dihydropyridines and Heart-Failure

dihydropyridines has been researched along with Heart-Failure* in 49 studies

Reviews

13 review(s) available for dihydropyridines and Heart-Failure

ArticleYear
A Reappraisal of the Effects of L-type Ca
    Function (Oxford, England), 2023, Volume: 4, Issue:6

    Dihydropyridines such as amlodipine are widely used as antihypertensive agents, being prescribed to ∼70 million Americans and >0.4 billion adults worldwide. Dihydropyridines block voltage-gated Ca

    Topics: Amlodipine; Antihypertensive Agents; Calcium; Calcium Channel Blockers; Dihydropyridines; Fura-2; Heart Failure; Humans; Hypertension; Prospective Studies

2023
Pharmacological treatment of aldosterone excess.
    Pharmacology & therapeutics, 2015, Volume: 154

    Primary aldosteronism, caused by autonomous secretion of aldosterone by the adrenals, is estimated to account for at least 5% of hypertension cases. Hypertension explains the considerable cardiovascular morbidity caused by aldosteronism only partly, calling for specific anti-aldosterone drugs. The pharmacology of aldosterone is complex due to high homology with other steroids, the resemblance of steroid receptors, and the common pathways of steroid synthesis. Classically, pharmacological treatment of aldosteronism relied on the mineralocorticoid receptor (MR) antagonist spironolactone, which is highly effective, but causes considerable, mainly sexual side-effects due to limited selectivity for the MR. New agents have been developed or are being developed that aim at higher selectivity for MR antagonists (eplerenone, dihydropyridine-derived calcium channel blockers (CCB)), or inhibition of aldosterone synthesis. Eplerenone is less potent than spironolactone, but causes fewer adverse effects due to its selectivity for the MR. Non-steroidal MR antagonists have been developed from dihydropyridine CCBs, having lost their CCB activity and being highly selective for the MR. The first clinical studies with these drugs are underway. Aldosterone synthase inhibitors are an attractive alternative, but are prone to interference with cortisol synthesis due to the inhibition of 11-β-hydroxylation, an essential step in both cortisol and aldosterone synthesis, and accumulation of mineralocorticoid precursors. In coming years clinical research will provide the answers as to which drugs and strategies to treat high-aldosterone states are the most effective.

    Topics: Aldosterone; Cytochrome P-450 CYP11B2; Dihydropyridines; Drug Interactions; Epithelial Sodium Channel Blockers; Eplerenone; Glucocorticoids; Heart Failure; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone

2015
[Calcium antagonists: current and future applications based on new evidence. Cardio-protective effect of calcium antagonists].
    Clinical calcium, 2010, Volume: 20, Issue:1

    Calcium antagonists block calcium influx through the L-type calcium channel to produce dilatation of resistant arteries including coronary arteries. Due to arterial vasodilatation, calcium antagonists have beneficial effects for ischemic heart disease, left ventricular hypertrophy and heart failure. Some of calcium antagonists are known to have the inhibitory action for T-type or N-type calcium channel which might be beneficial for the inhibition of reactive tachycardia. Calcium antagonists may also retard the progression of atherosclerosis to prevent cardiovascular events.

    Topics: Atherosclerosis; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Calcium Channels, T-Type; Dihydropyridines; Heart; Heart Failure; Humans; Hypertrophy, Left Ventricular; Muscle, Smooth, Vascular; Myocardial Ischemia

2010
Cardiac Ca2+ signaling and Ca2+ sensitizers.
    Circulation journal : official journal of the Japanese Circulation Society, 2008, Volume: 72, Issue:12

    The role of Ca2+ in cardiac excitation-contraction (E-C) coupling has been established by simultaneous measurements of contractility and Ca2+ transients by means of aequorin in intact myocardium and Ca2+ sensitive fluorescent dyes in single myocytes. The E-C coupling process can be classified into 3 processes: upstream (Ca2+ mobilization), central (Ca2+ binding to troponin C) and downstream mechanism (thin filament regulation and crossbridge cycling). These mechanisms are regulated differentially by various inotropic interventions. Positive force-frequency relationship and effects of beta-adrenoceptor stimulation, phosphodiesterase 3 inhibitors and digitalis are essentially exerted via upstream mechanism. Alpha-adrenoceptor stimulation, endothelin-1, angiotensin II, and clinically available Ca2+ sensitizers, such as levosimendan and pimobendan, act by a combination of the upstream and central/downstream mechanism. The Frank-Starling mechanism and effects of Ca2+ sensitizers such as EMD 57033 and Org 30029 are primarily induced via the central/downstream mechanism. Whereas the upstream and central mechanisms are markedly suppressed in failing myocytes and under acidotic conditions, Ca2+ sensitizers such as EMD 57033 and Org 30029 can induce cardiotonic effects under such conditions. Ca2+ sensitizers have high therapeutic potential for the treatment of contractile dysfunction in congestive heart failure and ischemic heart diseases, because they have energetic advantages and less risk of Ca2+ overload and can maintain effectiveness under pathological conditions.

    Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Angiotensin II; Animals; Azocines; Calcium; Calcium Signaling; Cardiotonic Agents; Cholinergic Agonists; Dihydropyridines; Endothelins; Heart Failure; Humans; Hydrazones; Myocardial Contraction; Myocardium; Phosphodiesterase Inhibitors; Pyridazines; Quinolines; Simendan; Thiadiazines; Troponin C

2008
Meta-analysis of efficacy and safety of second-generation dihydropyridine calcium channel blockers in heart failure.
    The American journal of cardiology, 2001, Feb-15, Volume: 87, Issue:4

    Second-generation dihydropyridine calcium channel blockers slightly increase cardiac index, left ventricular ejection fraction, and exercise treadmill tests in patients with chronic heart failure, and do not increase norepinephrine levels; these drugs seem to be safe and beneficial in this category of patients. A 6% reduction in mortality was found, which, although not significantly different from 0%, does indicate that these drugs do not increase mortality in this category of patients.

    Topics: Calcium Channel Blockers; Data Interpretation, Statistical; Dihydropyridines; Heart Failure; Humans

2001
Pharmacology of SCH00013: a novel Ca2+ sensitizer.
    Cardiovascular drug reviews, 2001,Winter, Volume: 19, Issue:4

    Cardiotonic agents that facilitate cardiac pump function by direct improvement of contractile dysfunction are indispensable for the treatment of hemodynamic disorders in acute myocardial failure and the aggravating phase of congestive heart failure. Cardiotonic agents currently available for the treatment of hemodynamic crisis in congestive heart failure are catecholamines, selective phosphodiesterase (PDE) III inhibitors and digitalis, all of which are Ca2+ mobilizers. Considering the number of serious adverse effects of these clinically available cardiotonic agents, development of agents that act via a novel mechanism of action may contribute to the progress of pharmacotherapy of congestive heart failure. Ca2+ sensitizers that act by increasing in myofilament Ca2+ sensitivity may be able to overcome the disadvantage of Ca2+ mobilizers. Ca2+ sensitizers do not increase activation energy, do not produce Ca2+ overload and may be effective even under pathophysiological states such as acidosis, myocardial stunning and heart failure. SCH00013 ((4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6-tetrahydropyrido-4-yl]pyridazin-3(2H)-one)) is a novel Ca2+ sensitizer that elicits a moderate positive inotropic effect without significant alteration of Ca2+ transients. SCH00013 does not have a positive chronotropic effect and has a weak PDE III inhibitory action and class III antiarrhythmic action. SCH00013 prolonged the survival in a animal heart failure model with genetic cardiomyopathy. The oral bioavailability of SCH00013 is high and equivalent to that via intravenous administration. The unique pharmacological profiles of SCH00013 imply that this agent may be potentially beneficial for pharmacotherapy of contractile dysfunction in congestive heart failure.

    Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Anti-Arrhythmia Agents; Blood Pressure; Calcium; Cardiotonic Agents; Cyclic Nucleotide Phosphodiesterases, Type 3; Delayed Rectifier Potassium Channels; Dihydropyridines; Heart Failure; Heart Rate; Muscle, Smooth, Vascular; Myocardial Contraction; Phosphodiesterase Inhibitors; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridazines; Sodium-Potassium-Exchanging ATPase; Stereoisomerism; Stimulation, Chemical; Ventricular Function, Left

2001
Efficacy and safety of calcium channel blockers in heart failure: focus on recent trials with second-generation dihydropyridines.
    American heart journal, 2000, Volume: 139, Issue:2 Pt 1

    Chronic heart failure (CHF) has high morbidity and mortality rates despite treatment with angiotensin-converting enzyme inhibitors, diuretics, and digoxin. Adjunctive vasodilation through calcium channel blockade has been suggested as potentially useful. However, the first-generation calcium channel blockers, including the dihydropyridine nifedipine, showed disappointing results in CHF. The second-generation dihydropyridines were expected to be of more value, and of all the calcium channel blockers, these drugs were the ones most studied in patients with CHF.. The Medline databank was used to search studies in human beings (published in 1990 or later) that used dihydropyridines in patients with CHF. The references of the studies found were subsequently checked for additional data. In 17 studies and more than 2000 patients with CHF, no consistent beneficial effect was observed with regard to exercise tolerance and functional capacity, whereas plasma neurohormones were not affected. On the other hand, in general, no worsening of CHF was seen with these second-generation dihydropyridines. Two larger studies (PRAISE and V-HeFT III) have given some estimates on the long-term effects of dihydropyridines, and no overall influence on mortality rate was found. Of note, subanalysis of the PRAISE study has suggested that in patients with a nonischemic cause of CHF, amlodipine might have a beneficial effect on survival.. In this review we have focused on the efficacy and safety of dihydropyridines in patients with CHF, as reported in recent trials. The data do not support the use of dihydropyridines when primarily given as treatment for CHF. The results, however, suggest that these drugs can be safely given to patients with left ventricular dysfunction or CHF who need additional treatment for angina pectoris or hypertension.

