L-Type Ca2+ Channel Inhibition Rescues the LPS-Induced Neuroinflammatory Response and Impairments in Spatial Memory and Dendritic Spine Formation.

Ca2+ signaling is implicated in the transition between microglial surveillance and activation. Several L-type Ca2+ channel blockers (CCBs) have been shown to ameliorate neuroinflammation by modulating microglial activity. In this study, we examined the effects of the L-type CCB felodipine on LPS-mediated proinflammatory responses. We found that felodipine treatment significantly diminished LPS-evoked proinflammatory cytokine levels in BV2 microglial cells in an L-type Ca2+ channel-dependent manner. In addition, felodipine leads to the inhibition of TLR4/AKT/STAT3 signaling in BV2 microglial cells. We further examined the effects of felodipine on LPS-stimulated neuroinflammation in vivo and found that daily administration (3 or 7 days, i.p.) significantly reduced LPS-mediated gliosis and COX-2 and IL-1ß levels in C57BL/6 (wild-type) mice. Moreover, felodipine administration significantly reduced chronic neuroinflammation-induced spatial memory impairment, dendritic spine number, and microgliosis in C57BL/6 mice. Taken together, our results suggest that the L-type CCB felodipine could be repurposed for the treatment of neuroinflammation/cognitive function-associated diseases.

Influence of 3 calcium channel blockers on gingival overgrowth in a population of severe refractory hypertensive patients.

OBJECTIVE: The aim of the current study was to assess the association between 3 different calcium channel blockers (CCBs) (nifedipine, amlodipine and felodipine) and gingival overgrowth in patients with a diagnosis of severe refractory hypertension. METHODS: One hundred and sixty-two patients with severe refractory hypertension, taking CCBs, were selected. Gingival overgrowth was graded and periodontal measurements were recorded (probing pocket depth, clinical attachment level, plaque index and bleeding on probing). Unconditional multivariable binary logistic regression analyses were performed to assess the association between CCB intake and gingival overgrowth after adjusting for potential confounders. RESULTS: Of the 162 patients, 26 (16.0%) were current smokers and 101 (62.3%) were females. The mean age (SD) was 54.1 (8.5) years and the median age (range) 52.5 (39-78) years. Gingival overgrowth was observed in 55 patients (34.0%). Nifedipine was the most common medication (35.2%; 57 of 162). The results of multiple binary logistic regression showed statistically significant associations between CCB intake (exposure) and gingival overgrowth (outcome) after adjusting for the variables treatment time with antihypertensive and plaque index. Patients with gingival overgrowth were 2.5 (odds ratio = 2.46; 95% confidence interval: 1.04-5.82) and 4.0 (odds ratio = 3.90; 95% confidence interval: 1.47-10.35) times more likely to be taking nifedipine and amlodipine, respectively, than patients without gingival overgrowth. On the other hand, this significant association was not observed for felodipine. CONCLUSION: Nifedipine and amlodipine, but not felodipine, were associated with gingival overgrowth in patients with severe refractory hypertension.

Effect of felodipine on indomethacin-induced gastric ulcers in rats.

Felodipine is a calcium channel blocker with antioxidant and anti-inflammatory properties. Researchers have stated that oxidative stress and inflammation also play a role in the pathophysiology of gastric ulcers caused by nonsteroidal anti-inflammatory drugs. The aim of this study was to investigate the antiulcer effect of felodipine on indomethacin-induced gastric ulcers in Wistar rats and compare it with that of famotidine. The antiulcer activities of felodipine (5 mg/kg) and famotidine were investigated biochemically and macroscopically in animals treated with felodipine (5 mg/kg) and famotidine in combination with indomethacin. The results were compared with those of the healthy control group and the group administered indomethacin alone. It was observed that felodipine suppressed the indomethacin-induced malondialdehyde increase (P<0.001); reduced the decrease in total glutathione amount (P<0.001), reduced the decrease superoxide dismutase (P<0.001), and catalase activities (P<0.001); and significantly inhibited ulcers (P<0.001) at the tested dose compared with indomethacin alone. Felodipine at a dose of 5 mg/kg reduced the indomethacin-induced decrease in cyclooxygenase-1 activity (P<0.001) but did not cause a significant reduction in the decrease in cyclooxygenase-2 activity. The antiulcer efficacy of felodipine was demonstrated in this experimental model. These data suggest that felodipine may be useful in the treatment of nonsteroidal anti-inflammatory drug-induced gastric injury.

