Cardioactive Agents Research Articles

Pulmonary Delivery of Metoprolol Reduces Ventricular Rate During Atrial Fibrillation and Accelerates Conversion to Sinus Rhythm.

Safe, effective pulmonary delivery of cardioactive agents in humans is under development. We examined whether intratracheal delivery of metoprolol can reduce ventricular rate during atrial fibrillation (AF) and accelerate conversion to sinus rhythm. In 7 closed-chest, anesthetized Yorkshire pigs, AF was induced by intrapericardial infusion of acetylcholine (1 mL of 102.5-mM solution) followed by atrial burst pacing and was allowed to continue for 2 minutes before intratracheal instillation of sterile water or metoprolol (0.2-mg/kg bolus) using a catheter positioned at the bifurcation of the main bronchi. High-resolution electrograms were obtained from catheters fluoroscopically positioned in the right atrium and left ventricle. Rapid intratracheal instillation of metoprolol caused a 32-beat/min reduction in ventricular rate during AF (from 272 ± 13.7 to 240 ± 12.6 beats/min, P = 0.008) and a 2.3-minute reduction in AF duration (from 10.3 ± 2.0 to 8.0 ± 1.4 minutes, P = 0.018) compared with sterile water control. Conversion of AF to sinus rhythm was associated with rapid restoration (5-6 minutes) of heart rate and arterial blood pressure toward control values. Intratracheal metoprolol reduced AF dominant frequency by 31% (from 8.7 ± 0.9 to 6.0 ± 1.1 Hz, P = 0.04) compared with control and resulted in a trend toward a 5% increase in PR interval (from 174 ± 11.2 to 182 ± 11.4 ms, P = 0.07). Intratracheal delivery of metoprolol effectively reduces ventricular rate during AF and accelerates conversion to normal sinus rhythm in a pig model of acetylcholine-induced AF.

Response of J point elevation to cardio-active agents and risk of ventricular fibrillation in patients with early repolarization syndrome

Response of J point elevation to cardio-active agents and risk of ventricular fibrillation in patients with early repolarization syndrome

A Review on Pyridazinone Ring Containing Various Cardioactive Agents

In this work, some pyridazinones were studied for their cardioactive activity. These compounds showed significant cardio-active action with respect to the regular used drugs. However, it was found that the existence of the pyridazine ring is a crucial necessity in the structure of these pyridazinonecompounds to show the improved cardioactive activities. It was also understood that the substitution of the different group on the pyridazinone ring with other related bioisosteres or isosteres along with the existence of pyridazine ring may provide better cardioactive compounds. Pyridazinoneis, a component of various cardio-active agents, which are in uses clinically or in clinical trials. These contain pimobendan, indolidan, levosimendan, imazodan, CI-930, meribendan, bemoradan, senazodan, siguazodan, amipizone, prinoxodan, Y-590, SK&F-93741, SKF 95654, NSP-805, NSP-804 and KF 15232. This study briefly reviews the pyridazinone ring for the progress of new cardio-active drugs.

Response of J point elevation to cardio-active agents and risk of ventricular fibrillation in patients with early repolarization syndrome

Response of J point elevation to cardio-active agents and risk of ventricular fibrillation in patients with early repolarization syndrome

6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone - An important chemical moiety for development of cardioactive agents: A review

6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone moiety is a vital structural part of many cardio-active pyridazinone derivatives which are either in clinical use or have been tested in clinical trials. These include imazodan, CI-930, pimobendan, indolidan, levosimendan, SK&F-93741, Y-590, meribendan, NSP-804, NSP-805, bemoradan, senazodan, amipizone, prinoxodan, SKF 95654, siguazodan and KF 15232. This article briefly reviews relevant literature on various reports on the synthesis and use of this moiety for development of cardio-active agents. Keywords : 6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone, Cardio-active agents, Imazodan, Pimobendan, Indolidan, Levosimendan

Selectivity Problems with Drugs Acting on Cardiac Na<sup>+</sup> and Ca<sup>2+</sup> Channels

