cardiovascular-agents and Bradycardia

Cardioneuroablation is increasingly being utilized to improve outcomes in patients with vagally mediated bradyarrhythmias. However, there are still controversial issues in the field including patient selection, safety and efficacy, and procedural end-points.. In this review, the current role of cardioneuroablation is summarized, and controversial issues related to the modality are discussed.. According to small open-label cohort studies, overall freedom from syncope recurrence was higher than 90% after cardioneuroablation in patients with vasovagal syncope (VVS). Use of the electrogram-based strategy or high-frequency stimulation demonstrate similar success rate except in procedures limited to the right atrium. Based on a recently published randomized controlled trial and metanalysis, it may be possible now to make a strong recommendation for cardioneuroablation in patients <40 years of age, and those with the cardioinhibitory or mixed type of VVS who continue to experience frequent and/or burdensome syncope recurrences. Considering patients with VVS are prone to significant placebo/expectation effect, sham-controlled trials may help to quantify the placebo effect. In well-selected patients with functional atrioventricular block and sinus bradycardia, may result in encouraging medium-term outcomes. However, functional bradycardia is identified in a minority of patients presenting with high-grade atrioventricular block or sinus node dysfunction.

Topics: Atrioventricular Block; Bradycardia; Cardiovascular Agents; Catheter Ablation; Humans; Sick Sinus Syndrome; Syncope, Vasovagal

Topics: Angina Pectoris; Benzazepines; Bradycardia; Cardiovascular Agents; Heart Failure; Heart Rate; Humans; Ivabradine; Patient Safety; Recovery of Function; Risk Assessment; Risk Factors; Treatment Outcome; Ventricular Function, Left

Topics: Atrial Fibrillation; Benzazepines; Bradycardia; Cardiovascular Agents; Drug Costs; Heart Failure; Humans; Hypertension; Ivabradine; Treatment Outcome

Quality improvement in cardiology over the past decade focused on management of acute coronary syndrome with invasive and innovative medical therapies, optimizing treatment of congestive heart failure and the development of repair procedures in valvular heart disease. On the other hand cardiologist and the attendant physicians are confronted with changes in the characteristics of patients in the light of demographic facts. Comorbidity and polypharmacy raise the need for clear concepts. Therapeutic and diagnostic tools of geriatric medicine may help in that context.

Topics: Aged; Aged, 80 and over; Bradycardia; Cardiovascular Agents; Drug Interactions; Drug Therapy, Combination; Frail Elderly; Heart Diseases; Humans; Long QT Syndrome; Prescription Drugs; Syncope; Tachycardia

Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Bradycardia; Calcium Channel Blockers; Cardiovascular Agents; Humans; Tachycardia

The management of bradycardia-tachycardia syndrome (BTS) includes bradycardia and tachyarrhythmia therapy. At present, the treatment for symptomatic bradycardia in BTS patients is permanent cardiac pacing. The pharmacological treatment of atrial tachyarrhythmias comprises of rhythm and rate control, and prevention of thromboembolism. Patients with BTS often require both pacemaker and drug therapy. This article reviews the interactions of pacing and drug therapies in BTS. Drugs that alter cardiac electrophysiological properties may influence pacemaker indications, pacing mode selection, efficacy of pacing algorithms and pacing performance. Pacing by preventing drug-induced bradycardia increases the safety of pharmacotherapy and, thus, allows the intensification of those treatments. Pacing therapy and antiarrhythmic drugs used together as a hybrid therapy have a synergistic effect in the prevention of atrial tachyarrhythmias. Atrial-based pacing may reduce atrial tachyarrhythmia burden, allowing reduction of rhythm and rate control. Contemporary pacemakers' memory functions may help guide rhythm and rate control, as well as anticoagulation pharmacotherapy.

Topics: Bradycardia; Cardiac Pacing, Artificial; Cardiovascular Agents; Humans; Pacemaker, Artificial; Syndrome; Tachycardia

Topics: Bradycardia; Cardiac Pacing, Artificial; Cardiovascular Agents; Electrocardiography; Female; Heart Arrest; Humans; Male; Middle Aged

Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization-activated cyclic nucleotide-gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact.. We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading.. HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917.

Topics: Adult; Autonomic Nervous System; Baroreflex; Benzazepines; Biological Clocks; Blood Pressure; Bradycardia; Cardiovascular Agents; Cross-Over Studies; Double-Blind Method; Electrocardiography; Germany; Healthy Volunteers; Heart Rate; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ivabradine; Male; Muscle Proteins; Muscle, Skeletal; Potassium Channels; Sinoatrial Node; Time Factors; Young Adult

The aim of this study was to determine the impact of emergent bradycardia and atrial fibrillation (AF) on cardiovascular outcomes in 19 083 patients with stable coronary artery disease (CAD) receiving ivabradine or placebo (SIGNIFY, Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease).. Emergent bradycardia (resting heart rate <50 b.p.m. on 12-lead electrocardiogram) with ivabradine was reported in 3572 patients (37.4%) overall, and in 2242 (37.2%) patients with Canadian Cardiovascular Society (CCS) class ≥ 2 angina. There was no difference in outcomes over the course of the study in ivabradine-treated patients with and without emergent bradycardia in the whole population (2.5 vs. 2.9% per year, respectively, for primary composite endpoint of cardiovascular death or non-fatal myocardial infarction) or in the angina subgroup (2.5 vs. 3.2% per year). Neither was there an increase in the rate of primary endpoint after emergent bradycardia was recorded compared with those without emergent bradycardia. There were 754 cases of emergent AF on treatment (2.2% per year ivabradine vs. 1.5% per year placebo) and 469 in the patients with angina (2.2 vs. 1.5% per year). While outcomes occurred more frequently in patients in whom emergent AF had been recorded, there was no treatment-placebo difference in outcomes, including stroke, and no difference in treatment effect in patients with limiting angina.. Both in the overall population as well as in the angina subset, bradycardia was common in ivabradine-treated patients, but did not appear to impact outcomes. Emergent AF was relatively rare and did not appear to have an impact on outcomes relative to placebo.. ISRCTN61576291.

Topics: Aged; Atrial Fibrillation; Benzazepines; Bradycardia; Cardiovascular Agents; Coronary Artery Disease; Double-Blind Method; Female; Humans; Ivabradine; Male; Middle Aged; Risk Factors

The purpose of this study was to determine whether atrial pacing is a safe alternative to minimal (backup-only) ventricular pacing in defibrillator recipients with impaired ventricular function.. The DAVID (Dual Chamber and VVI Implantable Defibrillator) trial demonstrated that dual chamber rate responsive pacing as compared with ventricular backup-only pacing worsens the combined end point of mortality and heart failure hospitalization. Although altered ventricular activation from right ventricular pacing was presumed to be the likely cause for these maladaptive effects, this supposition is unproven.. In all, 600 patients with impaired ventricular function from 29 North American sites, who required an implanted defibrillator for primary or secondary prevention, with no clinical indication for pacing, were randomly assigned to atrial pacing (at 70 beats/min) versus minimal ventricular pacing (at 40 beats/min) and followed up for a mean of 2.7 years.. There were no significant differences between pacing arms in patients' baseline characteristics, use of heart failure medications, and combined primary end point of time to death or heart failure hospitalization during follow-up, with an overall incidence of 11.1%, 16.9%, and 24.6% at 1, 2, and 3 years, respectively. Similarly, the incidence of atrial fibrillation, syncope, appropriate or inappropriate shocks, and quality of life measures did not significantly differ between treatment groups.. The effect of atrial pacing on event-free survival and quality of life was not substantially worse than, and was likely equivalent to, backup-only ventricular pacing. Atrial pacing may be considered a "safe alternative" when pacing is desired in defibrillator recipients, but affords no clear advantage or disadvantage over a ventricular pacing mode that minimizes pacing altogether. (Dual Chamber and VVI Implantable Defibrillator [DAVID] Trial II; NCT00187187).