Use of clopidogrel and calcium channel blockers and risk of major adverse cardiovascular events.

BACKGROUND: The CYP3A4 inhibition by calcium channel blockers (CCBs) may attenuate the effectiveness of clopidogrel. Using time-varying drug exposure ascertainment, we examined whether CCB use modified the association between clopidogrel use and major adverse cardiovascular events (MACE) after coronary stent implantation. DESIGN: We conducted this population-based cohort study in western Denmark (population 3 million) using medical databases. We identified all 13,001 patients with coronary stent implantation between 2002 and 2005 and their comorbidities. During 12-month follow-up, we tracked the use of clopidogrel and CCBs and the rate of MACE (composite of myocardial infarction, ischaemic stroke, stent thrombosis, target lesion revascularization, or cardiac death). We used Cox regression to compute hazard ratios, controlling for potential confounders. RESULTS: Overall, the 12-month risk for MACE was 14·5%. The rate was 130 per 1000 person years for concomitant clopidogrel and CCB use, 106 for clopidogrel without CCB use, 213 for CCB without clopidogrel use, and 248 for no use of either drug. The adjusted hazard ratio for MACE comparing clopidogrel use with nonuse was 0·52 [95% confidence interval (CI): 0·42-0·64] for CCB users and 0·48 (95% CI: 0·42-0·54) for nonusers, yielding an interaction effect, i.e. relative rate increase, of 1·09 (95% CI: 0·86-1·38). The adjusted hazard ratio for MACE comparing CCB use with nonuse was 1·06 (95% CI: 0·89-1·25) among clopidogrel users. CONCLUSIONS: Concomitant use of CCBs as a class did not modify the protective effect of clopidogrel and was not associated with increased cardiovascular risk among patients using clopidogrel after coronary stent implantation.

[Comparative eficacy of antihypertensive therapy in patients with arterial hypertension and various sensitivity to salt].

In 102 patients with high risk (52 patients with history of myocardial infarction, 50 patients with history of cerebral stroke within previous 6-48 months) arterial hypertension (AH) we studied clinical efficacy on angiotensin converting enzyme inhibitor (ACEI) lisinopril, calcium antagonist felodipine, and nonselective - -blocker carvedilol in dependence on salt sensitivity of AH. Efficacy of treatment was assessed with the help of office pressure measurement and 24 hour arterial pressure monitoring before and after 12 weeks of therapy. Patients who showed 10 or more mm Hg lowering of AP at transition from high salt (15 g/day) to low salt ( 3 g/day) diet were considered salt sensitive. On the basis of obtained results optimal for the treatment of AH in salt resistant patients are ACEI while in the treatment of salt sensitive patients it is expedient to administer calcium antagonists. The use of -adrenoblockers is equally effective in AH with various salt sensitivity.

Severity of coeliac disease and clinical management study when using a CYP3A4 metabolised medication: a phase I pharmacokinetic study.

OBJECTIVE: Severity of coeliac disease depends in part on the extent of small intestinal mucosa injury. Patients with the most abnormal pathology have loss of duodenal villi CYP3A4, a drug-metabolising enzyme that inactivates many drugs. These patients are hypothesised to have greater systemic concentrations of felodipine, a drug which normally has low oral bioavailability secondary to intestinal CYP3A4-mediated metabolism. It serves as a representative for a class containing many medications. DESIGN: A phase I, open-label, single-dose, pharmacokinetic study. SETTING: London, Ontario, Canada. PARTICIPANTS: Patients with coeliac disease (n=47) with positive serology and healthy individuals (n=68). MAIN OUTCOME MEASURES: Patients with coeliac disease-upper gastrointestinal endoscopy and oral felodipine pharmacokinetics study within a 3-week period. Healthy individuals-oral felodipine pharmacokinetics study with water and grapefruit juice. RESULTS: Coeliac stratification categories: Group A (n=15, normal), B+C (n=16, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=16, moderate/severe villous blunting). Groups A, B+C and D had linear trends of increasing felodipine AUC0-8; mean±SEM, 14.4±2.1, 17.6±2.8, 25.7±5.0; p<0.05) and Cmax (3.5±0.5, 4.0±0.6, 6.4±1.1; p<0.02), respectively. Healthy subjects receiving water had lower felodipine AUC0-8 (11.9±0.9 vs 26.9±0.9, p=0.0001) and Cmax (2.9±0.2 vs 7.7±0.2, p=0.0001) relative to those receiving grapefruit juice. CONCLUSIONS: Increased felodipine concentrations in patients with coeliac disease were most probably secondary to decreased small intestinal CYP3A4 expression. Patients with severe coeliac disease and healthy individuals with grapefruit juice had equivalently enhanced effect. Thus, patients with severe coeliac disease would probably experience similarly altered drug response, including overdose toxicity, from many important medications known to be metabolised by CYP3A4. Patients with coeliac disease with severe disease should be considered for other clinical drug management, particularly when there is the potential for serious drug toxicity.