    Topics: Amlodipine; Calcium Channel Blockers; Dihydropyridines; Exercise Test; Exercise Tolerance; Felodipine; Heart Failure; Hemodynamics; Humans; Ventricular Function, Left

2000
[Ca2+ sensitizers].
    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme, 2000, Volume: 45, Issue:6 Suppl

    Topics: Animals; Calcium; Cardiotonic Agents; Cyclic AMP; Dihydropyridines; Drug Design; Heart Failure; Humans; Hydrazones; Myocardium; Pyridazines; Signal Transduction; Simendan

2000
Major differences among the three classes of calcium antagonists.
    European heart journal, 1997, Volume: 18 Suppl A

    The safety of calcium antagonists has recently become a controversial issue among cardiologists. Thus, the role of calcium antagonists in the treatment of myocardial infarction and in secondary cardiovascular prevention is under review. As a consequence, the concept that the words 'calcium antagonists' comprise various drug classes has re-emerged. These differ in basic pharmacological properties, tissue selectivity, pharmacokinetics, and final haemodynamic effect. Obviously, such differences alter their therapeutic effect. In this article, the major differences among the three classes of calcium antagonists, phenylalkylamines, dihydropyridines and benzothiazepines, are discussed and reviewed. A comparative analysis of available clinical trials focusing on the usefulness of each drug class is provided for the reader's interest. Some particularly relevant pathological conditions are considered: chronic stable angina pectoris, vasospastic angina, unstable angina pectoris with threatened myocardial infarction, myocardial infarction, and congestive heart failure.

    Topics: Aniline Compounds; Benzothiepins; Calcium Channel Blockers; Dihydropyridines; Heart Failure; Humans; Myocardial Ischemia

1997
[Calcium channel blockers in heart failure].
    Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke, 1997, Jun-20, Volume: 117, Issue:16

    Patients with heart failure are particularly susceptible to the negative effects of calcium channel blockers because the failing heart demonstrates a defect in the delivery of calcium to the contractile proteins, and an attenuation of the normal sympathetic reflexes. Currently these drugs have no place in the treatment of heart failure caused by systolic dysfunction of the left ventricle. Calcium channel blockers should probably not be described for patients with coronary artery disease and left ventricular dysfunction. When the patient needs additional treatment for angina and beta-blockers or nitrates have not given satisfactory results, it may be appropriate to prescribe amlodipine or felodipine.

    Topics: Calcium Channel Blockers; Dihydropyridines; Diltiazem; Heart Failure; Humans; Ventricular Dysfunction, Left; Verapamil

1997
[Calcium antagonists and treatment of chronic heart failure].
    Archives des maladies du coeur et des vaisseaux, 1995, Volume: 88, Issue:4 Suppl

    The history of the treatment of heart failure may be divided into three stages, the consequences of different conceptions of the physiopathology of the disease, with diuretics to counteract salt and water retention, vasodilators to improve conditions of cardiac load, angiotensin converting enzyme inhibitors to limit the effect of neurotumoral and sympathetic activation. There are two main reasons for using calcium antagonist in heart failure, the first being arterial vasodilatation leading to improve systolic function and the second being the beneficial effect on ventricular relaxation. However, their use has been controversial because of the results obtained with the first generation of these drugs. New molecules derived from dihydropyridine have been developed. Clinical trials with these second generation calcium antagonists are analysed.

    Topics: Animals; Atrial Fibrillation; Calcium Channel Blockers; Dihydropyridines; Felodipine; Heart Failure; Hemodynamics; Humans; Systole; Ventricular Function, Left

1995
Inhibitors of cyclic nucleotide phosphodiesterases as therapeutic agents.
    Biochemical Society transactions, 1992, Volume: 20, Issue:2

    Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; Benzimidazoles; Dihydropyridines; Enoximone; Heart Failure; Hemodynamics; Humans; Imidazoles; Isoenzymes; Milrinone; Oxindoles; Phosphodiesterase Inhibitors; Pyridazines; Pyridones; Vasodilator Agents

1992
Calcium antagonists and heart failure.
    The Medical clinics of North America, 1989, Volume: 73, Issue:2

    The systemic vasodilatory actions of the calcium antagonists make them potentially attractive for use as afterload reducing agents in patients with left ventricular failure. However, unlike other vasodilator drugs, these drugs also exert a direct negative inotropic effect on the myocardium. Clinical data suggest a limited role for the calcium antagonists as vasodilator therapy in patients with heart failure.

    Topics: Calcium Channel Blockers; Dihydropyridines; Heart Failure; Heart Rate; Humans; Myocardial Contraction

1989

Trials

4 trial(s) available for dihydropyridines and Heart-Failure

ArticleYear
Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial.
    Journal of hypertension, 2004, Volume: 22, Issue:4

    To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension, we extended the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial by an open-label follow-up study lasting 4 years.. The Syst-Eur trial included 4695 randomized patients with minimum age of 60 years and an untreated blood pressure of 160-219 mmHg systolic and below 95 mmHg diastolic. The double-blind trial ended after a median follow-up of 2.0 years (range 1-97 months). Of 4409 patients still alive, 3517 received open-label treatment consisting of nitrendipine (10-40 mg daily) with the possible addition of enalapril (5-20 mg daily), hydrochlorothiazide (12.5-25 mg daily), or both add-on drugs. Non-participants (n = 892) were also followed up.. Median follow-up increased to 6.1 years. Systolic pressure decreased to below 150 mmHg (target level) in 2628 participants (75.0%). During the 4-year open-label follow-up, stroke and cardiovascular complications occurred at similar frequencies in patients formerly randomized to placebo and those continuing active treatment. These rates were similar to those previously observed in the active-treatment group during the double-blind trial. Considering the total follow-up of 4695 randomized patients, immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28% (P = 0.01) and 15% (P = 0.03), respectively, with a similar tendency for total mortality (13%, P = 0.09). In 492 diabetic patients, the corresponding estimates of long-term benefit (P < 0.02) were 60, 51 and 38%, respectively.. Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension. Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years. These findings underscore the necessity of early treatment of isolated systolic hypertension.

    Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus; Dihydropyridines; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Enalapril; Europe; Female; Follow-Up Studies; Heart Failure; Humans; Hydrochlorothiazide; Hypertension; Incidence; Linear Models; Male; Myocardial Infarction; Nitrendipine; Stroke; Survival Rate; Time Factors; Treatment Outcome

2004
Dose-related hemodynamic and electrocardiographic effects of the calcium promoter BAY y 5959 in the presence or absence of congestive heart failure.
    Journal of the American College of Cardiology, 1997, Volume: 30, Issue:7

    The aim of this study was to assess the cardiovascular effects of BAY y 5959, a calcium promoter modulating myocardial calcium channels, in the presence or absence of congestive heart failure.. There is still a clinical need for short-term administration of intravenous positive inotropes. BAY y 5959 was developed as a new approach to increase myocardial performance by selectively enhancing calcium influx in the myocytes.. Forty-one patients (21 without and 20 with congestive heart failure) were studied in an open label, dose-ranging study. Hemodynamic variables (including left ventricular [LV] angiography) and plasma samples were obtained at baseline and after 20 min of intravenous infusion of BAY y 5959 at doses ranging from 0.25 to 4.5 microg/kg body weight per min.. In both study groups, BAY y 5959 produced dose-dependent increases in the indexes of inotropic state, without affecting isovolumetric relaxation rate. The magnitude of the response was comparable in patients with or without heart failure (average 38% increase in maximal first derivative of LV pressure [dP/dt max] at plasma levels of 100 microg/liter). BAY y 5959 also induced mild but statistically significant bradycardia and significantly decreased end-systolic volume while producing a leftward shift of the pressure-volume loop. Mean aortic pressure was unaffected at doses up to 3.0 microg/kg per min, and cardiac index improved in patients with heart failure at doses of 2.0 microg/kg per min (+23%, p < 0.05). However, at a dose of 4.5 microg/kg per min, mean aortic pressure and LV systolic wall stress increased, suggesting systemic vasoconstriction. The QT interval was also prolonged significantly at most doses.. BAY y 5959 exhibits positive inotropic effects in patients with and without heart failure. The optimal response--combining bradycardia, reduced preload and improved cardiac output--appeared to be achieved at a dose of approximately 2.0 microg/kg per min. The impact of QT prolongation with regard to potential antiarrhythmic or proarrhythmic effects is unclear at this time.

    Topics: Calcium Channel Agonists; Cardiotonic Agents; Case-Control Studies; Dihydropyridines; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Stimulation, Chemical; Ventricular Dysfunction, Left

1997
Effects of lacidipine on peak oxygen consumption, neurohormones and invasive haemodynamics in patients with mild to moderate chronic heart failure.
    Heart (British Cardiac Society), 1996, Volume: 75, Issue:2

    To evaluate the efficacy and safety of the second generation dihydropyridine calcium channel blocker lacidipine in patients with heart failure.. Placebo controlled, parallel group, double blind study over 8 weeks.. General community hospital in Breda, The Netherlands.. A random sample was studied of 25 outpatients with symptoms of mild to moderate heart failure, despite treatment with diuretics, digoxin, and angiotensin converting enzyme inhibitors. Their mean age was 65 years, with mean left ventricular ejection fraction of 0.24 and a peak oxygen consumption of 14.4 ml/min/kg. Two patients dropped out on lacidipine, one patient on placebo.. Treatment with lacidipine 4 mg once daily or placebo for eight weeks.. Cardiopulmonary exercise testing, invasive haemodynamics, and plasma neurohormones.. Treatment with lacidipine 4 mg once daily, as compared to placebo treatment, significantly improved peak oxygen consumption (P < 0.02), cardiac index (P < 0.01), and stroke volume (P < 0.03) paralleled by a decrease in systemic vascular resistance (P < 0.03) and arteriovenous oxygen content difference (P < 0.01). Plasma noradrenaline, plasma renin activity, and aldosterone values did not differ between lacidipine and placebo.. This second generation dihydropyridine may be of value as an adjunct to standard treatment in congestive heart failure patients.

