug, drug insurance coverage, and duration of hypertension, the odds of reporting a side effect were significantly higher among patients treated with an ACEI (odds ratio [OR] = 1.78; 95% CI, 1.02–3.12) or a CCB (OR = 2.65; 95% CI, 1.47–4.78) compared with patients treated with losartan. Conclusions: In a community-based setting, we observed that losartan is better tolerated than ACEIs and CCBs. Given that the occurrence of side effects may contribute to lower adherence to drug treatment, the low incidence of side effects associated with losartan makes it an attractive antihypertensive drug choice.

Calcium channel blockers in hypertension: the debate reawakens

Ever since the publication of the Puget Sound pharmacosurveillance study in 1995, there has been a continuing debate on the effectiveness or safety of the calcium channel blockers (CCBs) in the treatment of hypertension and heart disease. Various retrospective case-control studies had raised the possibility that these drugs may cause haemorrhage, suicide, cancer and excess cardiovascular morbidity and mortality. Several observational studies and some individual randomised trials in hypertension have even suggested that, compared with other drugs, CCBs may be associated with a higher risk of coronary events, despite similar blood pressure control. Many of these anxieties seemed to have been allayed by the placebo-controlled SYST-EUR Trial where the CCB, nitrendipine, bought about a major reduction in stroke and a large but nonsignificant fall in heart attacks, with no excess of cancer of haemorrhage. Similarly, the use of the CCB, felodipine, was beneficial in the HOT study. Was the debate over? So it seemed, but the focus of the argument changed slightly. No one doubted that CCBs were better than placebo, but how do they compare with other agents? The STOP-H2 trial perported to show evidence of equivalence of calcium channel blockers (felodipine or isradipine) with the older agents (diuretics and beta-blockers) and was deemed by a Lancet commentary to be ‘a draw’. However, there was still the tendency for the CCBs to be ‘slightly better’ than other agents at preventing stroke but to be ‘slightly less effective’ at preventing myocardial infarction and heart failure, with no difference in all-cause mortality. Two more trials with CCBs which were published in 2000 (INSIGHT and NORDIL) broadly produced similar findings but statistical and methodological considerations limited

Impaired exercise capacity late after cardiac transplantation: Influence of chronotropic incompetence, hypertension, and calcium channel blockers

Background and Methods Patients undergoing orthotopic cardiac transplantation manifest reduced exercise capacity during the first postoperative year, which is related primarily to chronotropic incompetence of the denervated heart. To determine whether exercise capacity improves during the long term after transplantation, we prospectively studied 45 patients from 1 month to 6 years after cardiac transplantation by use of maximal treadmill exercise testing for measurement of exercise duration, peak heart rate, and peak V o 2. All had normal left ventricular ejection fractions. Patients were categorized according to length of time since transplant and compared to 14 untrained normal subjects. Results Peak exercise heart rate and exercise duration were progressively higher as time after transplantation increased. However, patients who had undergone transplantation more than 2 years earlier continued to manifest a significant reduction in peak exercise heart rate (157 ± 3 beats/min vs 178 ± 14 beats/min) and reduced exercise duration (8.6 ± 0.5 minutes vs 13.2 ± 2.0 minutes) compared with controls. In contrast, peak V o 2 was similar at all times after transplant and remained markedly reduced in patients who underwent transplantation more than 2 years earlier as compared with controls (22.1 ± 0.7 mL/kg/min vs 42.1 ± 9.1 mL/kg/min). The potential effects of 14 clinical variables on exercise performance were evaluated by regression modeling. Patients with poorly controlled hypertension had a shorter median exercise duration (7.4 minutes vs 9.7 minutes) and a lower median peak V o 2 (20.3 mL/kg/min vs 23.2 mL/kg/min) compared with patients with normal or well-controlled blood pressure. Patients treated with calcium channel blockers for hypertension had greater chronotropic incompetence during exercise (peak heart rate 139 beats/min vs 158 beats/min). There was no relation between exercise capacity and recipient age, donor age, recipient sex, donor ischemic time, pretransplant diagnosis, length of peritransplant hospitalization, percentage of ideal body weight, left ventricular ejection fraction, frequency or severity of allograft rejection, or long-term use of oral prednisone therapy. Conclusions Exercise capacity, as measured by treadmill exercise time and peak heart rate, improves in the first 2 years after transplantation, but does not reach normal values in patients up to 6 years after transplant. Peak V o 2 remains significantly reduced at all times after transplantation despite the presence of normal resting left ventricular systolic function. (Am Heart J 1998;136:465-73.)