Different roles of pummelo furanocoumarin and cytochrome P450 3A5*3 polymorphism in the fate and action of felodipine.

OBJECTIVE: Herein we aim to test if pummelo furanocoumarins can inhibit cytochrome P450 (CYP) 3A both in vitro and in vivo, and to explore the influence of CYP3A5*3 (GenBank AC005020: A22893-->G) polymorphism in the pharmacokinetics and pharmacological response to felodipine. METHOD: Fruit juices of pummelo grapefruit (Citrus paradisi Macf., G), 'Guanximiyou' (C. grandis Osbeck vs. Guanxi, P) and 'Changshanhuyou' (C. changshanhuyou Y.B. Chang, H) were selected by screening Citrus fruit juices for their furanocoumarin contents and their inhibition of testosterone 6beta-hydroxylation in human liver microsomes. Twelve healthy male Chinese were administered 250 mL G, P, H or water (W) alternatively with 26-mumol (10-mg) plain tablet felodipine, and were observed for 12 h. RESULTS: G had more furanocoumarins and at higher levels than P while H had none, and their potencies for in vitro CYP3A inhibition were in the order as G > P > H. The geometric mean and 90% confidence intervals of pharmacokinetic parameters for human oral felodipine with G, P, H and W were respectively as follows: peak plasma concentration (nmol.L(-1)), 37 (32-44), 25 (21-29), 19 (16-22) and 18 (15-21); area under the plasma concentration-time curve (nmol.h.L(-1)), 118 (103-136), 84 (73-97), 64 (56-74) and 59 (51-68). Subjects showed higher heart rates with G than with H or W. CYP3A5*3 polymorphism showed no significant effect on felodipine pharmacokinetics and related hemodynamic changes. CONCLUSIONS: This work supports the hypothesis that CYP3A inhibition by furanocoumarins caused pummelo fruit juice-drug interaction; while the role of CYP3A5 in the population pharmacokinetics of felodipine and blood pressure response appear to be limited.

[Efficacy, safety and tolerance of Felodipine controlled release tablets and Felodipine controlled release tablets associated combination therapy in the treatment of mild to moderate essential hypertension in China].

OBJECTIVE: To evaluate the efficacy, safety and tolerance of Felodipine controlled release tablets and Felodipine controlled release tablets associated combination each with Metoprolol, Lisinopril or Hydrochlorothiazide in the 12 weeks treatment of mild to moderate essential hypertension in China. METHODS: Multicenter, random samples, and open study have been processed. RESULTS: (1)After 12 weeks associated combination treatment of anti-hypertension, the percentages of the persons who had attained the target were 80.2% of ITT group in Felodipine controlled release tablets associated combination with Hydrochlorothiazide, 74.1% of ITT group in with Metoprolol,and 80.5% of ITT group in with Lisinopril, respectively. (2)Mean reductions of systolic/diastolic blood pressure from baseline were 16.8/10.6 mm Hg in combination with Hydrochlorothiazide, 16.6/10.7 mm Hg in combination with Metoprolol,and 18.0/12.8 mm Hg in combination with Lisinopril each. There was no significant difference among these three groups (P>0.05). With the Felodipine controlled release tablets treatment alone, the mean reductions from baseline was 24.8/17.5 mm Hg. But in combination with Lisinopril, the blood pressure could lower more quickly, and then could reach the target more rapidly. (3)In the ITT group, the drug compliance with Felodipine controlled release tablets was 97.7%, with those in combination with Hydrochlorothiazide 89.8%, with those in combination with Metoprolol 100.0%, and with those in combination with Lisinopril 96.4%. The main adverse event related to Felodipine was headache, and to Lisinopril was cough. CONCLUSION: Antihypertensive drug Felodipine controlled release tablets are good and effective. And Felodipine controlled release tablet associated combination each with Metoprolol, Lisinopril or Hydrochlorothiazide can make most patients reach the treatment target, with safety, good tolerance, and high compliance.