    Topics: Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Digoxin; Dihydropyridines; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Oxygen Consumption; Prospective Studies; Renin; Stroke Volume; Vascular Resistance

1996
The potential role of calcium antagonists in the management of congestive heart failure: initial experience with lacidipine.
    Journal of cardiovascular pharmacology, 1995, Volume: 25 Suppl 3

    First-generation calcium antagonists have been used in patients with congestive heart failure with rather disappointing results. Therefore, second-generation dihydropyridine calcium-channel blockers, such as felodipine and lacidipine, have been developed that may be beneficial in congestive heart failure owing to their high vasoselectivity and more favorable neurohumoral modulation. The effects of lacidipine in patients with congestive heart failure, who remain symptomatic despite receiving long-term therapy with angiotensin-converting enzyme inhibitors, digoxin, and diuretics, were investigated during a prospective, double-blind, randomized, placebo-controlled, parallel-group study. Twenty-five patients were randomized to receive either lacidipine (4 mg once daily; 12 patients) or placebo (once daily; 13 patients). After 8 weeks of treatment patients receiving lacidipine showed a significantly higher increase in cardiac output (p < 0.01), and a significantly greater reduction in vascular resistance (p < 0.02) than those patients in the placebo group. No significant changes were observed in filling pressures and heart rate. The arteriovenous oxygen content difference was significantly reduced in the lacidipine group (p < 0.01) without significant changes in arterial oxygenation, suggesting an increase in flow that was not a result of pulmonary shunting. Further peak oxygen consumption during cardiopulmonary exercise testing increased significantly in the lacidipine patients (p < 0.02). These beneficial effects were achieved without significant changes in neurohumoral parameters. Analysis of right and left ventricular ejection fractions revealed no cardiodepressant effects. Lacidipine was well tolerated during the course of the study, and adverse reactions were minor. These data suggest that lacidipine has a promising profile for the treatment of congestive heart failure patients, and that further investigation with second-generation dihydropyridines in the field of congestive heart failure appears warranted.

    Topics: Aged; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Epinephrine; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Prospective Studies; Renin

1995

Other Studies

32 other study(ies) available for dihydropyridines and Heart-Failure

ArticleYear
Clinical predictors of hyponatremia in patients with heart failure according to severity of chronic kidney disease.
    Wiener klinische Wochenschrift, 2022, Volume: 134, Issue:17-18

    Chronic kidney disease (CKD) has been associated with adverse clinical outcomes. Hyponatremia, a marker of illness severity and poor prognosis, is commonly exhibited in patients with CKD.. This cross-sectional study included patients hospitalized due to heart failure (HF). We used stepwise logistic regression to investigate the independent association of cardiovascular drugs, markers of HF severity, and baseline clinical characteristics with hyponatremia in three subgroups; normal renal function, mild-to-moderate CKD, and severe CKD.. Of the 1232 patients, 38.6% were hyponatremic. Patients with severe CKD, compared to those with normal renal function and mild-to-moderate CKD, were more likely to be hyponatremic (47.1%, 34.4% and 36.6%, respectively; p ≤ 0.0001). Alcohol consumption, female sex, n-terminal pro-brain natriuretic peptide (NT-proBNP), hydrochlorothiazide (HCT), and mineralocorticoid receptor antagonist (MRA) use, or angiotensin II receptor I blocker (ARB) non-use were associated with hyponatremia in patients with normal renal function (p ≤ 0.03 in all cases). Current smoking, diabetes mellitus, NT-proBNP, loop diuretic dose, and MRA use were predictors in mild-to-moderate CKD (p ≤ 0.04 in all cases). ARB use, loop diuretic dose, and HCT use were predictors in severe CKD (p ≤ 0.03 in all cases). Non-use of dihydropyridine calcium channel blocker (CCB) was an independent predictor of hyponatremia in all CKD stages (p ≤ 0.04 in all cases).. Apart from a firm favorable effect of CCBs, cardiovascular therapy should be carefully tailored to avoid hyponatremia in patients with cardiorenal syndrome.

    Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Calcium Channel Blockers; Cross-Sectional Studies; Dihydropyridines; Female; Heart Failure; Humans; Hydrochlorothiazide; Hyponatremia; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Peptide Fragments; Receptors, Angiotensin; Renal Insufficiency, Chronic; Sodium Potassium Chloride Symporter Inhibitors

2022
[Treatment of patients with arterial hypertension in clinical practice in 2010-2020 (according to the national register of hypertension)].
    Terapevticheskii arkhiv, 2022, Jan-15, Volume: 94, Issue:1

    To analyze therapy in patients with arterial hypertension (AH) in 20102020.. Data of hypertensive patients observed in primary health care, entered into the base of hypertension registry for 20102020 years in the whole group (n=44 653) and in a separate subgroup of hypertensive patients in the absence of: ischemic heart disease, a history of myocardial infarction, chronic heart failure (n=20 569).. About 80% of hypertensive patients are patients of high and very high risks (from 2010 to 2020, the proportion of very high cardiovascular risk (CVR) increased from 18.1 to 57.3%). The number of hypertensive patients with a history of myocardial infarction increased in 5 times, in 3 times with ischemic heart disease and with chronic heart failure. The number of prescribed drugs increased: mineralocorticoid receptor antagonist (in 5.8 times), loop diuretics (in 7.2) angiotensin receptor blockers (in 3 times), b-adrenoblockers, calcium channel blockers of the dihydropyridine series, thiazide-like diuretics in 2 times. Patients at high and very high risk are more likely reached target blood pressure values. Angiotensin-converting enzyme inhibitors were prescribed in more than 70% of patients with hypertension and the absence of coronary heart disease, chronic heart failure, history of myocardial infarction; the prescription of b-adrenoblockers, angiotension receptor blockers, thiazide-like and loop diuretics increased.. The proportion of more severe and comorbid patients has increased in observed in primary health care patients with AH over a 10-year period (20102020). This was probably the main factor of increasing antihypertensive therapy and prescribing drugs with additional indications and improving the achievement of target blood pressure in patients with high and very high cardiovascular risk.. Цель. Анализ лечения больных артериальной гипертонией (АГ) в 20102020 гг. Материалы и методы. Проведен анализ медицинских данных 44 653 больных АГ, наблюдавшихся в первичном звене здравоохранения, аккумулированных в регистре АГ за период 20102020 гг. и в подгруппе, включившей 20 569 больных АГ без диагностированных сердечно-сосудистых заболеваний (ССЗ) ишемической болезни сердца, инфаркта миокарда в анамнезе, хронической сердечной недостаточности. Результаты. За 10-летний период среди больных АГ, наблюдаемых в условиях первичного звена здравоохранения, 80% больных были высокого и очень высокого сердечно-сосудистого риска (ССР); с 2010 по 2020 г. регистрируется увеличение доли больных очень высокого ССР с 18,1 до 57,3%. В 5 раз увеличилось число больных АГ, перенесших инфаркт миокарда; в 3 раза ишемическую болезнь сердца и хроническую сердечную недостаточность. Отмечено увеличение назначаемых препаратов: антагонистов минералокортикоидных рецепторов в 5,8 раза, петлевого диуретика в 7,2, блокаторов рецепторов ангиотензина в 3 раза, -адреноблокаторов, дигидропиридиновых блокаторов кальциевых каналов и тиазидоподобных диуретиков в 2 раза. У больных высокого и очень высокого риска чаще достигался целевой уровень артериального давления. У больных АГ без ССЗ (ишемическая болезнь сердца, хроническая сердечная недостаточность, перенесенный инфаркт миокарда) ингибиторы ангиотензинпревращающего фермента назначались более чем 70% больных; чаще стали назначаться -адреноблокаторы, блокаторы рецепторов ангиотензина, тиазидоподобный диуретик, петлевой диуретик. Заключение. В структуре больных АГ, наблюдаемых в первичном звене здравоохранения за 10-летний период, увеличилась доля более тяжелых больных АГ, у которых диагностированы ССЗ. Это, вероятно, явилось основным фактором усиления антигипертензивной терапии и назначения препаратов с учетом дополнительных показаний, что, по-видимому, улучшило достижение целевого артериального давления у больных высокого и очень высокого ССР.

    Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Coronary Disease; Dihydropyridines; Diuretics; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Sodium Potassium Chloride Symporter Inhibitors; Thiazides

2022
Effect of Switching from Cilnidipine to Azelnidipine on Cardiac Sympathetic Nerve Function in Patients with Heart Failure Preserved Ejection Fraction.
    International heart journal, 2018, Jan-27, Volume: 59, Issue:1

    Topics: Adult; Aged; Aged, 80 and over; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Drug Substitution; Echocardiography; Female; Follow-Up Studies; Heart; Heart Failure; Humans; Male; Middle Aged; Radionuclide Imaging; Retrospective Studies; Stroke Volume; Sympathetic Nervous System; Treatment Outcome

2018
Azelnidipine is a useful medication for the treatment of heart failure preserved ejection fraction.
    Clinical and experimental hypertension (New York, N.Y. : 1993), 2017, Volume: 39, Issue:4

    The optimal therapy in patients with heart failure preserved ejection fraction (HFpEF) and hypertension (HT) has not been revealed. The beta blocker (BB) and the renin angiotensin aldosterone system inhibitor (RAAS-I) are recommend as class IIa in patients with HFpEF. The calcium channel blocker (CCB), a major anti-hypertensive drugs in Japan, is also recommend as class IIa in patients with HFpEF. However, the difference between azelnidipine, an L type CCB, and cilnidipine, an N type CCB, is unclear. We investigated the difference between azelnidipine and cilnidipine in patients with HFpEF and HT.. Twenty-five consecutive HFpEF patients treated with BB and RAAS-I from April 2013 to March 2015 were enrolled. Initially, cilnidipine was used, and then switched to azelnidipine. Age, gender, blood pressure (BP), heart rate (HR), blood tests, echocardiography, and cardiac-scintigraphy (. There was no statistically significant difference in BP. B type natriuretic peptides were significantly reduced (pre-state: 195.4 ± 209.7 pg/ml and post-state: 140.7 ± 136.4 pg/ml, p = 0.050). In echocardiography, the TEI index tended to be decreased (pre-state: 0.47 ± 0.15 and post-state: 0.42 ± 0.08, p = 0.057). As for MIBG, there was no significant change in the heart/mediastinum ratio. However, the washout rate was significantly reduced (pre-state: 44.7 ± 12.2 and post-state: 40.7 ± 12.1, p = 0.011). In addition, there was no statistically significant change, although HR tended to decrease by switching to azelnidipine (pre-state: 62.7 ± 11.6 and post-state: 61.8 ± 16.5, p = 0.373).. In patients with HT and HFpEF, azelnidipine improved the severity of HF and cardiac sympathetic nerve activity compared with cilnidipine.

    Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Echocardiography; Female; Heart Failure; Heart Rate; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Radionuclide Imaging; Renin-Angiotensin System; Stroke Volume

2017
Comparative evaluation of calcium-sensitizing agents, pimobendan and SCH00013, on the myocardial function of canine pacing-induced model of heart failure.
    Journal of pharmacological sciences, 2014, Volume: 124, Issue:3

    Pimobendan and SCH00013 are calcium sensitizers that possess dual action of calcium sensitization and phosphodiesterase-III inhibition. This study was conducted to comparatively evaluate the effect of these medications on the myocardial function of the canine pacing-induced heart failure model using echocardiography. Heart failure was induced in 20 dogs, to which pimobendan and two different doses of SCH00013 were administered orally to 15 dogs for 3 weeks, and the remaining 5 dogs served as the control. Cardiac evaluations were performed at baseline, week 1, week 2, and week 3. Significant thinning and dilation of the left ventricles, with systolic dysfunction, indicated by reduction of fractional shortening (FS) and strain values, were observed with a low dose of SCH00013. Whereas, although systolic dysfunction was observed with reduction of FS and radial strain, significant dilation and thinning of the left ventricles and reduction of circumferential strain were not observed with pimobendan. Pimobendan had a potent positive inotropic effect, with little effect on synchronicity, while low-dose SCH00013 had a weaker positive inotropic effect but was able to sustain synchronicity. Although, it failed to show significant statistical differences, the results of this study allow speculations that administration of pimobendan and SCH00013 may have differing effect on the myocardial function in the canine pacinginduced heart failure model.

    Topics: Administration, Oral; Animals; Calcium; Cardiotonic Agents; Dihydropyridines; Dilatation, Pathologic; Disease Models, Animal; Dogs; Echocardiography; Female; Heart Failure; Heart Ventricles; Myocardial Contraction; Phosphodiesterase Inhibitors; Pyridazines; Stimulation, Chemical; Systole

2014
Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure.
    Cardiovascular research, 2014, Oct-01, Volume: 104, Issue:1

    Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca(2+) channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure.. We compared the effects of cilnidipine, a dual N- and L-type Ca(2+) channel blocker, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B(+/-) mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B(+/+) mice.. Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

    Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Autonomic Nervous System; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cardiomyopathy, Dilated; Death, Sudden, Cardiac; Dihydropyridines; Disease Models, Animal; Heart; Heart Failure; Mice, Knockout; Mice, Transgenic; Nitrendipine; Repressor Proteins; Time Factors; Ventricular Function, Left

2014
N-type calcium channel blockade: a new approach to preventing sudden cardiac death?
    Cardiovascular research, 2014, Oct-01, Volume: 104, Issue:1

    Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Autonomic Nervous System; Calcium Channel Blockers; Calcium Channels, N-Type; Death, Sudden, Cardiac; Dihydropyridines; Heart; Heart Failure

2014
Basal and β-adrenergic regulation of the cardiac calcium channel CaV1.2 requires phosphorylation of serine 1700.
    Proceedings of the National Academy of Sciences of the United States of America, 2014, Nov-18, Volume: 111, Issue:46

    L-type calcium (Ca(2+)) currents conducted by voltage-gated Ca(2+) channel CaV1.2 initiate excitation-contraction coupling in cardiomyocytes. Upon activation of β-adrenergic receptors, phosphorylation of CaV1.2 channels by cAMP-dependent protein kinase (PKA) increases channel activity, thereby allowing more Ca(2+) entry into the cell, which leads to more forceful contraction. In vitro reconstitution studies and in vivo proteomics analysis have revealed that Ser-1700 is a key site of phosphorylation mediating this effect, but the functional role of this amino acid residue in regulation in vivo has remained uncertain. Here we have studied the regulation of calcium current and cell contraction of cardiomyocytes in vitro and cardiac function and homeostasis in vivo in a mouse line expressing the mutation Ser-1700-Ala in the CaV1.2 channel. We found that preventing phosphorylation at this site decreased the basal L-type CaV1.2 current in both neonatal and adult cardiomyocytes. In addition, the incremental increase elicited by isoproterenol was abolished in neonatal cardiomyocytes and was substantially reduced in young adult myocytes. In contrast, cellular contractility was only moderately reduced compared with wild type, suggesting a greater reserve of contractile function and/or recruitment of compensatory mechanisms. Mutant mice develop cardiac hypertrophy by the age of 3-4 mo, and maximal stress-induced exercise tolerance is reduced, indicating impaired physiological regulation in the fight-or-flight response. Our results demonstrate that phosphorylation at Ser-1700 alone is essential to maintain basal Ca(2+) current and regulation by β-adrenergic activation. As a consequence, blocking PKA phosphorylation at this site impairs cardiovascular physiology in vivo, leading to reduced exercise capacity in the fight-or-flight response and development of cardiac hypertrophy.

    Topics: Adaptation, Physiological; Adrenergic beta-Agonists; Amino Acid Substitution; Animals; Arrhythmias, Cardiac; Barium; Calcium; Calcium Channels, L-Type; Cardiomyopathy, Hypertrophic; Casein Kinase II; Dihydropyridines; Exercise Tolerance; Heart Failure; Ion Transport; Isoproterenol; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Models, Molecular; Mutation, Missense; Myocardial Contraction; Myocytes, Cardiac; Phosphorylation; Phosphoserine; Point Mutation; Protein Conformation; Protein Processing, Post-Translational; Receptors, Adrenergic, beta; Signal Transduction; Transfection

2014
[Combined heart protection for the hypertensive patient].
    MMW Fortschritte der Medizin, 2013, Jan-21, Volume: 155, Issue:1

    Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Fibrillation; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Combinations; Enalapril; Heart Failure; Humans; Hypertension; Hypertrophy, Left Ventricular; Myocardial Ischemia

2013
Ca(2+) channel blocker benidipine promotes coronary angiogenesis and reduces both left-ventricular diastolic stiffness and mortality in hypertensive rats.
    Journal of hypertension, 2010, Volume: 28, Issue:7

    The beneficial cardiac effects of some Ca(2+) channel blockers have been attributed to blood pressure reduction, but these pleiotropic effects require further investigation. We compared the effects of benidipine, which has beneficial cardiac effects, and nitrendipine, which does not, in an animal model of hypertensive diastolic heart failure (DHF).. Male Dahl salt-sensitive rats were fed a high-salt diet from age 7 weeks to induce hypertension and were either vehicle or orally administered benidipine (3 mg/kg daily) or nitrendipine (10 mg/kg daily) from age 10 to 18 weeks. Control rats were maintained on a low-salt diet. In vehicle-treated rats, left-ventricular (LV) fractional shortening was preserved but LV end-diastolic pressure was increased, indicative of DHF. Benidipine and nitrendipine had similar antihypertensive effects and reduced both LV weight and cardiomyocyte hypertrophy. Benidipine reduced LV diastolic stiffness and mortality to a greater extent than did nitrendipine. Benidipine, but not nitrendipine, also reduced lung weight. The extent of interstitial fibrosis and the abundance of mRNAs for prohypertrophic, profibrotic, or proinflammatory genes in the left ventricle were reduced by benidipine and nitrendipine. Benidipine, but not nitrendipine, increased capillary density and restored the expression of hypoxia-inducible factor 1alpha, vascular endothelial growth factor, and endothelial nitric oxide synthase in the left ventricle.. Benidipine reduced LV diastolic stiffness and increased survival, effects likely attributable predominantly to promotion of coronary angiogenesis rather than to attenuation of interstitial fibrosis. Benidipine may thus be more effective than purely L-type Ca(2+) channel blockers in preventing hypertensive DHF.

    Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Coronary Circulation; Diastole; Dihydropyridines; Heart Failure; Heart Ventricles; Hypertension; Male; Neovascularization, Physiologic; Nitrendipine; Rats; Rats, Inbred Dahl

2010
Mechanism of diastolic stiffening of the failing myocardium and its prevention by angiotensin receptor and calcium channel blockers.
    Journal of cardiovascular pharmacology, 2009, Volume: 54, Issue:1

    To investigate the mechanism responsible for the increased cardiac stiffness associated with hypertensive heart failure in Dahl salt-sensitive (DS) rats and the effects of treatment with the combination of a calcium channel blocker [azelnidipine (AZE)] and angiotensin II type 1 receptor blocker [olmesartan (OLM)].. DS rats fed a high-salt diet from 7 weeks of age were treated (or not) from 12 to 19 weeks of age with the vasodilator hydralazine, OLM plus AZE, or the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. Rats fed a low-salt diet served as controls.. Treatment with OLM plus AZE attenuated changes in the expression of collagen isoforms and a decrease in the ratio of elastin to collagen in the left ventricle and prevented the increase in myocardial stiffness and diastolic dysfunction in DS rats in a manner independent of the hypotensive effect of these drugs. Such treatment also inhibited the expression and activation of elastolytic proteases (including cathepsins S and K and metalloproteinases-2, -9, and -12), NADPH oxidase-dependent superoxide production, and inflammatory changes in the failing myocardium. All these effects were mimicked by treatment with apocynin.. The changes in collagen isoform expression and the decrease in the elastin to collagen ratio in the failing myocardium likely account for the increase in diastolic stiffness in this model of hypertensive heart failure. Administration of angiotensin receptor and calcium channel blockers prevented these changes in a manner independent of the hypotensive effect of these drugs by inhibiting the increase in elastolytic activity induced by activation of NADPH oxidase.

    Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diastole; Dihydropyridines; Heart Failure; Imidazoles; Male; Myocardium; Rats; Rats, Inbred Dahl; Receptor, Angiotensin, Type 1; Tetrazoles

2009
Cardioprotective effect of benidipine on cardiac performance and remodeling in failing rat hearts.
    American journal of hypertension, 2008, Volume: 21, Issue:2

    We have known that endothelial nitric-oxide synthase (eNOS) and oxidative stress may play a key role in cardiac performance in failing rat hearts. However, the interactions between eNOS or oxidative stress and bradykinin (BK) under treatment of calcium channel blockers (CCBs) remain unknown. To elucidate the mechanism underlying the cardioprotective effect of long-acting dihydropyridine CCBs, we evaluated the effect of benidipine on the BK-eNOS and NAD(P)H oxidase pathway in Dahl salt-sensitive (DS) rats with heart failure.. 11-week-old DS rats were treated with one of the following drug combinations for 7 weeks until the onset of the failing stage: vehicle, BK B2 receptor antagonist (FR172357 (FR)) alone, hydralazine, benidipine, and benidipine plus FR. The left ventricular end-systolic pressure-volume relationship (ESPVR) (contractility: Ees) was evaluated using a conductance catheter.. Downregulated Ees and per cent of fractional shortening (%FS) assessed by echocardiography and eNOS expression in the failing stage were both significantly increased by using benidipine; this result was not found, however, when using FR alone or hydralazine or benidipine plus FR. Upregulated expression of NAD(P)H oxidase p22phox and p47phox and lectin-like oxidized low-density lipoprotein receptor-1, and downregulated superoxide dismutase-1 (SOD-1) were significantly ameliorated by benidipine, but not by FR alone or by hydralazine or benidipine plus FR. Benidipine effectively inhibited vascular lesion formation and suppressed atrial natriuretic peptide (ANP) and transforming growth factor-beta1 (TGF-beta1), but this was not the case when using FR alone or hydralazine or benidipine plus FR.. These results suggest that benidipine may be useful for cardioprotective agents in preventing the cardiac dysfunction and remodeling associated with the BK-eNOS and oxidative stress pathway.

    Topics: Animals; Atrial Natriuretic Factor; Cardiotonic Agents; Collagen Type I; Dihydropyridines; Gene Expression; Heart Failure; Hypertension, Renal; Intercellular Adhesion Molecule-1; Myosin Heavy Chains; NADPH Oxidases; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Rats, Inbred Dahl; Scavenger Receptors, Class E; Superoxide Dismutase; Superoxide Dismutase-1; Transcription Factor RelA; Transforming Growth Factor beta1; Vascular Cell Adhesion Molecule-1; Vasodilator Agents; Ventricular Function; Ventricular Remodeling

2008
Comparative effects of pranidipine with amlodipine in rats with heart failure.
    Pharmacology, 2006, Volume: 77, Issue:1

    The aim of the present study was to compare the cardioprotective properties of long-acting calcium channel antagonist pranidipine with amlodipine in rat model of heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were randomized for the oral administration of low-dose amlodipine (1 mg/kg/day), high-dose amlodipine (5 mg/kg/day), pranidipine (0.3 mg/kg/day) or vehicle (0.5% methylcellulose). After oral administration for 1 month, the animals underwent echocardiography and hemodynamic analysis. Histopathology, immunohistochemistry, and Western immunoblotting were carried out in the heart samples. Both pranidipine and high-dose amlodipine increased survival rate. Although the heart rate did not differ among the four groups, left ventricular end-diastolic pressure was significantly decreased and +/-dP/dt was increased in the pranidipine- and high-dose amlodipine-treated rats, but not in low-dose amlodipine-treated rats. In comparison to amlodipine treatment, pranidipine treatment significantly reduced myocyte size and central venous pressure. Furthermore, both pranidipine and high-dose amlodipine treatment significantly reduced myocardial protein levels of atrial natriuretic peptide and inducible nitric oxide synthase, whereas pranidipine only significantly decreased tumor necrosis factor-alpha, and improved sarcoplasmic reticulum Ca2+ ATPase2 protein levels. We conclude that pranidipine ameliorates the progression of left ventricular dysfunction and cardiac remodeling in rats with heart failure after autoimmune myocarditis in a lower dose when compared to amlodipine and which may be a clinically potential therapeutic agent for the treatment of heart failure.

    Topics: Administration, Oral; Amlodipine; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Calcium-Transporting ATPases; Cardiac Myosins; Dihydropyridines; Dose-Response Relationship, Drug; Echocardiography; Fibrosis; Heart Failure; Heart Rate; Male; Myocarditis; Myocardium; Nitric Oxide Synthase Type II; Rats; Rats, Inbred Lew; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Survival Rate; Time Factors; Ventricular Function, Left

2006
SCH00013, a novel Ca(2+) sensitizer with positive inotropic and no chronotropic action in heart failure.
    Journal of pharmacological sciences, 2005, Volume: 97, Issue:1

    We investigated the effects of the agent SCH00013 on Ca(2+)-induced force generation in rabbit skinned cardiac muscle fibers and in vivo cardiac function in high-pacing-induced heart failure dogs. The Ca(2+)-induced force generation in skinned cardiac muscle fibers was determined at pH 6.2 - 7.4, and SCH00013 was found to have a significant Ca(2+) sensitizing effect at pH 7.2 to 7.4. There was no significant difference in the Ca(2+) sensitizing action between the enantiomers of SCH00013. The Ca(2+) sensitizing effect of SCH00013 was dependent on the sarcomere length, being significant only at a long sarcomere length. SCH00013 elicited a positive inotropic effect at more than 0.3 and 1 mg/kg, i.v. in normal and heart failure dogs, respectively, with no chronotropic action. These results strongly suggested that SCH00013 is a novel Ca(2+) sensitizer that elicits a positive inotropic and no chronotropic effect in heart failure, probably through enhancing the Frank-Starling mechanism.

    Topics: Amrinone; Animals; Calcium; Cardiotonic Agents; Dihydropyridines; Disease Models, Animal; Dogs; Heart Failure; Heart Rate; Hydrogen-Ion Concentration; Injections, Intravenous; Male; Myocardial Contraction; Myocytes, Cardiac; Pyridazines; Rabbits; Sarcomeres; Stereoisomerism; Ventricular Function, Left

2005
Benidipine, a long-acting calcium channel blocker, inhibits cardiac remodeling in pressure-overloaded mice.
    Cardiovascular research, 2005, Mar-01, Volume: 65, Issue:4

    The effects of long-acting calcium channel blockers (CCBs) on pressure overload-induced cardiac remodeling are seldom studied in animals. We evaluated the effects of benidipine, a long-acting CCB, on cardiac remodeling.. Rat neonatal cardiac myocytes were used to examine the influence of benidipine on protein synthesis. Cardiac remodeling was induced in C57 B6/J mice by transverse aortic constriction (TAC). Then the effects of benidipine (10 mg/kg/d) were assessed on myocardial hypertrophy and heart failure, cardiac histology, and gene expression.. Benidipine significantly inhibited protein synthesis by cardiac myocytes stimulated with phenylephrine (PE), and this effect was partially abolished by cotreatment with a nitric oxide synthase (NOS) inhibitor [N(G)-nitro-l-arginine methylester (l-NAME)]. Four weeks after the onset of pressure overload, benidipine therapy potently inhibited cardiac hypertrophy and prevented heart failure. The heart to body weight ratio was 6.89+/-0.48 mg/g in treated mice vs. 8.76+/-0.33 mg/g in untreated mice (P<0.01), and the lung to body weight ratio was 7.39+/-0.93 mg/g vs. 10.53+/-0.99 mg/g, respectively (P<0.05). Left ventricular fractional shortening (LVFS) was improved on echocardiography. Plasma NO levels were increased, while B type natriuretic peptide, protein inhibitor of neuronal NOS, and procollagen IV alpha were down-regulated in benidipine-treated mice.. These results indicate that benidipine inhibits cardiac remodeling due to pressure overload at least partly by acting on the nitric oxide signaling pathway.

    Topics: Animals; Biomarkers; Calcium Channel Blockers; Cardiomegaly; Cells, Cultured; Collagen Type IV; Dihydropyridines; Disease Progression; Gene Expression Regulation; Heart Failure; Male; Mice; Mice, Inbred C57BL; Muscle Proteins; Myocytes, Cardiac; Natriuretic Peptide, Brain; Nitric Oxide; Signal Transduction; Ventricular Remodeling

2005
Synthesis and biological evaluation of 1,4-dihydropyridine calcium channel modulators having a diazen-1-ium-1,2-diolate nitric oxide donor moiety for the potential treatment of congestive heart failure.
    Bioorganic & medicinal chemistry, 2004, Jul-15, Volume: 12, Issue:14

    A group of racemic 4-aryl(heteroaryl)-1,4-dihydro-2,6-dimethyl-3-nitropyridines possessing nitric oxide donor O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino, or 4-ethylpiperazin-1-yl)diazen-1-ium-1,2-diolate, C-5 ester substituents were synthesized by coupling the respective 4-aryl(heteroaryl)-1,4-dihydro-2,6-dimethyl-3-nitropyridine-5-carboxylic acids with either O(2)-acetoxymethyl-1-[N-(2-methylsulfonyloxyethyl)-N-methylamino]diazen-1-ium-1,2-diolate, or O(2)-acetoxymethyl-1-[4-(2-methylsulfonyloxyethyl)piperazin-1-yl]diazen-1-ium-1,2-diolate. Compounds having a C-4 2-pyridyl, 4-pyridyl, 2-trifluoromethylphenyl, or benzofurazan-4-yl substituent exhibited more potent smooth muscle calcium channel antagonist activity (IC(50)'s in the 0.37-1.09 microM range) than related analogs having a C-4 3-pyridyl substituent (IC(50)'s=3.03-9.14 microM range) relative to the reference drug nifedipine (IC(50)=9.13 nM). The point of attachment of C-4 isomeric pyridyl substituents was a determinant of smooth muscle calcium channel antagonist activity where the relative potency profile was 4-pyridyl>2-pyridyl>3-pyridyl. Replacement of the C-5 methyl ester substituent of methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate (Bay K 8644) by an O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate, or O(2)-acetoxymethyl-1-(4-ethylpiperazin-1-yl)diazen-1-ium-1,2-diolate, C-5 ester substituent provided compounds, which exhibited a lower, yet respectable, cardiac positive inotropic effect (IC(50)'s=4.82 and 4.05 microM, respectively) relative to the reference drug Bay K 8644 (IC(50)=0.30 microM). All compounds released nitric oxide upon incubation with either phosphate buffer at pH7, or porcine liver esterase. However, the percentage nitric oxide released was up to 3-fold higher (76%) when these O(2)-acetoxymethyl-1-(alkylamino)diazen-1-ium-1,2-diolates were incubated with guinea pig serum. These results suggest that *NO would be released in vivo, upon cleavage by nonspecific serum esterases, preferentially in the vascular endothelium where it may enhance smooth muscle calcium channel antagonist activity.