Topics: Aged; Atrial Fibrillation; Bradycardia; Cardiac Pacing, Artificial; Cardiovascular Agents; Combined Modality Therapy; Defibrillators, Implantable; Electric Countershock; Female; Heart Failure; Hospitalization; Humans; Incidence; Male; Middle Aged; Prosthesis Design; Quality of Life; Ventricular Dysfunction, Left

The Homburg Biventricular Pacing Evaluation (HOBIPACE) is the first randomized controlled study that compares the biventricular (BV) pacing approach with conventional right ventricular (RV) pacing in patients with left ventricular (LV) dysfunction and a standard indication for antibradycardia pacing in the ventricle.. In patients with LV dysfunction and atrioventricular block, conventional RV pacing may yield a detrimental effect on LV function.. Thirty patients with standard indication for permanent ventricular pacing and LV dysfunction defined by an LV end-diastolic diameter > or =60 mm and an ejection fraction < or =40% were included. Using a prospective, randomized crossover design, three months of RV pacing were compared with three months of BV pacing with regard to LV function, N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum concentration, exercise capacity, and quality of life.. When compared with RV pacing, BV stimulation reduced LV end-diastolic (-9.0%, p = 0.022) and end-systolic volumes (-16.9%, p < 0.001), NT-proBNP level (-31.0%, p < 0.002), and the Minnesota Living with Heart Failure score (-18.9%, p = 0.01). Left ventricular ejection fraction (+22.1%), peak oxygen consumption (+12.0%), oxygen uptake at the ventilatory threshold (+12.5%), and peak circulatory power (+21.0%) were higher (p < 0.0002) with BV pacing. The benefit of BV over RV pacing was similar for patients with (n = 9) and without (n = 21) atrial fibrillation. Right ventricular function was not affected by BV pacing.. In patients with LV dysfunction who need permanent ventricular pacing support, BV stimulation is superior to conventional RV pacing with regard to LV function, quality of life, and maximal as well as submaximal exercise capacity.

Topics: Aged; Arrhythmias, Cardiac; Atrial Fibrillation; Bradycardia; Cardiac Pacing, Artificial; Cardiovascular Agents; Combined Modality Therapy; Cross-Over Studies; Exercise Tolerance; Female; Heart Block; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Quality of Life; Single-Blind Method; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

In the SHIFT (Systolic Heart failure treatment with the I. The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days.. Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.

Topics: Benzazepines; Bradycardia; Cardiovascular Agents; Heart Failure; Heart Failure, Systolic; Heart Rate; Humans; Ivabradine; Stroke Volume; Treatment Outcome

Topics: Bradycardia; Cardiovascular Agents; Heart Rate; Humans; Ivabradine; Tachycardia, Ectopic Junctional

The lateral hypothalamus (LH) is a diencephalic structure that has been considered part of the central circuitry regulating the baroreflex function. However, the local neurochemical mechanisms involved in baroreflex control by this hypothalamic area are poorly understood. Therefore, in the present study we investigated the role of corticotropin-releasing factor (CRF) neurotransmission within the LH acting via local CRF

Topics: Aminopyridines; Animals; Baroreflex; Blood Pressure; Bradycardia; Cardiovascular Agents; Corticotropin-Releasing Hormone; Heart; Heart Rate; Hypothalamic Area, Lateral; Male; Peptide Fragments; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Synaptic Transmission; Tachycardia

Farnesol (FAR) is a sesquiterpene alcohol with a range of reported biological effects including cardioprotective, antioxidant and antiarrhythmic properties. However, due to its volatility, the use of drug incorporation systems, such as cyclodextrins, have been proposed to improve its pharmacological properties. Thus, the aim of this study was to evaluate and characterize the cardiovascular effects of FAR alone, and to investigate the antihypertensive effects of FAR complexed with β-cyclodextrin (βCD) in rats. Mean arterial pressure (MAP) and heart rate (HR) were measured before and after intravenous administration of FAR (0,5; 2,5; 5 and 7,5 mg/kg) in normotensive rats, and after oral acute administration (200 mg/kg) of FAR and FAR/βCD complex in NG-nitro-L-arginine-methyl-ester (L-NAME) hypertensive rats. In normotensive animals, FAR induced dose-dependent hypotension associated with bradycardia. These effects were not affected by pre-treatment with L-NAME or indomethacin (INDO), but were partially attenuated by atropine. Pre-treatment with hexamethonium (HEXA) only affected hypotension. In the hypertensive rats, FAR/βCD potentialized the antihypertensive effect when compared to FAR alone. Molecular docking experiments demonstrated for the first time that FAR has affinity to bind to the M

Topics: Animals; Arterial Pressure; beta-Cyclodextrins; Blood Pressure; Bradycardia; Cardiovascular Agents; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesol; Heart Rate; Hypertension; Male; Molecular Docking Simulation; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar

A meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV), but candidate genes in these loci remain uncharacterized. We developed an image- and CRISPR/Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in eggs from fish that transgenically express GFP on smooth muscle cells (Tg[acta2:GFP]), to visualize the beating heart. An automated analysis of repeated 30 s recordings of beating atria in 381 live, intact zebrafish embryos at 2 and 5 days post-fertilization highlighted genes that influence HRV (hcn4 and si:dkey-65j6.2 [KIAA1755]); heart rate (rgs6 and hcn4); and the risk of sinoatrial pauses and arrests (hcn4). Exposure to 10 or 25 µM ivabradine-an open channel blocker of HCNs-for 24 h resulted in a dose-dependent higher HRV and lower heart rate at 5 days post-fertilization. Hence, our screen confirmed the role of established genes for heart rate and rhythm (RGS6 and HCN4); showed that ivabradine reduces heart rate and increases HRV in zebrafish embryos, as it does in humans; and highlighted a novel gene that plays a role in HRV (KIAA1755).