Felodipine-influenced gingival enlargement in an uncontrolled type 2 diabetic patient.

BACKGROUND: The potential of calcium channel blockers (CCBs) to induce gingival enlargement (GE) as well as the influence of diabetes mellitus on periodontal tissues has been well documented. This case report documents a conservative clinical approach to the management of felodipine-influenced gingival enlargement and displays a clinical and histologic case of felodipine-influenced GE in an undiagnosed type 2 diabetic patient. METHODS: At the initial examination, a medical consultation was requested and two incisional biopsies were taken for pathological evaluation. The patient was diagnosed with uncontrolled type 2 diabetes. Felodipine was withdrawn and the diabetes was controlled before dental treatment was initiated. The patient then underwent selective extractions and full-mouth scaling and root planing as well as oral hygiene instructions. No surgical therapy was indicated. RESULTS: The histological results demonstrated the presence of elongated rete pegs; fibrous hyperplasia; a low-grade chronic inflammatory infiltrate, predominantly consisting of lymphocytes; and collagen bundle groups randomly distributed. These features were similar to those present in other drug-influenced GE. Clinical results have demonstrated almost complete resolution of GE after the withdrawal of felodipine and the control of diabetes. Further improvements were seen after scaling and root planing and oral hygiene instructions. No recurrences were noted 12 months after initial therapy. CONCLUSIONS: This report demonstrated that the control of systemic factors seemed to have the most influence on success for this particular case. Since the control of diabetes was managed at the same time as the felodipine withdrawal, it remains difficult to speculate how these two factors impacted both the severity of the GE and the therapeutic results. More importantly, the conservative treatment rendered demonstrated the stability of periodontal status during maintenance phase and the avoidance of surgical interventions.

Pharmacology, Efficacy and Safety of Felodipine with a Focus on Hypertension and Angina Pectoris.

Calcium channel blockers (CCBs) are a heterogeneous group of drugs often used in the therapy for hypertension and angina. Though CCBs are generally similar in terms of their efficacy yet, they differ in their ability of causing selective inhibition in the contractility of vascular smooth muscle in comparison to cardiac muscle. Felodipine is one of the most vascular selective of the available CCBs and it has no negative inotropic effects at clinically administered doses. Focus of this review is to comprehensively summarize the pharmacokinetics, efficacy, safety and tolerability of felodipine. This review is based on evaluation of relevant literature on felodipine using meta-database PubMed and ScienceDirect and internet search engine (Google Scholar). Clinical studies summarized in this review testify, on technical lines, the clinical efficacy, safety and placebo- like tolerability profile of felodipine, administered alone as well as in combination.

Diltiazem stimulates parathyroid hormone secretion in vivo whereas felodipine does not.

The impact of two calcium channel blockers of different structure, diltiazem and felodipine, on PTH secretion was studied under hyper- and hypocalcemic conditions. Six healthy volunteers were investigated before and after treatment with felodipine, then after treatment with diltiazem. Under each of these three conditions, they received first a calcium infusion (0.109 mmol/kg over 130 min). Blood was drawn every 5-10 min for measurements of Ca2+ and intact PTH concentrations, and urine was collected over the infusion periods for measurements of calcium and creatinine. Basal levels of Ca2+ and intact PTH concentrations were similar under the three conditions. During calcium infusion, Ca2+ increased linearly from 1.27 to 1.51 mmol/L during the control period. Based on the whole response curve, Ca2+/time, this rise was less marked (P < 0.002) during each of the calcium channel blocker periods than under control conditions, although the three values of urinary calcium excretion were similar. In addition, PTH secretion was less suppressed on diltiazem than on felodipine therapy or during the control period (P < 0.04). During EDTA infusion, Ca2+ decreased in a linear way from 1.27 to 1.07 mmol/L during the control period. Based on the whole response curve, Ca2+/time, this decrease was more marked during felodipine than during diltiazem treatment or in the control period (P < 0.001). Although Ca2+ concentrations did not differ between the control and diltiazem periods, PTH levels were 1.3-fold higher (P < 0.0001) during diltiazem, but similar in the control and felodipine periods. These data demonstrate that diltiazem, but not felodipine, stimulates PTH secretion in vivo in man, with a maximal effect observed under hypocalcemic conditions.

Quinidine interaction with nifedipine and felodipine: pharmacokinetic and pharmacodynamic evaluation.