    Topics: Animals; Azo Compounds; Dihydropyridines; Drug Evaluation, Preclinical; Guinea Pigs; Heart Failure; Humans; In Vitro Techniques; Magnetic Resonance Spectroscopy; Muscle, Smooth; Nitric Oxide Donors; Spectrophotometry, Infrared

2004
Effects of pranidipine, a novel calcium channel antagonist, on the progression of left ventricular dysfunction and remodeling in rats with heart failure.
    Pharmacology, 2004, Volume: 72, Issue:1

    The cardioprotective properties of pranidipine were studied in a rat model of heart failure after autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were divided into three groups and received oral treatment of 0.03 mg/kg/day (group 0.03) or 0.3 mg/kg/day (group 0.3) of pranidipine or vehicle (group V) for 1 month. High-dose pranidipine (group 0.3) improved the survival rate, and significantly reduced heart weight, heart weight to body weight ratio, myocardial fibrosis, central venous pressure and left ventricular end-diastolic pressure than low-dose pranidipine (group 0.03) and group V. Pranidipine at high dose also decreased the left ventricular systolic and diastolic dimensions, and increased fractional shortening compared with group V. The increase in level of TGF-beta1 and collagen-III mRNA were suppressed by pranidipine in a dose-dependent manner. Our results indicated that pranidipine has cardioprotective effects on heart failure, and that the beneficial effect can be partly explained by attenuation of fibrotic response through suppression of TGF-beta1 and collagen-III mRNA expression, and regression of myocyte hypertrophy.

    Topics: Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Heart Failure; Heart Rate; Male; Myocarditis; Rats; Rats, Inbred Lew; Transforming Growth Factor beta; Ventricular Dysfunction, Left; Ventricular Remodeling

2004
Effects of lercanidipine on coronary reactivity and myocardial remodeling in transition to heart failure in cardiomyopathic hamsters.
    Acta pharmacologica Sinica, 2003, Volume: 24, Issue:3

    Lercanidipine is a new vasoselective dihydropyridine calcium channel blocker with a short plasma half-life, long duration of action, and demonstrated cardioprotective properties. We hypothesized that it might be effective at attenuating the adverse impact observed on the coronary compartment and myocardium in the transition phase to heart failure in the UM-X7.1 cardiomyopathic (CM) hamster.. The effects of 4-month exposure to lercanidipine 3 and 10 mg/kg (daily oral administration) were evaluated in 150-day-old CM hamsters and in age-matched normal hamsters. Coronary reactivity (reactive hyperemia to 30-s coronary occlusion) and the response to the administration of acetylcholine (100 nmol/L) and sodium nitroprusside (1 micromol/L) were assessed monthly, using the isolated perfused heart model. The left ventricular chamber dilatation index and wall thickness, myocardial fibrosis and myocardial capillary density (papillary muscle) were estimated in selected subgroups at monthly intervals.. High-dose lercanidipine had beneficial effects on coronary dysfunctions: at month 4 of the treatment period, reactive hyperemia to short duration ischemia was improved, as was the endothelium-dependent vasodilator response (acetylcholine=68 %+/-16 % vs 11 %+/-5 % in untreated CM hamsters, P<0.05) and endothelium-independent vasodilator response (sodium nitroprusside=36 %+/-5 % vs 22 %+/-12 % in untreated CM hamsters, P<0.05). Capillary density averaged 10,879+/-474 capillaries per mm2 in papillary muscle from normal hamsters; this value did not change over time in normal hamsters and was not affected during the transition phase to heart failure in CM hamsters. Lercanidipine preserved myocardial capillary density in these conditions. Chronic exposure to lercanidipine had no impact on myocardial remodeling observed in CM hamsters.. Lercanidipine had a beneficial impact on the coronary compartment in the transition phase to heart failure in a model of dilated cardiomyopathy.

    Topics: Acetylcholine; Animals; Calcium Channel Blockers; Capillaries; Cardiomyopathies; Cardiotonic Agents; Cricetinae; Dihydropyridines; Female; Heart Failure; Male; Mesocricetus; Myocardium; Nitroprusside; Vasodilator Agents; Ventricular Remodeling

2003
[Clinical usefulness of a dual L/N-type Ca2+ channel blocker, cilnidipine, in patients with chronic heart failure: assessment with 123I-MIBG myocardial scintigraphy].
    Kaku igaku. The Japanese journal of nuclear medicine, 2003, Volume: 40, Issue:4

    Sympathetic nerve system is activated as a compensatory mechanism in heart failure. However, excessive activation of sympathetic nerve system deteriorates disease state. Sympathetic nerve system can be suppressed with N-type Ca2+ channel blocker. An antihypertensive drug, cilnidipine, is a dual L/N-type Ca2+ channel blocker. We studies usefulness of cilnidipine in treating with chronic heart failure with 123I-MIBG myocardial scintigraphy. We enrolled 24 patients with stable chronic heart failure. Twelve patients were treated with ACE-inhibitors, diuretics and cardiotonics (control group), and the other 12 patients were treated with ACE-inhibitors, diuretics, cardiotonics and cilnidipine (cilnidipine group). We examined blood pressure, heart rate, norepinephrine level, brain natriuretic peptide (BNP) level, cardiothoracic ratio on chest X-ray, ejection fraction of left ventricle on two-dimensional echocardiography, count rate of heart to mediastinum (H/M) and washout rate (WOR) on 123I-MIBG myocardial scintigraphy before and six months after medication. Symptom was improved in 8 patients in the control group and 10 patients in the cilnidipine group after medication. And another parameters were also improved in the both groups after medication. However the degree of change in blood pressure (mmHg) was 21.2 +/- 8.0 in the cilnidipine group and 10.8 +/- 9.1 in the control group, that in heart rate (/min) was 24.1 +/- 6.8 and 16.2 +/- 11.0, that in BNP level (pg/ml) was 65.2 +/- 12.0 and 42.8 +/- 11.1, that in H/M was 0.30 +/- 0.08 and 0.19 +/- 0.09, that in WOR was 19.4 +/- 5.6 and 12.2 +/- 7.0, respectively. And the degree of these changes were larger in the cilnidipine group (p < 0.05). These findings suggested that cilnidipine, a dual L/N-type Ca2+ channel blocker, might be useful in treating with chronic heart failure.

    Topics: 3-Iodobenzylguanidine; Calcium Channel Blockers; Dihydropyridines; Female; Heart Failure; Humans; Male; Middle Aged; Radionuclide Imaging; Radiopharmaceuticals

2003
Combination treatment with a calcium channel blocker and an angiotensin blocker in a rat systolic heart failure model with hypertension.
    Hypertension research : official journal of the Japanese Society of Hypertension, 2002, Volume: 25, Issue:3

    The mechanism and treatment of hypertensive systolic heart failure are not well defined. We compared the effect of an angiotensin-converting enzyme inhibitor (cilazapril, 10 mg/kg), an angiotensin receptor blocker (candesartan, 3 mg/kg), a calcium channel blocker (benidipine, 1, 3 or 6 mg/kg), and the same calcium channel blocker combined with renin-angiotensin blockers on systolic heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed an 8% Na diet from 6 weeks of age and then subjected to the above drug treatments. Benidipine (1 mg/kg), cilazapril, and candesartan had compatible hypotensive effects and similar beneficial effects on cardiac hypertrophy, gene expression, and survival rate. The combination of benidipine with cilazapril or candesartan was found to have no additional beneficial effects on the above parameters, with the exception of a reduction in atrial natriuretic polypeptide gene expression. On the other hand, candesartan normalized serum creatinine, but serum creatinine was unaffected by either benidipine at 1 or 3 mg/kg or cilazapril. Further, the combined use of benidipine and either candesartan or cilazapril resulted in an additional reduction of urinary albumin excretion in DS rats. Thus systolic heart failure in DS rats is mainly mediated by hypertension, while renal dysfunction of DS rats is due to both hypertension and the AT1 receptor itself. These findings suggest that the combination of a calcium channel blocker with an AT1 receptor blocker or ACE inhibitor may be more effective in treating the renal dysfunction associated with systolic heart failure than monotherapy with either agent alone. However, further studies will be needed before reaching any definitive conclusion on the efficacy of this combination therapy in patients with heart failure.

    Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Cilazapril; Dihydropyridines; Drug Therapy, Combination; Heart Failure; Hypertension; Kidney; Natriuretic Peptide, Brain; Organ Size; Rats; Receptor, Angiotensin, Type 1; RNA, Messenger; Survival Rate; Systole; Transforming Growth Factor beta

2002
Reduction in density of transverse tubules and L-type Ca(2+) channels in canine tachycardia-induced heart failure.
    Cardiovascular research, 2001, Feb-01, Volume: 49, Issue:2

    Persistent supraventricular tachycardia leads to the development of a dilated cardiomyopathy with impairment of excitation-contraction (EC) coupling. Since the initial trigger for EC coupling in ventricular muscle is the influx of Ca(2+) through L-type Ca(2+) channels (I(Ca)) in the transverse tubules (T-tubules), we determined if the density of the T-tubule system and L-type Ca(2+) channels change in canine tachycardia pacing-induced cardiomyopathy.. Confocal imaging of isolated ventricular myocytes stained with the membrane dye Di-8-ANEPPS was used to image the T-tubule system, and standard whole-cell patch clamp techniques were used to measure I(Ca) and intramembrane charge movement.. A complex staining pattern of interconnected tubules including prominent transverse components spaced every approximately 1.6 microm was present in control ventricular myocytes, but failing cells demonstrated a far less regular T-tubule system with a relative loss of T-tubules. In confocal optical slices, the average % of the total cell area staining for T-tubules decreased from 11.5+/-0.4 in control to 8.7+/-0.4% in failing cells (P<0.001). Whole-cell patch clamp studies revealed that I(Ca) density was unchanged. Since whole-cell I(Ca) is due to both the number of channels as well as the functional properties of those channels, we measured intramembrane charge movement as an assay for changes in channel number. The saturating amount of charge that moves due to gating of L-type Ca(2+) channels, Q(on,max), was decreased from 6.5+/-0.6 in control to 2.8+/-0.3 fC/pF in failing myocytes (P<0.001).. Cellular remodeling in heart failure results in decreased density of T-tubules and L-type Ca(2+) channels, which contribute to abnormal EC coupling.