Topics: Animals; Animals, Genetically Modified; Bradycardia; Cardiovascular Agents; CRISPR-Cas Systems; Embryo, Nonmammalian; Genes, Reporter; Genome-Wide Association Study; Green Fluorescent Proteins; Heart Rate; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ivabradine; Meta-Analysis as Topic; Myocardial Contraction; Myocytes, Smooth Muscle; Optical Imaging; Pleckstrin Homology Domains; RGS Proteins; Zebrafish

Topics: American Heart Association; Bradycardia; Cardiac Conduction System Disease; Cardiac Resynchronization Therapy; Cardiac Surgical Procedures; Cardiovascular Agents; Electrophysiologic Techniques, Cardiac; Heart Rate; Humans; Patient Care Management; Patient Selection; Practice Guidelines as Topic; Quality of Life; United States

Topics: American Heart Association; Bradycardia; Cardiac Conduction System Disease; Cardiac Resynchronization Therapy; Cardiac Surgical Procedures; Cardiovascular Agents; Electrophysiologic Techniques, Cardiac; Heart Rate; Humans; Patient Care Management; Patient Selection; Quality of Life; United States

Topics: Amlodipine; Antidepressive Agents; Antihypertensive Agents; Bradycardia; Cardiovascular Agents; Drug Therapy, Combination; Female; Humans; Hypertension; Hypoglycemic Agents; Middle Aged

The GABA

Topics: Animals; Atropine; Autonomic Nervous System; Boidae; Bradycardia; Cardiovascular Agents; Electrocardiography; GABA Modulators; Heart; Heart Rate; Hypnotics and Sedatives; Midazolam; Propranolol

Patients hospitalized for first acute coronary syndrome (ACS) are frequently discharged on multiple new medications. The short-term tolerability of these medications is unknown.. This single-center cohort study assessed 30-day health-care utilization and how it may be impacted by medication prescribing trends. We included Olmsted County patients presenting with ACS and previously undiagnosed coronary artery disease in 2008 to 2009. All health-care contacts were reviewed 30 days after index hospital discharge for potential adverse medication effects including documented hypotension or bradycardia, or symptoms likely attributed to the medications.. The study included 86 patients; their mean age was 63 (standard deviation: 15.5 years). Antianginal or antihypertensive cardiovascular (CV) medications were prescribed to 98% of patients at discharge; 76% were prescribed 2 or more. There were 233 health-care contacts in 30 days; 90 (39%) of these contacts were unscheduled. More CV medications tended to be prescribed to patients with unscheduled contacts, both pre-ACS ( P = .045) and upon hospital discharge ( P = .051). Hypotension and/or bradycardia at follow-up occurred in 52 patients (60%). Surprisingly, there was no association between hypotension and/or bradycardia at follow-up and increased health-care utilization ( P = .12). Potential adverse drug effects were reported in 34 (40%) patients. These patients had significantly more total health-care contacts ( P < .001) and unscheduled health-care contacts (median 0 vs 1.5; P < .001).. Symptoms of adverse drug effects were associated with more frequent health-care utilization after ACS. Clinicians need to consider this while striving to increase patient compliance with post-ACS medications and optimize care transitions.

Topics: Acute Coronary Syndrome; Aged; Appointments and Schedules; Bradycardia; Cardiovascular Agents; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Emergency Service, Hospital; Female; Health Resources; Humans; Hypotension; Male; Middle Aged; Minnesota; Office Visits; Patient Discharge; Patient Readmission; Polypharmacy; Practice Patterns, Physicians'; Time Factors

We hypothesized that in chronic digoxin toxicity, anti-digoxin antibodies (Fab) would be efficacious in binding digoxin, but this may not translate into improved clinical outcomes.. This study aims to investigate changes in free digoxin concentrations and clinical effects on heart rate and potassium concentrations in chronic digoxin poisoning when anti-digoxin Fab are given.. This is a prospective observational study. Patients were recruited if they have been treated with anti-digoxin Fab for chronic digoxin poisoning. Data was entered into a standardised prospective form, supplemented with medical records. Their serum or plasma was collected, analysed for free and bound digoxin and free anti-digoxin Fab concentrations.. From September 2013 to February 2015, 36 patients (median age, 78 years; 22 females) were recruited from 18 hospitals. Median heart rate (HR) was 49 beats/min. Initial median digoxin and potassium concentrations were 4.7 nmol/L (3.6 μg/L) (range: 2.3-11.2 nmol/L) and 5.3 mmol/L (range: 2.9-9.2 mmol/L) respectively. Beta-blockers (n = 18), calcium antagonists (n = 6), spironolactone and/or angiotensin blocking agents (n = 24) were also used concomitantly. Renal impairment and gastrointestinal symptoms were present in 31 (86%) and 22 (63%) patients respectively. Five patients died from conditions unrelated to digoxin toxicity. Median change in HR was 8 beats/min post-Fab with no effect on blood pressure; they were 4, 10 and 17 beats/min for the 1, 2 and ≥3 vials of anti-digoxin Fab groups respectively. Concomitant treatments with potassium lowering agents (12/36) and inotropic drugs (7/36) were used. Gastrointestinal effects resolved in all 22 patients. The median decrease for potassium was 0.3 mmol/L. Digoxin concentration reduced from 3.8 to 0 nmol/L post-Fab. There was a rebound observed in the free digoxin concentration in 25 patients but none had associated clinical deterioration.. One to two vials of anti-digoxin Fab initially bound all free digoxin confirming Fab efficacy. However, this was associated with only a moderate improvement in HR and potassium, suggesting bradyarrhythmia and hyperkalaemia may be from other co-morbidities.

Topics: Aged; Aged, 80 and over; Bradycardia; Cardiovascular Agents; Chronic Disease; Digoxin; Drug Overdose; Female; Heart Rate; Humans; Hyperkalemia; Immunoglobulin Fab Fragments; Male; Middle Aged; Poisoning; Potassium; Prospective Studies

Topics: Benzazepines; Bradycardia; Cardiovascular Agents; Heart Failure; Heart Rate; HIV; HIV Infections; Humans; Ivabradine

Topics: Benzazepines; Bradycardia; Cardiovascular Agents; Heart Failure; Heart Rate; HIV; HIV Infections; Humans; Ivabradine

While heart rate reduction (HRR) is a target for the management of patients with heart disease, contradictory results were reported using ivabradine, which selectively inhibits the pacemaker I

Topics: Adrenergic beta-1 Receptor Antagonists; Animals; Benzazepines; Bradycardia; Cardiovascular Agents; Disease Models, Animal; Dyslipidemias; Echocardiography; Energy Metabolism; Female; Glucose; Glycolysis; Heart; Heart Rate; Hemodynamics; Ivabradine; Longitudinal Studies; Male; Metoprolol; Mice; Myocardium; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stroke Volume; Telemetry; Transcriptome

Previously, we reported that microinjection of L-proline (L-Pro) into the paraventricular nucleus of the hypothalamus (PVN) caused vasopressin-mediated pressor responses in unanesthetized rats. In the present study, we report on the central mechanisms involved in the mediation of the cardiovascular effects caused by the microinjection of L-Pro into the PVN. Microinjection of increasing doses of L-Pro (3-100nmol/100nL) into the PVN caused dose-related pressor and bradycardic responses. No cardiovascular responses were observed after the microinjection of equimolar doses (33nmol/100nL) of its isomer D-Proline (D-Pro) or Mannitol. The PVN pretreatment with either a selective non-NMDA (NBQX) or selective NMDA (LY235959 or DL-AP7) glutamate receptor antagonists blocked the cardiovascular response to L-Pro (33nmol/100nL). The dose-effect curve for the pretreatment with increasing doses of LY235959 was located at the left in relation to the curves for NBQX and DL-AP7, showing that LY235959 is more potent than NBQX, which is more potent than DL-AP7 in inhibiting the cardiovascular response to L-Pro. The cardiovascular response to the microinjection of L-Pro into the PVN was not affected by local pretreatment with N