D004 Long acting calcium channel blockers in hypertension. Amlodipine vs nifedipine GITS comparative study

D004 Long acting calcium channel blockers in hypertension. Amlodipine vs nifedipine GITS comparative study

Efficacy and safety of losartan versus calcium channel blockers in hypertension

Efficacy and safety of losartan versus calcium channel blockers in hypertension

The calcium channel blocker controversy in perspective.

Periodically in the history of hypertensive therapy there have been minor storms that have significantly affected the utilization of entire classes of agents. The first storm struck with the case-control studies suggesting that reserpine was associated with an increased risk of carcinoma of the breast, a claim subsequently disproved by a number of other studies. The second storm was initiated by a subanalysis of the Multiple Risk Factor Intervention Trial (MRFIT), from which it was inferred that, in a subset of hypertensive patients, diuretic treatment may have been harmful rather than beneficial. Despite this claim and other speculations, diuretics-especially at low doses-remain a gold standard of antihypertensive therapy. Recently, a third storm has developed in the field of antihypertensive therapy: a case-control study report and a non-randomized cohort study have questioned the use of calcium channel blockers in hypertension. The case-control study suffers from the limitations inherent in this study design, which often gives rise to conflicts and contradiction. In fact, another case-control study published in 1995 reached exactly the opposite conclusions and claimed that calcium channel blockers were associated with significantly less myocardial infarction than traditional antihypertensive therapy. A meta-analysis was also presented as supporting the non-randomized studies questioning the safety of calcium channel blockers. However, it refers to patients with coronary heart disease, not to patients with hypertension, and also combined studies performed with different aims, and data from short-term and long-term studies using short-acting formulations of calcium channel blockers. The controversies generated by these reports have gone well beyond their scientific merit. For final judgement we should wait for well-designed prospective studies, several of which are under way. For the time being, there is no reason to change the current practice of antihypertensive therapy, as summarized in the recommendations of both the United States Joint National Committee and the World Health Organization/International Society of Hypertension Committee, that is, diuretics and beta-blockers are among those antihypertensive agents with clearly proven benefits in mortality-morbidity studies, but calcium channel blockers as well as ACE inhibitors and alpha-blockers can also be used profitably in the treatment of hypertension.

A personal view of the controversy regarding the use of calcium channel blockers in hypertension

Aim The purpose of this review is to add perspective to the current controversy surrounding the role of calcium channel blockers in the treatment of hypertension. Calcium blocker safety Well-conducted retrospective studies have raised concern about various aspects of the long-term safety of calcium blockers. These include: (1) a case cohort study by Psaty et al. in hypertensive patients indicating that calcium blockers were associated with an increased risk of myocardial infarction (> 50% increase) compared to diuretics or β-blockers; (2) a meta-analysis by Furberg et al. of 16 studies suggesting that nifedipine increases mortality in acute coronary syndromes; (3) a trial in which isradipine was associated with more cardiovascular events in hypertensive patients than in those taking hydrochlorothiazide; (4) a report by Pahor and colleagues of an increased risk of gastrointestinal bleeding in elderly patients taking isradipine; and (5) a further report by Pahor et al. that the incidence of most common cancers appeared to be higher in patients taking calcium blockers than other cardiac medications (relative risk = 1.72; 95% confidence interval 1.2–2.34, P = 0.0005). The majority of these observations were made with short-acting calcium blockers, which are not indicated for the treatment of hypertension. In contrast, other well-controlled clinical trials are consistent with long-term calcium blocker safety. Some reports support a difference in the safety of calcium blockers that increase heart rate and those that decrease heart rate. There is also an indication that longer acting formulations of dihydropyridines and verapamil and diltiazem may have a better long-term safety profile in hypertension than the short-acting calcium blockers (which were the primary focus of many of the adverse reports). Secondary prevention trials of diltiazem [Multicenter Diltiazem Postinfarction Trial (MDPIT), Diltiazem Reinfarction Study (DRS)] and secondary prevention trials of verapamil (Danish Study on Verapamil in Myocardial Infarction; DAVIT I, II) are generally supportive of long-term calcium blocker safety except in patients with heart failure. A retrospective study of > 11000 patients with coronary artery disease did not support an association between the use of calcium blockers and increased mortality. A case–control trial of general practice experience in the United Kingdom found no increased risk of myocardial infarction using calcium blockers compared to β-blockers for the treatment of hypertension. Conclusion I support the current recommendations of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure that thiazides and β-blockers be considered first as initial therapy. The studies questioning the safety of calcium blockers are certainly concerning but not sufficient to justify condemning their use in hypertension. Calcium blockers remain a reasonable alternative therapy in hypertension.