    Topics: Adrenergic beta-Agonists; Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Cell Size; Dihydropyridines; Dogs; Heart Failure; Image Processing, Computer-Assisted; Ion Channel Gating; Isoproterenol; Microscopy, Confocal; Models, Animal; Myocardium; Patch-Clamp Techniques; Tachycardia

2001
Gadolinium prevents stretch-mediated contractile dysfunction in isolated papillary muscles.
    American journal of physiology. Heart and circulatory physiology, 2001, Volume: 280, Issue:3

    We tested the hypothesis that overstretching the myocardium could induce and/or exacerbate contractile dysfunction via stretch-activated (SA) ion channels. Maximum developed tension (T(max)), normalized to a control value, was compared in guinea pig papillary muscles held at one of three resting lengths (physiological stretch, overstretch, and unloaded) for 85 min. Overstretched muscles exhibited decreased contractile force (T(max) = 0.77 +/- 0.03) compared with physiological and unloaded muscles (T(max) = 0.93 +/- 0.05 and 1.03 +/- 0.07, respectively). Gd(3+), an SA channel antagonist, eliminated the adverse effect of overstretching (T(max) = 0.98 +/- 0.06), but nifedipine, a dihydropyridine (DHP) antagonist of L-type calcium channels, did not (T(max) = 0.82 +/- 0.04). Exposure to modified hypoxia-reoxygenation (MHR) during physiological stretch resulted in decreased contractility (T(max) = 0.63 +/- 0.07), an effect that was exacerbated by overstretching (T(max) = 0.44 +/- 0.04). Gd(3+) mitigated the effects of overstretch during MHR (T(max) = 0.64 +/- 0.05), but DHP did not (T(max) = 0.48 +/- 0.04). These data suggest that overstretching of the myocardium contributes to contractile abnormalities via SA channels that are distinct from L-type calcium channels.

    Topics: Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Dihydropyridines; Gadolinium; Guinea Pigs; Heart Failure; Hypoxia; In Vitro Techniques; Ion Channel Gating; Muscle Contraction; Nifedipine; Oxygen; Papillary Muscles

2001
Regional expression and functional characterization of the L-type Ca2+-channel in myocardium from patients with end-stage heart failure and in non-failing human hearts.
    Journal of molecular and cellular cardiology, 1999, Volume: 31, Issue:1

    The purpose of the present study was to investigate the expression and functional relevance of sarcolemmal L-type Ca2+-channels in failing and non-failing human myocardium. The protein expression of sarcolemmal L-type Ca2+-channels was determined with 3H-(+)-PN 200-110-binding experiments and Western blot analysis using a specific antibody against the alpha1-subunit in membrane preparations of ventricular and atrial myocardium from both failing (n = 15) and non-failing hearts (n = 8). The gene expression of the ion conducting pore of the L-type Ca2+-channel was examined with Northern blot technique in human failing and non-failing RNA. For normalization the RNA expression of calsequestrin was used. In electrically driven ventricular papillary muscle strips and auricular trabeculae, the responses to nifedipine and Ca2+ as parameters of myocardial function were studied. The protein expression as measured by 3H-(+)-PN 200-110-binding (Bmax) and Western Blot analysis with calsequestrin as reference was similar in left ventricular failing and non-failing myocardium. However, both were reduced in atrial compared to ventricular tissue in failing and non-failing hearts. The KD remained unchanged. Calsequestrin levels were unaltered in failing and non-failing hearts. The gene expression of the alpha1-subunit was similar in human failing and non-failing hearts. The L-type Ca2+-channel antagonist nifedipine reduced force of contraction with the same potency and efficiency in ventricular failing and non-failing myocardium. In contrast, the potency of nifedipine was higher in atrial than in ventricular tissue. Consistently, atrial myocardium from patients with dilated cardiomyopathy was more sensitive towards Ca2+ than those of the control group. In conclusion, the altered Ca2+-homeostasis in failing human myocardium may be less due to changes in sarcolemmal L-type Ca2+-channel expression or function than due to an altered intracellular Ca2+-handling.

    Topics: Adolescent; Adult; Aged; Binding Sites; Blotting, Northern; Blotting, Western; Calcium; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Calsequestrin; Cardiomyopathy, Dilated; Dihydropyridines; Dose-Response Relationship, Drug; Female; Heart; Heart Failure; Humans; Male; Middle Aged; Myocardium; Nifedipine; Tissue Distribution

1999
Effect of BAY y 5959 on myocardial function and metabolism in normal and failing hearts.
    The American journal of physiology, 1998, Volume: 274, Issue:5

    BAY y 5959 is a dihydropyridine derivative with positive inotropic actions mediated by a direct increase in intracellular calcium. We characterized the direct myocardial actions of this new agent in hearts isolated from seven normal dogs and from five dogs with repeated coronary microembolization-induced heart failure. Inotropic actions of BAY y 5959 were accompanied by little effect on duration of contraction and by prolongation of the monophasic action potential (MAP); in contrast, isoproterenol decreased contraction and MAP durations. Whereas inotropic responsiveness to isoproterenol was blunted in embolized hearts, these actions of BAY y 5959 were relatively preserved in the heart failure state. Isoproterenol increased heart rate, whereas BAY y 5959 had little effect. Changes in coronary vascular resistance also decreased similarly for isoproterenol and BAY y 5959. Finally, for comparable inotropy, increases in myocardial oxygen consumption were similar for isoproterenol and for BAY y 5959. In summary, preserved inotropic responsiveness and lack of positive chronotropic actions are two clinically favorable features of this type of inotropic agents compared with a typical beta-adrenergic agonist.

    Topics: Animals; Cardiotonic Agents; Dihydropyridines; Dogs; Heart; Heart Failure; Heart Rate; Hemodynamics; Myocardial Contraction; Myocardium

1998
Hemodynamic effects of a calcium channel promoter, BAY y 5959, are preserved after chronic administration in ischemic heart failure in conscious dogs.
    The Journal of pharmacology and experimental therapeutics, 1998, Volume: 286, Issue:2

    BAY y 5959 is a dihydropyridine derivative that binds to L-type calcium channels in a voltage-dependent manner and promotes calcium entry into the cell during the plateau of the action potential by influencing mean open time. Because myofilament responsiveness to calcium is preserved in congestive heart failure (CHF), the inotropic responsiveness to this compound should be preserved in CHF, and tolerance should not develop despite long-term treatment. To test these hypotheses, CHF was induced in 14 chronically instrumented dogs by daily (30 +/- 5 days) intracoronary microsphere injections. The effects of BAY y 5959 (2-h i.v. infusions of 3 microg/kg/min and 10 microg/kg/min) were determined before heart failure, after heart failure was established and then 2 h after the end of a 5-day continuous BAY y 5959 intra-atrial infusion. Before CHF, the positive inotropic effect of BAY y 5959 at a dose of 10 microg/kg/min [left ventricular dP/dt (LVdP/dt) increased from 2955 +/- 132 mmHg to 4897 +/- 426 mmHg, P < .05] was associated with bradycardia (HR decreased from 92 +/- 4 to 78 +/- 6 b/min, P <.05), slight increases in mean arterial pressure (it increased from 100 +/- 2 mmHg to 113 +/- 5 mmHg, P <.05) and did not alter left ventricular end-diastolic pressure. In CHF, BAY y 5959 continued to induce dose-dependent increases in left ventricular systolic pressure, LVdP/dt and mean arterial pressure, as well as causing bradycardia and a significant decrease in left ventricular end-diastolic pressure. After a 5-day infusion of BAY y 5959, base-line LVdP/dt and left ventricular end-diastolic pressure improved. The responses of LVdP/dt and mean arterial pressure to BAY y 5959 were similar to those of the control state. The sustained responses in CHF and after long-term infusion suggest that BAY y 5959 may be an effective and potent inotropic agent for treatment of CHF that does not lead to tolerance to its positive inotropic effects.

    Topics: Animals; Calcium Channel Agonists; Dihydropyridines; Dogs; Dose-Response Relationship, Drug; Female; Heart Failure; Hemodynamics; Infusions, Intravenous; Male; Myocardial Contraction; Myocardial Ischemia; Time Factors

1998
Voltage-dependent calcium channel promoter restores baroreflex sensitivity in conscious dogs with heart failure.
    Circulation, 1998, Sep-29, Volume: 98, Issue:13

    The aim of this study was to determine the mechanism by which the calcium channel promoter BAY y 5959 affects the control of heart rate and baroreflex sensitivity in conscious dogs with pacing-induced heart failure (HF).. We compared responses to BAY y 5959, which increases inotropy and decreases chronotropy, with those to norepinephrine (NE), which coincidentally exerts the same directional effects on inotropy and chronotropy, albeit through different mechanisms, in the presence and absence of ganglionic blockade both in control and in HF. Both BAY y 5959 and NE elicit direct effects on the heart and indirect effects through activation of reflexes, primarily the sinoaortic baroreceptor reflex. BAY y 5959 still reduced heart rate in dogs with arterial baroreceptor denervation, but not after ganglionic blockade. HF induced classic catecholamine desensitization to the inotropic effects of NE and blunted reflex bradycardia. In contrast, inotropic responses to BAY y 5959 were preserved in HF. Surprisingly, the autonomically mediated bradycardia induced by BAY y 5959 was also preserved in HF. Baroreflex sensitivity was assessed in control and in HF by pulse interval-systolic arterial blood pressure (PI/SAP) slopes constructed in response to pharmacological alterations in arterial pressure. HF depressed the PI/SAP slope from 11.5+/-1.3 to 4.8+/-0.9 ms/mm Hg, but during BAY y 5959 infusion in HF, the PI/SAP slope was restored to 24.1+/-5.2 ms/mm Hg. To assess central versus peripheral actions of BAY y 5959, the agent was infused with intra-carotid artery perfusion at a low dose, which acted centrally but did not have an effect peripherally. Under these conditions, it still decreased heart rate and restored baroreflex sensitivity (PI/SAP slope, 12.7+/-2.8 ms/mm Hg).. Thus, the calcium promoter restores arterial baroreflex sensitivity in HF. Based on intra-carotid artery experiments, this occurs through a central nervous system and vagal mechanism.