Topics: Animals; Blood Pressure; Bradycardia; Cardiovascular Agents; Cardiovascular System; Central Nervous System Agents; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Heart Rate; Male; Microinjections; Neurotransmitter Agents; Paraventricular Hypothalamic Nucleus; Proline; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

Topics: Atrial Flutter; Benzazepines; Bradycardia; Cardiovascular Agents; Catheter Ablation; Cyclic Nucleotide-Gated Cation Channels; Electrocardiography, Ambulatory; Humans; Ivabradine; Male; Middle Aged

Three new alkaloids (1, 4 and 8), together with nine known analogues (2, 3, 5-7, and 9-12), were isolated from the marine-derived fungus Penicillium expansum Y32. Their structures including the absolute configurations were elucidated by spectroscopic and Mosher's and Marfey's methods, along with quantum electronic circular dichroism (ECD) calculations. Each of the compounds was evaluated for cardiovascular effects in a live zebrafish model. All of the compounds showed a significant mitigative effect on bradycardia caused by astemizole (ASM) in the heart rate experiments. Compounds 4-6 and 8-12 exhibited potent vasculogenetic activity in vasculogenesis experiments. This is the first study to report that these types of compounds show cardiovascular effects in zebrafish. The results suggest that these compounds could be promising candidates for cardiovascular disease lead compounds.

Topics: Alkaloids; Animals; Astemizole; Bradycardia; Cardiovascular Agents; Circular Dichroism; Heart Rate; Neovascularization, Physiologic; Penicillium; Secondary Metabolism; Zebrafish

Topics: Anticoagulants; Arrhythmogenic Right Ventricular Dysplasia; Atrial Fibrillation; Benzazepines; Bradycardia; Cardiovascular Agents; Heart Diseases; Hemorrhage; Humans; Ivabradine; Point-of-Care Systems

The search for new nitric oxide donors is warranted by the limitations of organic nitrates currently used in cardiology. The new organic nitrate 2-nitrate-1,3-dibuthoxypropan (NDBP) exhibited promising cardiovascular activities in previous studies. The aim of this study was to investigate the cardiorespiratory responses evoked by NDBP and to compare them to the clinically used organic nitrate nitroglycerine (NTG). Arterial pressure, heart rate and respiration were recorded in conscious adult male Wistar rats. Bolus i.v. injection of NDBP (1 to 15mg/kg; n=8) and NTG (0.1 to 5mg/kg; n=8) produced hypotension. NDBP induced bradycardia at all doses, while NTG induced tachycardia at three lower doses but bradycardia at higher doses. Hydroxocobalamin (20mg/kg; HDX), a NO scavenger, blunted hypotension induced by NDBP (15mg/kg), and its bradycardic effect (n=6). In addition, HDX blunted both hypotension and bradycardia induced by a single dose of NTG (2.5mg/kg; n=6). Both NDBP and NTG altered respiratory rate, inducing a biphasic effect with a bradypnea followed by a tachypnea; HDX attenuated these responses. Our data indicate that NDBP and NTG induce hypotension, bradycardia and bradypnea, which are mediated by nitric oxide release.

Topics: Animals; Arterial Pressure; Bradycardia; Cardiovascular Agents; Consciousness; Dose-Response Relationship, Drug; Heart Rate; Hydroxocobalamin; Hypotension; Male; Nitrates; Nitric Oxide; Nitroglycerin; Propane; Rats; Rats, Wistar; Respiration; Tachypnea; Vasodilator Agents

This study investigated the cardiovascular effects of the essential oil of Croton zehntneri (EOCZ) in deoxycorticosterone-acetate (DOCA)-salt hypertensive rats. Furthermore, in vitro experiments using isolated thoracic aortic rings were performed to assess the vascular effects of the EOCZ. In conscious hypertensive rats, intravenous (i.v.) injections of EOCZ (1-20 mg/kg) induced rapid (2-4 s) and dose-dependent hypotension and bradycardia (phase 1). The hypotension was followed by a significant pressor effect that was more evident at the higher doses (10 and 20 mg/kg) of EOCZ. Hypotension and bradycardia of EOCZ (phase 1) were abolished and respectively reversed into pressor and tachycardiac effects by methylatropine (1 mg/kg, i.v.) pretreatment. In isolated endothelium-intact aortic preparations, increasing concentrations (1-1000 microg/mL) of EOCZ relaxed the potassium-induced contraction in a concentration-dependent manner with an IC50 (geometric mean [95% confidence interval]) value of 202.0 [92.0-443.7] microg/mL. This vasorelaxant effect remained unaffected by either mechanical removal of functional vascular endothelium (IC50 = 189.0 [159.4-224.7] microg/mL) or the addition of atropine (1 microM) (IC50 = 158.6 [79.8-316.2] microg/mL) in the perfusion medium. These data show that i.v. administration of EOCZ in DOCA-salt hypertensive rats induces a vago-vagal reflex decreases in heart rate and blood pressure (phase 1). EOCZ may induce a second and delayed hypotension due to its direct endothelium-independent vasorelaxant effects, but it seems to be buffered by the pressor component (subsequent to phase 1) of EOCZ. This pattern of blood pressure and heart rate responses to EOCZ seems unaltered by DOCA-salt hypertension, as was similar to that previously reported in conscious normotensive rats.

Topics: Animals; Aorta, Thoracic; Bradycardia; Cardiovascular Agents; Croton; Desoxycorticosterone; In Vitro Techniques; Male; Oils, Volatile; Rats; Rats, Wistar

Topics: Aged; Atropine; Bradycardia; Bundle-Branch Block; Cardiovascular Agents; Comorbidity; Electrocardiography; Epinephrine; Humans; Injections, Subcutaneous; Male; Octreotide; Pancreatic Neoplasms; Radionuclide Imaging

Defence responses triggered experimentally in rats by stimulation of the dorsomedial nucleus of the hypothalamus (DMH) and the dorsolateral periaqueductal grey matter (PAG) inhibit the cardiac baroreflex response (i.e. bradycardia). It has also been proposed that the midbrain cuneiform nucleus (CnF) is involved in active responses. Our aim was to identify the neurocircuitry involved in defence-induced baroreflex inhibition, with a particular focus on the link between DMH, CnF and dorsolateral PAG. Microinjection of the anterograde tracer Phaseolus vulgaris leucoaggutinin into the CnF revealed a dense projection to the dorsolateral PAG. Moreover, activation of neurons in the CnF induced increased expression of Fos protein in the dorsolateral PAG. Inhibition of neurons of the CnF or dorsolateral PAG prevented the inhibition of baroreflex bradycardia induced by DMH or CnF stimulation, respectively. These results provide a detailed description of the brain circuitry underlying acute baroreflex modulation by neurons of the DMH. Our data have shown for the first time that the CnF plays a key role in defence reaction-associated cardiovascular changes; its stimulation, from the DMH, activates the dorsolateral PAG, which, in turn, inhibits baroreflex bradycardia.