Conflicting findings suggest that serum quinidine concentrations may be decreased or increased by nifedipine. We performed a double-blind, placebo-controlled trial of Latin-square design. Twelve healthy men received 3 days of pretreatment with nifedipine prolonged action (20 mg twice a day) or felodipine extended release (10 mg every day), another dihydropyridine calcium antagonist, followed by coadministration of quinidine (400 mg). Quinidine pharmacokinetics were not changed by either dihydropyridine. However, 3-hydroxyquinidine area under the concentration-time curve (AUC) and 3-hydroxyquinidine/quinidine AUC ratio were decreased by felodipine, consistent with reduced metabolite formation. Heart rates and adverse events were higher with felodipine, demonstrating lack of bioequivalence with nifedipine. The QTc interval did not deviate from that expected for the observed quinidine concentration, suggesting the pharmacokinetics of active quinidine metabolites were not markedly altered among treatments. Quinidine disposition did not appear to be changed sufficiently to be clinically important by sustained-release nifedipine and felodipine.

Extended-release felodipine in patients with mild to moderate hypertension. Felodipine ER Dose-Response Study Group.

Two hundred eighty-six patients with mild to moderate hypertension who had untreated diastolic blood pressure while seated of 95 to 115 mm Hg were randomized to receive placebo or once-daily doses of 2.5, 5, or 10 mg of the dihydropyridine calcium channel blocker felodipine extended release (ER). Blood pressure was measured 24 hours after dosing (at trough). Mean reductions in diastolic blood pressure after 8 weeks of double-blind treatment were significantly greater in each of the ER felodipine treatment groups (2.5, 5, and 10 mg ER felodipine: -7.8, -9.5, and -11.3 mm Hg, respectively) than in the placebo group (-5.3 mm Hg). The effect was dose dependent for both diastolic and systolic blood pressure. Moreover, much of the peak antihypertensive effect was still present at trough, confirming the 24-hour efficacy of the drug. Felodipine was well tolerated.

Bilateral reduction mammoplasty in a patient treated with calcium channel blocker and cyclosporine after renal transplant: a case report.

A 28-year-old woman with end-stage renal disease secondary to diabetes mellitus and hypertension underwent cadaver renal transplant in April 1992. After surgery, she developed bilateral breast enlargement while she was taking cyclosporine for immunosuppression therapy and felodipine, a calcium channel blocker, for blood pressure control. She underwent bilateral reduction mammoplasty in June 1995 to treat progressive breast enlargement which interfered with her normal life activities. Through mechanisms only partially understood, calcium channel blockers and cyclosporine are reported to increase the serum prolactin level, producing gynecomastia in men. There is no report in current literature to support a similar phenomenon in women.

Twenty-four-hour activity of felodipine extended release in chronic stable angina pectoris.

To investigate the antiischemic efficacy and duration of action of the dihydropyridine calcium antagonist felodipine, 15 patients with stable exertional angina were enrolled in a double-blind, crossover study comparing 2 doses (5 and 10 mg) of felodipine extended release (ER) and placebo given once daily for 1 week. Bicycle exercise tests were repeated at the end of each treatment period 4 and 24 hours after dosing. Four hours after dosing with both felodipine doses, only 5 patients discontinued the exercise test because of greater than 2 mm of ST-segment depression, whereas 10 continued until exhaustion (p less than 0.01 vs placebo). Compared with placebo, total exercise time was increased by 19% (p less than 0.001), with no difference between doses. After 24 hours, exercise duration was prolonged up to physical exhaustion in 6 patients taking felodipine 10 mg (p less than 0.05 vs both placebo and felodipine 5 mg); moreover, 11 patients taking 10 mg and 5 taking 5 mg increased time to 1 mm of ST depression greater than or equal to 15% compared with exercise time during the placebo test. Mean time to 1 mm of ST depression at 24 hours was increased by 8% with 5 mg and by 18% with 10 mg (p less than 0.001 vs placebo; p less than 0.01 between doses). Total exercise time at 24 hours was increased with both doses (p less than 0.001), with greater efficacy with the 10-mg dose (p less than 0.05 vs 5 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Overview of the safety of felodipine based on clinical trials in patients with hypertension.

All clinical studies of at least 1 week's duration with felodipine in patients with hypertension were included in a safety analysis. The major finding was that felodipine does not increase mortality or the incidence of major cardiovascular events and that the data indicate a favorable effect.