Action of the calcium channel blocker lacidipine on cardiac hypertrophy and endothelin-1 gene expression in stroke-prone hypertensive rats.

1. The tissue-protective effects of calcium channel blockers in hypertension are not well dissociated from their effect on systolic blood pressure (SBP). We have previously shown that lacidipine, a dihydropyridine-type calcium antagonist, reduced the cardiac hypertrophy and the cardiac endothelin-1 (ET-1) gene overexpression occurring in salt-loaded stroke-prone spontaneously hypertensive rats (SL-SHRSP), an effect occurring without systolic blood pressure (SBP) change. In the present study, we have examined whether this action was dose-related and if it could be associated with ET receptor changes. The action of lacidipine was also examined in control SHRSP and in Wistar Kyoto rats (WKY). 2. The daily dose of 0.3 mg kg-1 lacidipine which did not lower SBP but significantly prevented ventricle hypertrophy and cardiac preproET-1-mRNA expression in SL-SHRSP was inactive in control SHRSP. With the higher dose of lacidipine (1 mg kg-1 day-1), we observed a further reduction of cardiac hypertrophy and of ET-1 gene expression in SL-SHRSP and a significant effect on those parameters in control SHRSP but only a small reduction of SBP in both groups. 3. In WKY, salt loading did not induce change in SBP or increase of cardiac ET-1 gene expression and ventricle mass. In these normotensive rats, lacidipine (1 mg kg-1 day-1) did not modulate the basal preproET-1-mRNA expression and did not affect SBP or heart weight. 4. The maximum binding capacity (Bmax) and the dissociation constant (KD) of [125I]-ET-1 binding and the relative proportion of low- and high-affinity binding sites for ET-3 were not significantly affected by salt loading or lacidipine treatment in SHRSP. 5. These results show that lacidipine exerted a dose-related inhibition of ventricle hypertrophy and preproET-1-mRNA expression in SHRSP and indicate that this effect was unrelated to SBP changes. The dose-dependency of this inhibition suggests that salt-induced cardiac hypertrophy could be related to ET-1 gene overexpression. The results further show that ET receptor changes are not involved in the pathophysiological process studied here.

Fortnightly Review: Short acting dihydropyridine (vasodilating) calcium channel blockers for hypertension: is there a risk?

Summary points Only thiazide diuretics and β blockers have been shown to prevent myocardial infarction and stroke in properly randomised and blinded studies in patients with hypertension The efficacy of calcium channel blockers and angiotensin converting enzyme inhibitors in preventing myocardial infarction and stroke and reducing mortality in hypertensive patients has not been studied The current licensing and clinical use of calcium channel blockers and angiotensin converting enzyme inhibitors in hypertension have been based on surrogate end points such as reduction of blood pressure or left ventricular hypertrophy, or both, or reduction of microproteinuria or macroproteinuria Observational data on short acting dihydropyrridine calcium channel blockers are worrying; there is urgent need for proper large scale randomised trials of calcium channel blockers in hypertension Trials in ischaemic heart disease suggest that in the absence of left ventricular dysfunction verapamil and diltiazem are preferred choices if a calcium, channel blocker is needed in the non-acute setting

Effect of amlodipine and felodipine on sympathetic activity and baroreflex function in normal humans

Baroreflex sensitization and direct sympatholytic effects have been suggested as contributing mechanisms to the effects of dihydropyridine calcium channel blockers in hypertension and heart failure. In this study, we tested the hypothesis that either amlodipine or felodipine would decrease norepinephrine levels and enhance cardiac, peripheral vascular, or sympathetic responses to baroreflex perturbation in healthy humans. Six healthy male volunteers aged 21 to 40 participated. Heart rate, forearm blood flow, arterial pressure, and norepinephrine kinetics were assessed in the supine position, after 15 min of 60 degrees head-up tilt, after 15 min of 30 degrees head-down tilt, and after 15 min head-down tilt with phenylephrine infused to raise mean arterial pressure 10 to 15 mm Hg. Studies were conducted double-blind on 3 different days 8 to 12 h after placebo, 5 mg amlodipine, and 10 mg felodipine. Resting heart rate, mean arterial pressure, forearm vascular resistance, plasma norepinephrine, and norepinephrine spillover were not affected by amlodipine or felodipine. During upright tilt, head-down tilt, and phenylephrine, each variable increased and decreased as expected after placebo. There was no effect of either amlodipine or felodipine on any response to any maneuver. Baseline sympathetic activity as reflected by plasma norepinephrine and norepinephrine spillover are not altered by either amlodipine or felodipine. Neither drug acutely sensitizes baroreflex function in normal humans over the degree of perturbation produced in these protocols.