Topics: Analysis of Variance; Animals; Baroreflex; Bradycardia; Cardiovascular Agents; Defense Mechanisms; Feedback, Physiological; Heart Rate; Male; Mediodorsal Thalamic Nucleus; Mesencephalon; Microinjections; Neural Inhibition; Neural Pathways; Neuroanatomical Tract-Tracing Techniques; Neuronal Tract-Tracers; Neurotransmitter Agents; Periaqueductal Gray; Phytohemagglutinins; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley

Topics: Adrenergic beta-Antagonists; Aged; Amiodarone; Atrial Fibrillation; Bisoprolol; Bradycardia; Calcium Channel Blockers; Cardiovascular Agents; Combined Modality Therapy; Digoxin; Diltiazem; Female; Humans; Hypothyroidism; Kidney Failure, Chronic; Myocardial Infarction; Pacemaker, Artificial; Renal Dialysis

The therapy of cardiovascular diseases has improved rapidly over the past 20 years. The most commonly used medications in cardiac patients are drugs affecting potassium homeostasis in the kidneys or the gastrointestinal tract, particularly inhibitors of renin-angiotensin-aldosterone (RAA) axis. They all can lead to hyperkalemia. This disorder may cause severe damage to the muscles and both the nervous and cardiovascular systems.. The aim of this study was to evaluate the incidence and clinical course of moderate and severe iatrogenic hiperkalemia in patients hospitalized for cardiovascular disease.. The present study analyzed a history of 26 patients with severe or moderate iatrogenic hyperkalemia, selected from among 5553 patients hospitalized in the years 2005-2006 in the Department of Clinical Cardiology of the Swietokrzyskie Cardiology Center, Kielce. They accounted for 0.46% of all patients treated at that time at the Ward.. The concentration of potassium on admission to hospital was > 6.0 mmol/l. Before admission all patients were treated in out-patient clinics with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, spironolactone, amiloride, triam-terene, beta-blockers, or potassium supplements administered in monotherapy or in combination. A mean age of patients was 79 years, most of them (80%) were women. The average blood potassium level was 7.3 mmol/l on admision and 5.1 mmol/l at discharge. Severe bradyarrhythmia and complete atrioventricular block requiring temporary pacing (n = 13) were observed in 21 patients (81%). Twenty-four patients (85%) had elevated levels of renal function parameters on admission. The average creatinine level on admission was 2.64 mg/dl, and 2.06 mg/dl on discharge. Ten (38%) out of 26 patients suffered from diabetes and 21 patients (81%) had arterial hypertension. Three out of 26 patients died in the hospital despite intensive therapy.. Polypharmacy should be used with particular caution in subjects treated on the ambulatory basis. During administration of inhibitors of RAA system, particularly in elderly out patients, renal function and serum electrolytes should be appropriately monitored both prior to and during the treatment.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Atrioventricular Block; Bradycardia; Cardiovascular Agents; Cardiovascular Diseases; Comorbidity; Diuretics; Fatal Outcome; Female; Humans; Hyperkalemia; Iatrogenic Disease; Incidence; Male; Polypharmacy; Potassium

Slow coronary flow is an angiographic phenomenon characterized by delayed opacification of vessels in the absence of any evidence of obstructive epicardial coronary disease. In this article, we present serious clinical manifestations of extremely slow coronary flow in two hypertensive patients with preserved ejection fraction in echocardiographical examination: a 57 year-old woman with acute coronary syndrome and temporary ST elevation; and a 65 year-old man with atrial tachycardia which was leading to sudden arrest of circulation. The woman was admitted to hospital due to recurrent syncope and chest pain. Because of severe bradycardia, an AAI pacemaker was implanted. Coronary angiography without evident obstructive lesion revealed extremely slow flow of dye through arteries. The man was admitted to hospital because of heart palpitations (paroxysmal atrial tachycardia, PAT) followed by chest pain. During hospitalization, a sudden arrest of circulation in the course of supraventricular tachycardia of 220/min with atrioventricular conduction of 1:1 occurred. Coronary arteriography did not show any occlusions in the coronary arteries, although extremely slow dye flow was seen. Electrophysiological examination revealed arrhythmia of the left atrial (PAT) (tricuspid valve anulus mapping) without induced ventricular arrhythmia. Because of symptomatic bradyarrhythmia, a VVI heart pacemaker was implanted. Over a 12-month observation, his heart rate remained under control, and the patient did not complain of chest pains or heart palpitations.

Topics: Acute Coronary Syndrome; Aged; Angina Pectoris; Blood Flow Velocity; Bradycardia; Cardiac Pacing, Artificial; Cardiovascular Agents; Combined Modality Therapy; Coronary Angiography; Coronary Circulation; Coronary Disease; Drug Therapy, Combination; Electrocardiography; Female; Heart Rate; Humans; Male; Middle Aged; Syncope; Tachycardia, Paroxysmal; Tachycardia, Supraventricular; Treatment Outcome

Inhibition of cardiac sympathetic tone represents an important strategy for treatment of cardiovascular disease, including arrhythmia, coronary heart disease, and chronic heart failure. Activation of presynaptic alpha2-adrenoceptors is the most widely accepted mechanism of action of the antisympathetic drug clonidine; however, other target proteins have been postulated to contribute to the in vivo actions of clonidine.. To test whether clonidine elicits pharmacological effects independent of alpha2-adrenoceptors, we have generated mice with a targeted deletion of all 3 alpha2-adrenoceptor subtypes (alpha2ABC-/-). Alpha2ABC-/- mice were completely unresponsive to the analgesic and hypnotic effects of clonidine; however, clonidine significantly lowered heart rate in alpha2ABC-/- mice by up to 150 bpm. Clonidine-induced bradycardia in conscious alpha2ABC-/- mice was 32.3% (10 microg/kg) and 26.6% (100 microg/kg) of the effect in wild-type mice. A similar bradycardic effect of clonidine was observed in isolated spontaneously beating right atria from alpha2ABC-knockout and wild-type mice. Clonidine inhibited the native pacemaker current (I(f)) in isolated sinoatrial node pacemaker cells and the I(f)-generating hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 and HCN4 channels in transfected HEK293 cells. As a consequence of blocking I(f), clonidine reduced the slope of the diastolic depolarization and the frequency of pacemaker potentials in sinoatrial node cells from wild-type and alpha2ABC-knockout mice.. Direct inhibition of cardiac HCN pacemaker channels contributes to the bradycardic effects of clonidine gene-targeted mice in vivo, and thus, clonidine-like drugs represent novel structures for future HCN channel inhibitors.