With the increase of our knowledge on cardioactive agents it comes more and more clear that practically none of the currently used compounds shows absolute selectivity to one or another ion channel type. This is particularly true for Na(+) and Ca(2+) channel modulators, which are widely applied in the clinical practice and biomedical research. The best example might be probably the marine guanidine poison tetrodotoxin, which has long been considered as a selective Na(+) channel blocker, while recently it turned out to effectively inhibit cardiac Ca(2+) currents as well. In the present study the cross actions observed between the effects of various blockers of Na(+) channels (such as toxin inhibitors, class I antiarrhythmics and local anesthetics) and Ca(2+) channels (like phenylalkylamines, dihydropyridine compounds, diltiazem and mibefradil) are overviewed in light of the known details of the respective channel structures. Similarly, activators of Na(+) channels, including veratridine and batrachotoxin, are also compared. The binding of tetrodotoxin and saxitoxin to Cav1.2 and Nav1.5 channel proteins is presented by construction of theoretical models to reveal common structures in their pore forming regions to explain cross reactions. Since these four domain channels can be traced back to a common ancestor, a close similarity in their structure can well be demonstrated. Thus, the poor selectivity of agents acting on cardiac Na(+) and Ca(2+) channels is a consequence of evolution. As a conclusion, since the limited selectivity is an intrinsic property of drug receptors, it has to be taken into account when designing new cardioactive compounds for either medical therapy or experimental research in the future.

Unusual case of severe arrhythmia developed after acute intoxication with tosylchloramide

BackgroundDrugs not commonly considered to be cardioactive agents may cause prolongation of the QT interval with resultant torsades de pointes and ventricular fibrillation. This form of drug toxicity often causes cardiac arrest or sudden death.Case presentationAfter accidental ingestion of tosylchloramide a caucasian 77-year-old woman, with a family history of cardiovascular disease and hypertension, was admitted to the intensive care unit following episodes of torsades de pointes with a prolonged QT/QTc interval (640/542 ms). The patient received an implantable cardioverter-defibrillator, was discharged from the hospital with normal QT/QTc interval and did not experience additional ventricular arrhythmias during one year of follow-up.ConclusionThis is the first report concerning an unusual case of torsades de pointes after accidental intoxication by ingestion of tosylchloramide. The pronounced impact of the oxidyzing agent tosylchloramide on the activity of some of the ion channels regulating the QT interval was identified as a probable cause of the arrhythmia.

Heart rate adjustment of PR interval in middle-aged and older adults

Prolonged PR interval has been associated with adverse cardiac events. Consequently, the scientific community and regulatory agencies have become concerned about PR interval prolongation induced by cardioactive agents. We evaluated PR dependence on heart rate (HR) in 5757 men and women aged 40 years and older from the US third National Health and Nutrition Survey with the objective to determine if rate adjustment for the PR interval is warranted as is the case with QT interval. Electrocardiograms were computer-processed in a central electrocardiogram laboratory. There was a statistically significant negative correlation between PR and HR ( r = −0.15; P < .001); notably weaker than that between QT and HR ( r = −0.76; P < .001). Evaluation of subgroups stratified by sex, race, and age revealed a significant interaction between PR and HR with age ( P = .006). A subsequent search for optimal rate-adjusted PR (PRa) formula that eliminates PR dependence on HR within each age group produced the formula: PRa = PR + 0.26 (HR − 70) for age group younger than 60 years and PRa = PR + 0.42 (HR − 70) for age group 60 years or older. The application of this formula in the study population effectively made the PR interval rate-invariant (residual slope of regression, −0.0054; 95% confidence interval, −0.064 to 0.053; P = .86). Based on the distribution of PRa, the 98th percentile limit of 220 milliseconds would be a reasonable overall threshold for defining first-degree AV block, with the 95th percentile limit of 205 as a threshold for borderline PR prolongation. In conclusion, the association between PR and HR is age- and rate-dependent and a separate rate-adjustment formula is needed for adults in younger and older age groups. The prognostic significance of the rate-adjusted PR needs to be investigated.

Drug-induced changes in action potential duration are proportional to action potential duration in rat ventricular myocardium

Several cardioactive agents exhibit direct or reverse rate-dependent effects on action potential duration (APD) depending on the experimental conditions. Recently, a new theory has been proposed, suggesting that the reverse rate-dependent mode of drug-action may be a common property of canine, rabbit, guinea pig and human cardiac tissues, and this phenomenon is based on the dependence of drug-action on baseline APD. The aim of the present work was to examine the limitations of this hypothesis by studying the APD lengthening effect of K(+) channel blockers and the APD shortening effect of Ca(2+) channel blockers during the electrical restitution process of rat ventricular action potentials. Rat ventricular muscle was chosen because it has a set of ion currents markedly different from those of other species, its APD is shorter by one order of magnitude than that of the "plateau-forming" larger mammals, and most importantly, its APD increases at higher heart rates - opposite to many other species. The restitution of APD was studied as a function of the diastolic interval, a parameter indicating the proximity of action potentials. It was found that drug-induced APD changes in rat myocardium are proportional with the pre-drug value of APD but not with the diastolic interval, indicating that not the proximity of consecutive action potentials, but the baseline APD itself may determine the magnitude of drug-induced APD changes.