    Topics: Animals; Calcium Channel Agonists; Dihydropyridines; Dogs; Female; Heart Failure; Heart Rate; Male; Norepinephrine; Pressoreceptors; Reflex

1998
Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: II. Effects on myocyte contractile processes.
    Circulation, 1997, Oct-07, Volume: 96, Issue:7

    The goal of this study was to determine the effects of ACE inhibition alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade in a model of congestive heart failure (CHF) on isolated LV myocyte function and fundamental components of the excitation-contraction coupling process.. Pigs were randomly assigned to one of five groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) concomitant AT1 Ang II receptor blockade (valsartan, 3 mg/kg/d) and rapid pacing (n=9), (4) concomitant ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). LV myocyte shortening velocity was reduced with chronic rapid pacing compared with control (27.2+/-0.6 versus 58.6+/-1.2 microm/s, P<.05) and remained reduced with AT1 Ang II receptor blockade and rapid pacing (28.0+/-0.5 microm/s, P<.05). Myocyte shortening velocity increased with ACEI or combination treatment compared with rapid pacing only (36.9+/-0.7 and 42.3+/-0.8 microm/s, respectively, P<.05). Myocyte beta-adrenergic response was reduced by >50% in both the rapid pacing group and the AT1 Ang II blockade group and improved by 25% with ACEI and increased by 54% with combined treatment. Both L-type Ca2+ channel density and the relative abundance of sarcoplasmic reticulum Ca2+ ATPase density were reduced with rapid pacing and returned to control levels in the combined ACEI and AT1 Ang II blockade group.. The unique findings of this study were twofold. First, basic defects in specific components of the myocyte excitation-contraction coupling process that occur with CHF are reversible. Second, combined ACEI and AT1 Ang II blockade may provide unique benefits on myocyte contractile processes in the setting of CHF.

    Topics: Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzazepines; Calcium Channels; Calcium Channels, L-Type; Calcium-Binding Proteins; Calcium-Transporting ATPases; Cardiac Pacing, Artificial; Cell Membrane; Cells, Cultured; Dihydropyridines; Heart Failure; Myocardial Contraction; Myocardium; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System; Sarcoplasmic Reticulum; Sodium-Potassium-Exchanging ATPase; Swine; Tetrazoles; Valine; Valsartan; Ventricular Function, Left

1997
Calcium channel antagonists. What do the second-generation agents have to offer?
    Postgraduate medicine, 1994, Volume: 95, Issue:1

    Calcium channel antagonists have gained widespread acceptance for treatment of a variety of cardiovascular disorders. Newer drugs of the dihydropyridine class are especially attractive for treating hypertension and angina because of their increased vascular selectivity, favorable side-effect profile, and pharmacokinetics that allow once-daily dosing. In the future, calcium channel antagonists may also play a role in antiatherogenic therapy and in treatment of congestive heart failure and cerebrovascular disease as results of prospective studies become available and new agents are developed.

    Topics: Arteriosclerosis; Calcium Channel Blockers; Cardiovascular Diseases; Cerebrovascular Disorders; Dihydropyridines; Diltiazem; Heart Failure; Humans; Verapamil

1994
Hemodynamic and electrophysiologic effects of first- and second-generation calcium antagonists.
    The American journal of cardiology, 1994, Jan-27, Volume: 73, Issue:3

    The calcium antagonists currently available exert significantly different in vitro and in vivo electrophysiologic, hemodynamic, and contractile effects on cardiovascular function, mediated through differential cardiac and vascular smooth muscle responses to calcium channel blockade. These differences have important implications regarding choice of agent in specific clinical conditions, such as sinus or atrioventricular nodal disease, depressed left ventricular function, or congestive heart failure--conditions that may coexist with angina or hypertension. Recognizing and utilizing the properties of the different calcium antagonists is important to ensure maximally effective clinical outcomes. For example, in patients with hypertrophic cardiomyopathy and supraventricular arrhythmias, verapamil is singularly effective, whereas in post-myocardial infarction patients with pulmonary congestion, diltiazem may produce an added risk. Calcium antagonists of the dihydropyridine class, such as nifedipine and amlodipine, have the greatest peripheral vasoselective effects and thus the greatest potential to reduce afterload, minimizing direct left ventricular depression of contractility. Despite favorable effects of calcium antagonists, most of the agents currently available are not clearly safe in congestive heart failure and may adversely affect left ventricular function. However, newer calcium antagonists such as amlodipine are being investigated with regard to their safety in congestive heart failure.

    Topics: Amlodipine; Calcium Channel Blockers; Cardiac Output; Dihydropyridines; Electrophysiology; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Hypertension; Male; Myocardial Contraction; Myocardial Ischemia; Ventricular Function, Left

1994
Beta-adrenergic receptor-G protein-adenylate cyclase complex in experimental canine congestive heart failure produced by rapid ventricular pacing.
    Circulation research, 1991, Volume: 69, Issue:6

    Changes in the beta-adrenergic receptor-G protein-adenylate cyclase complex were investigated in an experimental canine model of low-output heart failure produced by chronic rapid ventricular pacing. The contractile response occurring after exposure to the beta-adrenergic agonist dobutamine, measured as peak left ventricular + dP/dt, was decreased after 3 weeks of pacing. To further characterize the diminished functional responsiveness to beta-adrenergic receptor stimulation, beta-adrenergic receptor-adenylate cyclase coupling was investigated using membranes prepared from both control and paced animals. The density of beta-adrenergic receptors was decreased by 40% with a selective downregulation of the beta 1-subtype. The affinity of the receptor for the antagonist radioligand [125I]iodocyanopindolol remained unchanged. A defect in coupling was suggested by a decreased ability of isoproterenol, fluoride, and forskolin to stimulate adenylate cyclase in membranes prepared from failing hearts. Determination of the levels of Gi alpha (the alpha-subunit of Gi) by immunoblotting and pertussis toxin labeling revealed modest increases of approximately 30%. Furthermore, Mn2+ and purified Gs failed to stimulate adenylate cyclase in membranes prepared from failing hearts, indicating an impairment in the catalytic moiety of adenylate cyclase itself or in the ability of adenylate cyclase to couple to Gs. In contrast, complementation assay did not reveal differences in the functional activity of Gs alpha (the alpha-subunit of Gs). Taken together, these data demonstrate a selective decrease in the beta 1-subtype of adrenergic receptors and an increase in a 40-kd G1-like protein in the failing heart. Similar changes have been described in human idiopathic dilated cardiomyopathy. In addition to these changes, we identified a possible defect at the level of the catalytic subunit of adenylate cyclase.

    Topics: Adenylate Cyclase Toxin; Adenylyl Cyclases; Animals; Catecholamines; Dihydropyridines; Dobutamine; Dogs; Electric Stimulation; GTP-Binding Proteins; Heart Failure; Heart Rate; Hemodynamics; Pertussis Toxin; Receptors, Adrenergic, beta; Virulence Factors, Bordetella

1991
Regulation of K+ and Ca2+ channels in experimental cardiac failure.
    The American journal of physiology, 1991, Volume: 261, Issue:6 Pt 2

    To examine the status of ATP-sensitive K+ (K+ATP) channels and 1,4-dihydropyridine-sensitive Ca2+ (Ca2+DHP) channels during experimental cardiac failure, we have measured the radioligand binding properties of [3H]glyburide and [3H]PN 200 110, respectively, in tissue homogenates from the rat cardiac left ventricle, right ventricle, and brain 4 wk after myocardial infarction induced by left coronary artery ligation. The maximal values (Bmax) for [3H]glyburide and [3H]PN 200 110 binding were reduced by 39 and 40%, respectively, in the left ventricle, and these reductions showed a good correlation with the right ventricle-to-body weight ratio in heart-failure rats. The ligand binding affinities were not altered. In the hypertrophied right ventricle, Bmax values for both the ligands were not significantly different when data were normalized to DNA content or right ventricle weights but showed an apparent reduction when normalized to unit protein or tissue weight. Moderate reductions in channel densities were observed also in whole brain homogenates from heart failure rats. Assessment of muscarinic receptors, beta-adrenoceptors and alpha 1-adrenoceptors by [3H]quinuclidinyl benzilate, [3H]dihydroalprenolol, and [3H]prazosin showed reductions in left ventricular muscarinic and beta-adrenoceptor densities but not in alpha 1-adrenoceptor densities, consistent with earlier observations. It is suggested that these changes may in part contribute to the pathology of cardiac failure.

    Topics: Animals; Body Weight; Brain; Calcium Channel Blockers; Calcium Channels; Coronary Vessels; Dihydropyridines; Glyburide; Heart Failure; Heart Ventricles; Isradipine; Ligation; Male; Organ Size; Potassium Channels; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Receptors, Muscarinic

1991
Acute neurohormonal and hemodynamic response to a new peak III phosphodiesterase inhibitor (ICI 153,110) in patients with chronic heart failure.
    Journal of cardiovascular pharmacology, 1990, Volume: 16, Issue:3

    Peak III phosphodiesterase (PDE) inhibitors have combined positive inotropic and vasodilator effects. We studied 10 patients with chronic heart failure during and after infusion of intravenous (i.v.) ICI 153,110, an investigational peak III PDE inhibitor. Maximum hemodynamic response for the group occurred after cessation of infusion at a lower plasma drug concentration. At maximum hemodynamic response, cardiac index (CI) increased (2.4 +/- 0.5 vs. 3.2 +/- 0.37 L/min/m2, p less than 0.05) with a decrease in mean arterial pressure (MAP 91 +/- 5 vs. 80 +/- 3 mm Hg, p less than 0.05), pulmonary capillary wedge pressure (PCWP 25 +/- 2 vs. 17 +/- 3.1 mm Hg, p less than 0.01), systemic vascular resistance (SVR 1,422 +/- 106 vs. 983 +/- 97 dynes.s.cm-5, p less than 0.05) and pulmonary vascular resistance (PVR 227 +/- 39 vs. 16 +/- 31 dynes.s.cm-5, p less than 0.05). During the infusion, plasma renin activity (PRA) decreased from 6.34 +/- 2.53 to 3.6 +/- 3 ng/ml/h (NS). The five patients with high baseline PRA had a significant decrease (11.2 +/- 2.5 vs. 5.4 +/- 1.67 ng/ml/h, p less than 0.01) that preceded changes in CI and SVR by 1-2 h. These data suggest that reduction in PRA may have contributed to the hemodynamic effects of this peak III PDE inhibitor.

    Topics: Dihydropyridines; Dobutamine; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Norepinephrine; Phosphodiesterase Inhibitors; Pyridazines; Renin

1990