Topics: Animals; Bradycardia; Cardiovascular Agents; Cell Line; Clonidine; Cyclic Nucleotide-Gated Cation Channels; Female; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ion Channels; Male; Mice; Mice, Inbred Strains; Muscle Proteins; Potassium Channels; Sympathetic Nervous System

Topics: Algorithms; Bradycardia; Cardiovascular Agents; France; Heart Arrest; Hospital Units; Humans; Myocardial Infarction; Myocardial Reperfusion; Patient Transfer; Shock, Cardiogenic; Tachycardia

Topics: Bradycardia; Cardiovascular Agents; Electrocardiography; Heart Block; Humans; Infant, Newborn; Infant, Premature; Long QT Syndrome; Mexiletine; NAV1.5 Voltage-Gated Sodium Channel; Sodium Channel Blockers; Sodium Channels; Tachycardia; Torsades de Pointes

We tested the hypothesis that induction of chronic bradycardia would trigger an upregulation of key growth factors and receptors, which would then lead to angiogenesis and improve coronary reserve in the left ventricle after myocardial infarction.. Bradycardia was induced in rats by administering alinidine via osmotic pumps beginning 1 day after coronary artery ligation. Echocardiographic analysis was conducted before and after treatment. Morphometric analysis was used in perfusion-fixed hearts to document arteriolar and capillary growth. Western blots were used to evaluate growth factor and receptor changes. During the first week of treatment, vascular endothelial growth factor (VEGF), VEGF receptor 1 (Flt-1), and basic fibroblast growth factor proteins were higher in the treated group, whereas VEGF receptor 2 (Flk-1), angiopoietin-1, and angiopoietin-2 were not affected by treatment. After 3 weeks, VEGF protein remained elevated, and bradycardia was associated with a higher capillary length density in the border (40%) and remote (14%) regions and a higher arteriolar length density in the septum (62%), despite a greater increase in left ventricular mass. Although arteriolar length density increased in all size classes, the greatest increase occurred in the smallest (terminal) arterioles. This vascular growth was associated with a 23% greater coronary reserve. Echocardiography revealed a smaller increase in ventricular volume and a greater preservation of ejection fraction in rats treated with bradycardia.. Pharmacologic induction of bradycardia enhances vascularity and coronary reserve, preserves function of surviving myocardium, and therefore, is a noninvasive, therapeutic avenue that provides an alternative to gene therapy.

Topics: Angiopoietin-1; Angiopoietin-2; Animals; Bradycardia; Cardiovascular Agents; Clonidine; Coronary Vessels; Drug Evaluation, Preclinical; Extracellular Matrix Proteins; Fibroblast Growth Factor 2; Heart Ventricles; Hypertrophy, Left Ventricular; Ligation; Male; Models, Animal; Myocardial Infarction; Myocytes, Cardiac; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley; Stroke Volume; Ultrasonography; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

We examined the role of hyperpolarization-activated currents (Ih) in heart rate regulation in mongrel white rats. The ZD 7288 blocking agent decreased the heart rate. Vagus stimulation in bradycardia also decreased the heart rate and was dose-depended. Vagotomy following the ZD 7288 administration induced different dose-dependent changes in heart activity. The index figures of the heart activity following beta-AR isoproterenol administration depended on the level of hyperpolarization-activated currents. The data suggest existence of a possible modulating effect of the ANS on the hyperpolarization-activated activity of the channels.

Topics: Animals; Autonomic Nervous System; Bradycardia; Cardiovascular Agents; Cyclic Nucleotide-Gated Cation Channels; Dose-Response Relationship, Drug; Electric Conductivity; Electric Stimulation; Electrocardiography; Heart; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ion Channels; Potassium Channels; Pyrimidines; Rats; Vagotomy; Vagus Nerve

A series of (+/-)-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines were prepared and their bradycardic activities were examined in isolated guinea-pigs' right atria and in anesthetized rats. Modifications on the benzyl moiety of the parent compound, 1, led to the identification of compound 11e as a potent and specific bradycardic agent.

Topics: Anesthesia; Animals; Bradycardia; Cardiovascular Agents; Guinea Pigs; Heart Atria; Heart Rate; In Vitro Techniques; Indicators and Reagents; Rats; Structure-Activity Relationship; Tetrahydroisoquinolines

Bilateral vagotomy eliminating extracardiac parasympathetic influences on the heart modulates the changes in variational pulsogram during blockade of hyperpolarization-activated currents, but has no significant effect on stroke volume after the blockade.

Topics: Animals; Bradycardia; Cardiovascular Agents; Cyclic Nucleotide-Gated Cation Channels; Electrocardiography; Heart; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Ion Channels; Parasympathetic Nervous System; Potassium Channels; Pyrimidines; Rats; Stroke Volume; Vagotomy; Vagus Nerve

Experiments on rats showed that blockade of hyperpolarization-activated currents moderates tachycardia induced by beta-adrenoceptor agonist isoproterenol and potentiates the increase in stroke volume produced by this agonist. Electrical stimulation of the vagus nerve against the background of isoproterenol treatment augmented bradycardia and increased stroke volume. Blockade of hyperpolarization-activated currents followed by application of isoproterenol moderated vagus-induced bradycardia and had no effect on the dynamics of stroke volume.

Topics: Animals; Bradycardia; Cardiovascular Agents; Electrophysiology; Heart; Isoproterenol; Pyrimidines; Rats; Receptors, Adrenergic, beta; Time Factors; Vagotomy; Vagus Nerve

Topics: Bradycardia; Cardiovascular Agents; Emergency Medical Services; Emergency Treatment; Humans; Infusions, Intravenous; United States

Based on the inactive metabolite approach, three different classes of soft drugs were designed and synthesized. Their cardiovascular effects and duration of actions were studied in anesthetized male Sprague-Dawley rats compared to the traditional drugs. During the experiments ECG (leads II, aVF) and beat-to-beat blood pressure (BP) from the left carotid artery were recorded (except during the anticholinergic studies). The soft anticholinergic methoxycarbonylphenylcyclopentyl-N,N-dimethyltropinium methyl sulfate was as potent as atropine in the prevention of carbachol induced bradycardia; however, its action only lasted up to 15-30 min, compared to 2 h of that of atropine. In the isoproterenol-induced tachycardia model, while bufuralol at an i.v. dose of 3.8 mumol/kg (1 mg/kg) diminished heart rate (HR) for at least 2 h, the effects of the soft drugs lasted for only 30-40 min at equimolar doses. The methyl-, ethyl-, isopropyl-, and tert-butyl ester-analogs of the carboxylic acid metabolite of bufuralol showed the highest beta-blocking potencies (i.e., 30-50% of that of bufuralol). When these compounds were infused for 10 min at doses ranging from 2-4 mumol/kg/min, they caused a 20-40% decrease in HR and a 30-40% reduction in mean arterial pressure (MAP). These effects were similar to those elicited by esmolol at a dose of 20 mumol/kg/min in respect of the kinetics and in the extent of the reductions in heart rate and MAP. The isopropyl-, the sec-butyl-, and the neopentyl-esters of the acidic metabolite of amiodarone, with plasma hydrolytic half-lives of 60, 240 and 300 min, were tested in the benzene/adrenaline induced ventricular tachycardia (VT) model of the rat. All drugs were administered at a dose of 5 mumol/kg i.v. bolus immediately followed by an infusion at 15 mumol/kg/h for 2 h. It was found, that amiodarone resulted a complete suppression of VTs at 30 min after the start of drug administration, but its effect lasted up to the total course of the experiment (up to 180 min). On the contrary, both the sec-butyl and the isopropyl-analog resulted in complete suppression of VTs already during the first benzene/adrenaline challenge after drug administration (i.e., at 5 min). However, their effects disappeared between 15 and 30 min after discontinuation of the drug infusions in accordance with the enzymatic inactivation (ester hydrolysis) of these soft drugs. All these three classes of soft cardioactive drugs are good examples for highly potent but short