Comparison between felodipine and isosorbide mononitrate as adjunct to beta blockade in patients > 65 years of age with angina pectoris.

Coronary artery disease is an increasingly common medical problem in the elderly, and relatively few studies investigating drug therapy focus on this population. To assess the efficacy and safety of the calcium channel blocker, felodipine, and isosorbide mononitrate (ISMN), as adjunct to optimal beta-blocker therapy in elderly patients, a placebo-controlled, double-blind study was conducted in 46 patients, aged between 65 and 80 years, with documented stress-induced angina pectoris and myocardial ischemia. With use of a latin-square design, with 3 periods of 4 weeks each, exercise testing was performed after each period. Felodipine, 5 mg once daily, significantly improved both time to ischemic threshold and pain threshold (p = 0.02 and p = 0.003, respectively, vs placebo), and tended to increase total exercise time (p = 0.06 vs placebo). In contrast, ISMN, 20 mg twice daily, did not significantly affect these parameters. Comparison of the 2 active treatment arms showed that, overall, felodipine was more effective than ISMN, with a statistically significant difference for time to ischemic threshold (p = 0.02). With regard to safety, felodipine was also better tolerated than ISMN, which led to more patients discontinuing study medication with ISMN (p < 0.05 between ISMN and felodipine). It is concluded that in elderly patients who are treated with optimal beta blockade, felodipine, but not ISMN, leads to an additional significant reduction in ischemic parameters during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipine ER, and angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension.

This report presents data on the safety and tolerability of losartan potassium (losartan), a selective antagonist of the angiotensin II AT-1 receptor, in approximately 2,900 hypertensive patients treated in double-blind clinical trials. In these studies, headache (14.1%), upper respiratory infection (6.5%), dizziness (14.1%), asthenia/fatigue (3.8%), and cough (3.1%) were the clinical adverse experiences most often reported in patients treated with losartan. These adverse experiences were also frequently reported in patients receiving placebo: 17.2%, 5.6%, 2.4%, 3.9%, and 2.6%, respectively. Dry cough as an adverse event was reported in 8.8% of patients treated with angiotensin-converting enzyme inhibitors, and in 3.1% and 2.6% of patients treated with losartan or placebo, respectively. Only dizziness was considered "drug-related" more often in losartan-treated (2.4%) than placebo-treated (1.3%) patients. In controlled clinical trials, losartan was better tolerated than other antihypertensive agents as determined by the incidence of patients reporting any drug-related adverse experiences. Rates of discontinuation due to clinical adverse experiences in patients who received losartan monotherapy or losartan+hydrochlorothiazide were 2.3% and 2.8%, respectively, compared with placebo (3.7%). No laboratory adverse experiences were unexpected or of clinical importance. First-dose hypotension rarely occurred with losartan or with losartan plus hydrochlorothiazide, and withdrawal effects such as rebound hypertension were not observed in clinical trials. There were no clinically important differences in the clinical or laboratory safety profiles in the demographic subgroups for age, gender, or race. In controlled clinical trials, losartan demonstrated an excellent tolerability profile.

Comparison of effects on peak oxygen consumption, quality of life, and neurohormones of felodipine and enalapril in patients with congestive heart failure.

Angiotensin-converting enzyme (ACE) inhibition is currently the cornerstone of congestive heart failure (CHF) therapy, but these drugs are not tolerated in up to 20% of patients. For these patients, therapeutic alternatives with comparable efficacy are needed. Felodipine, a vasoselective dihydropyridine calcium antagonist with a slow onset of action and a long plasma half-life, may be such an agent. Therefore, the efficacy and safety of felodipine were examined and compared with enalapril using a double-blind design. We studied 46 patients with a left ventricular ejection fraction < 0.40, peak oxygen consumption < 20 ml.min-1.kg-1, and symptoms of CHF despite therapy with diuretics and digoxin. After 16 weeks of therapy, there were no statistically significant differences in peak oxygen consumption (felodipine +1.6, enalapril +2.5 ml.min-1.kg-1) and exercise tolerance (felodipine +61 seconds, enalapril +64 seconds). Quality-of-life parameters were affected slightly better by felodipine than by enalapril. Plasma norepinephrine decreased by 143 pg.ml-1 with enalapril and by 12 pg.ml-1 with felodipine (p < 0.20 between groups). Both drugs were generally well tolerated. These data suggest that felodipine and enalapril have comparable effects on exercise parameters in patients with CHF. Neurohumoral activation was not observed with either drug.