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Atropine Derivatives; Biotransformation; Blood Pressure; Bradycardia; Carbachol; Cardiovascular Agents; Drug Design; Ethanolamines; Heart Rate; Isoproterenol; Male; Muscarinic Agonists; Prodrugs; Rats; Rats, Sprague-Dawley; Tropanes

We have previously shown that atrial natriuretic peptide (ANP) modulates cardiac barosensitive afferent pathways to enhance reflex bradycardia in rats. The present study examined whether B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) also modulate heart rate reflex function.. Baroreflex bradycardia was evoked by rapid (over 4-6 s) intravenous (i.v.) infusions of methoxamine (100 microg/kg; 'ramp' baroreflex technique) in the presence of infused i.v. natriuretic peptide and of vehicle (0.9% saline, 270 microl/h) in conscious adult Munich-Wistar rats. Initially a dose-response study to ANP (infused at 25, 50 and 100 pmol/kg per min i.v.) was performed in 10 rats to determine an appropriate dose for subsequent experiments with the other peptides. In a separate group of 11 animals, rat BNP-32 and rat CNP-22 were infused at 50 pmol/kg per min i.v.. Reflex responses to ANP were dose-related, with a significant increase in baroreflex sensitivity of 50+/-15% at the 25 pmol dose, 102+/-10% at the 50 pmol dose and 117+/-11% at 100 pmol dose (all P<0.05). BNP and CNP (50 pmol/kg/min i.v.) substantially increased baroreflex bradycardia (by 115+/-17% and 62+/-15%, respectively; P<0.05) compared to vehicle infusion.. Both BNP and CNP augmented baroreflex slowing of heart rate in response to rapid increases in blood pressure in rats. Whereas other reports have shown marked differences in cardiovascular responses between the natriuretic peptides, particularly with CNP, our findings demonstrate an important common action of ANP, BNP and CNP to facilitate vagal heart rate baroreflexes.

Topics: Animals; Atrial Natriuretic Factor; Baroreflex; Blood Pressure; Bradycardia; Cardiovascular Agents; Consciousness; Dose-Response Relationship, Drug; Heart Rate; Infusions, Intravenous; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Rats; Rats, Wistar

Topics: Adult; Anuria; Bradycardia; Cardiovascular Agents; Cold Temperature; Coma; Combined Modality Therapy; Drug Overdose; Electric Countershock; Emergencies; Extracorporeal Membrane Oxygenation; Female; Frostbite; Humans; Hypotension; Hypothermia; Intermittent Positive-Pressure Ventilation; Psychotropic Drugs; Resuscitation; Suicide, Attempted; Ventricular Fibrillation

Topics: Age Factors; Aged; Bradycardia; Cardiac Pacing, Artificial; Cardiovascular Agents; Carotid Sinus; Heart Rate; Humans; Hypotension; Myocardial Contraction; Neurotransmitter Agents; Pacemaker, Artificial; Pressoreceptors; Sympathetic Nervous System; Syncope, Vasovagal; Terminology as Topic; Tilt-Table Test; Vagus Nerve; Vasomotor System; Ventricular Function

The antiischemic and antiarrhythmic effects of alinidine and a number of novel alinidine analogs were examined by using perfused rat-heart models. In the isolated working rat heart, the alinidine analog TH91:21 (10 microM; a butyl derivative) significantly increased the postischemic recovery of the heart in terms of both power and efficiency when compared with the control group. In the in situ perfused heart model, this same compound, along with TH91:22 (10 microM; a pentyl derivative) also significantly reduced the severity of both ischemia- and reperfusion-induced arrhythmias in both paced and unpaced hearts. Thus this study is the first to demonstrate the potent antiarrhythmic efficacy of two novel alinidine analogs TH91:21 and TH91:22, with TH91:21 also demonstrated to be a potent antiischemic agent in the isolated working rat heart. Although the mode of action of these compounds remains unclear, results from this study suggest that it is not simply a result of bradycardia or blockade of KATP channels, two actions these compounds possess. These compounds thus possess a novel and beneficial pharmacologic profile worthy of further study.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bradycardia; Cardiac Pacing, Artificial; Cardiovascular Agents; Clonidine; Heart; Male; Potassium Channel Blockers; Rats; Rats, Inbred WKY; Reperfusion Injury; Structure-Activity Relationship

Heart rate (HR) is a major factor determining the severity of myocardial ischemia, and HR reduction is an effective therapy for myocardial ischemia. We tested the effects of HR reduction induced by either UL-FS 49 or atenolol on regional myocardial blood flow, function, and infarct size (IS) in a porcine model of 90-min low-flow ischemia and 2-h reperfusion. In 24 Göttinger miniswine, the left anterior descending coronary artery (LAD) was cannulated and hypoperfused at constant inflow to reduce anterior systolic wall thickening (AWT, sonomicrometry) by approximately 85%. Eight swine served as a placebo group, and 8 other swine received UL-FS 49 (0.60 mg/kg intravenously, i.v.) after 10-min ischemia. In the remaining 8 swine, atenolol was infused after 10-min ischemia at a dosage [mean 1.75 +/- 1.20 (SD) mg/kg i.v.] to mimic the HR reduction observed with UL-FS 49. Systemic hemodynamics, subendocardial blood flow (ENDO, microspheres) and AWT were measured under control conditions, at 10 and 90 min of ischemia. In the swine receiving UL-FS 49 or atenolol, additional measurements were made 5 min after administration of the respective drug. After 2-h reperfusion, IS (percentage of area at risk) was determined with TTC-staining. Five minutes after administration of UL-FS 49, HR was decreased from 113 +/- 9 to 83 +/- 13 beats/min (p < 0.05) and remained unchanged when ischemia was prolonged to 90 min. In the swine receiving atenolol, HR was reduced from 117 +/- 14 to 93 +/- 7 beats/min (p < 0.05) 5 min after drug administration and decreased further to 87 +/- 10 beats/min when ischemia was prolonged to 90 min. After 10 min of ischemia, AWT in the placebo, UL-FS 49, and atenolol group was decreased to 7.0 +/- 5.5, 6.4 +/- 3.5, and 6.2 +/- 3.3% (all p < 0.05 vs. control), respectively. The reduction in ENDO was also comparable among the three groups. In the placebo group, AWT remained unchanged when ischemia was prolonged to 90 min (4.4 +/- 2.6%). In swine receiving atenolol, AWT tended to increase (13.6 +/- 10.5%), whereas in swine receiving UL-FS 49, AWT was significantly increased to 21.4 +/- 7.1% (p < 0.05 vs. 10-min ischemia and vs. the placebo and atenolol groups). IS was significantly reduced in swine receiving atenolol (3.9 +/- 3.5%) or UL-FS 49 (5.8 +/- 4.6%) as compared with the placebo-group (10.4 +/- 8.9%).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adenosine Triphosphate; Animals; Atenolol; Benzazepines; Blood Pressure; Bradycardia; Cardiovascular Agents; Coronary Circulation; Disease Models, Animal; Female; Heart; Heart Rate; Injections, Intravenous; Lactates; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Oxygen Consumption; Phosphocreatine; Reperfusion Injury; Swine; Swine, Miniature

The effect of two doses (0.5 and 1.0 mg/kg i.v.) of a new specific bradycardic agent, AQ-A39 (5,6-dimethoxy-2-[3- [( alpha- (3,4,-dimethoxy)phenylethyl]methyl-amino)propyl]phthalimidine hydrochloride), on three indices of collateral function--retrograde pressure, retrograde flow, and tissue blood flow (radioactive microspheres)--was studied in anesthetized dogs following acute occlusion of the left anterior descending coronary artery. AQ-A39 produced a significant (p less than 0.05) dose-related decrease in heart rate without any other hemodynamic changes. Retrograde flow and subendocardial blood flow were significantly increased by the lower dose of AQ-A39, whereas retrograde pressure, retrograde flow, and midmyocardial and subendocardial flow were increased by the higher dose. Atrial pacing to the control heart rate eliminated the beneficial effects of AQ-A39 on collateral function. These results suggest that an increase in collateral perfusion may be one mechanism by which AQ-A39 alleviates myocardial ischemia.

Topics: Animals; Bradycardia; Cardiovascular Agents; Collateral Circulation; Coronary Circulation; Dogs; Female; Hemodynamics; Isoindoles; Male; Phthalimides; Regional Blood Flow

Indications for permanent pacing in the bradyarrhythmias are summarized. In the absence of symptoms, pacing is justified only when Mobitz type II block or complete atrioventricular (AV) block is localized in the bundle-branch system. All other abnormalities of impulse generation or conduction (incomplete AV block of any type, atrial fibrillation with slow ventricular response, or sinus node dysfunction) must be shown to be stable and intrinsic and to cause CNS symptoms or hemodynamic compromise to justify pacing. Isolated intra-Hisian abnormality without failure of AV conduction is benign. Measurement of HV interval does not contribute significant information. Correlation of carotid sinus sensitivity with carotid sinus syncope is poor (5%). Bradyarrhythmia produced by minimal effective doses of an essential drug is a rare indication for pacing and requires special documentation. Inadequate indications, sources of error, and misconceptions are discussed. Generally, it is important to exclude drug effect, transient clinical states, and correctable systemic disease as causes of the abnormality before making a conclusion about pacing.

Topics: Atrial Fibrillation; Atrioventricular Node; Bradycardia; Bundle of His; Bundle-Branch Block; Cardiac Pacing, Artificial; Cardiovascular Agents; Carotid Sinus; Electrophysiology; Heart Block; Heart Conduction System; Heart Rate; Humans; Myocardial Infarction; Pacemaker, Artificial; Sick Sinus Syndrome; Syncope

The role of presynaptic receptors in the bradycardic action of N-n-butyl dopamine (PBDA) was investigated. A biphasic effect on blood pressure and a decrease in heart rate were seen upon intravenous administration of PBDA to pentobarbital-anesthetized dogs. The bradycardia produced by PBDA was unaffected by bilateral vagotomy; however, it was abolished by cardiac sympathetic denervation. When PBDA was readministered following restoration of the cardiac sympathetic nerve activity by electrical stimulation, at frequency of 1 Hz, decrease in heart rate was again observed. The cardioinhibitory action of PBDA was completely abolished by sulpiride, whereas phentolamine and yohimbine caused only partial attenuation, suggesting the involvement of both presynaptic alpha-adrenoceptors as well as dopamine receptors in the bradycardiac action of PBDA. Additional experiments were performed to study the influence of stimulus frequency on the cardioinhibition produced by PBDA. Administration of PBDA to animals with different levels of cardiac sympathetic nerve activity (0.25-2 Hz) resulted in decreases in heart rate. However, yohimbine antagonized this action of PBDA only at the two higher frequencies of cardiac nerve stimulation. Sulpiride completely abolished the bradycardia observed at all the different frequencies of cardiac nerve stimulation. These results demonstrate that activation of presynaptic receptors on cardiac sympathetic nerves can result in a decrease in heart rate. PBDA causes bradycardia via an action on presynaptic dopamine receptors when the cardiac sympathetic nerve activity is low, while both presynaptic dopamine receptors as well as alpha-adrenoceptors are involved in the decrease in heart rate produced by this compound at higher levels of sympathetic nerve activity.

Topics: Adrenergic alpha-Antagonists; Animals; Bradycardia; Cardiovascular Agents; Dogs; Dopamine; Electric Stimulation; Female; Heart; Male; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Receptors, Dopamine; Sympathetic Nervous System

Alinidine (ST 567, N-Allyl-Clonidine) exerted concentration-dependent negative chronotropic effects in isolated, spontaneously-beating sinus node cells and Purkinje fibres of guinea pigs and in ventricular strips of chick embryonic myocardium. Reduction of beat frequency by 30% was found after addition of 8.6 mumol/l alinidine in the former. A chronotropic effect was not seen during Ba2+-induced automaticity or triggered activity in guinea-pig papillary muscles and in enzymatically disaggregated cells of embryonic chick myocardium, which lose the beta-adrenoceptor responsiveness of the intact embryonic ventricle. In contrast to alinidine, D600 showed very pronounced and quinidine minor negative chronotropic effects in these latter experiments. Reduction of excitability, rate of rise of the action potential and velocity of repolarization as well as prolongation of the refractory period were seen after applications of very high concentrations of alinidine (285 mumol/l). In electrically-driven atria isometric peak tension was only slightly changed (increased by 85.5 mumol/l, decreased by 285 mumol/l) but it was reduced (to 36.8%) by alinidine (85.5 mumol/l) in papillary muscles. Both in atria and in papillary muscles, the maximum rate of rise of the action potential was unchanged by alinidine up to 85.5 mumol/l and the slight reduction following 285 mumol/l alinidine application was independent of the rate of stimulation. The present findings confirm the selectivity of the bradycardic effects of alinidine which has a main mode of action different to that of membrane stabilizing compounds or inhibitors of the slow inward current.

Topics: Action Potentials; Animals; Barium; Bradycardia; Calcium; Cardiovascular Agents; Chick Embryo; Clonidine; Guinea Pigs; Heart; Heart Conduction System; In Vitro Techniques; Muscle Tonus; Papillary Muscles

Topics: Blood Circulation; Bradycardia; Cardiovascular Agents; Coronary Circulation; Coronary Vessels; Dogs; Metabolism; Muscle Relaxants, Central; Myocardium; Parasympatholytics; Pharmacology; Pyrroles; Research