ChemInform Abstract: Structures of Puwainaphycins A-E.

Abstract Puwainaphycins A–E, one of which (C) is a potent cardioactive agent in isolated mouse atria, are cyclic decapeptides that have beeen isolated from a terrestrial blue-green alga Annabaena sp. BQ-16-1. The structures of puwainaphycins A–E, including most of the stereochemical features, have been elucidated by a combination of spectral and chemical methods.

Comparison of Elimination and Cardiovascular Effects of Adenine Nucleosides Administered Intrapericardially or Intravenously in Anesthetized Dog

Intrapericardial (IP) administration of certain cardioactive agents allows investigation of local pharmacological actions on the heart and may carry potential benefit to influence myocardial function. The cardioprotective adenosine (ADO) and inosine (INO) may be the most representative candidates. Elimination and cardiovascular effects of IP and intravenously (IV) applied ADO and INO were compared on anesthetized dogs. Their pericardial and systemic concentrations were measured after consecutive administration of increasing ADO and INO doses. In the case of IP administration at the end of the incubation period, pericardial concentrations of adenine nucleosides significantly exceeded the control values. However, the IV applied ADO and INO were rapidly metabolized in the systemic plasma. As characteristic hemodynamic effects, small but sustained decrease in heart rate (IP ADO) and increase in myocardial contractility (IP INO) were observed. During IV administration, ADO and INO exerted remarkable effects on all hemodynamic variables, which then gradually disappeared in 15 minutes. In summary, the elimination of ADO and INO was significantly slower in the pericardial fluid than in the plasma. Considering the balanced cardiac actions and lack of strong systemic hemodynamic effects, IP administration of adenine nucleosides may suggest a promising approach in the local treatment of the diseased heart.

Cardioactive Agents from Plants

This review presents 201 compounds isolated and identified from plants that present cardioactive activity. These substances have been classified by chemical groups and each provides the most relevant information of its pharmacological activity, action mechanism, chemical structure, spectroscopic date and other properties. Chemical structures have been drawn to indicate the stereochemistry. In this review the summary of the scientific information of plants that present biological activity and the compounds responsible for this activity is presented, which introduces the reader to the study of medicinal plants and also provide bibliographic references, where a detailed study of pharmacology can be found.

Efficacy of Lidocaine for Pain Control in Subcutaneous Infiltration During Liposuction

Liposuction remains the most commonly performed aesthetic surgical procedure in the United States. Preoperative infiltration of the subcutaneous tissues with a wetting solution has become standard. These solutions typically contain some amount of lidocaine for pain control. High doses of lidocaine have been demonstrated to be safe, but large amounts of this cardioactive agent during elective cosmetic procedures may be unnecessary. A study was designed to examine the effects of wetting solutions with lower concentrations of lidocaine on perioperative pain. Seventeen patients were prospectively randomized to subcutaneous infiltration with one of 3 different lidocaine concentrations: 10 mg/kg, 20 mg/kg, or 30 mg/kg. Intra- and postoperative lidocaine and monoethylglycinexylidide (MEGX) plasma concentrations were measured and the total intraoperative inhalation gas requirements and minimum alveolar concentrations were recorded. Postoperative pain medication requirements were recorded and morphine equivalents were calculated. Patient pain level was subjectively assessed by using a visual analog pain scale. There was no difference in the intraoperative lidocaine or MEGX concentrations between any of the 3 groups. There was also no statistical difference between the 3 groups when comparing intraoperative inhalational gas requirement, postoperative morphine equivalence requirements, or subjective pain using the visual analog scale. Decreasing concentrations of lidocaine in infiltrative wetting solutions did not significantly affect intraoperative anesthesia requirements or postoperative pain with liposuction. Lower concentrations of lidocaine can effectively be used, use of any lidocaine may be unnecessary. Future investigations may examine whether total elimination of lidocaine yields similar results in terms of anesthesia requirements and postoperative pain.

The ATP-Binding Cassette Transporters and Their Implication in Drug Disposition: A Special Look at the Heart

The passage of drugs across cell membranes dictates their absorption, distribution, metabolism, and excretion. This process is determined by several factors including the molecular weight of the compounds, their shape, degree of ionization, and binding to proteins. Accumulation of xenobiotics into tissues does not depend only on their ability to enter cells, but also on their ability to leave them. For instance, the role of efflux transporters such as ATP-binding cassette (ABC) proteins in the disposition of drugs is now well recognized. Actually, ABC transporters act in synergy with drug-metabolizing enzymes to protect the organism from toxic compounds. The most studied transporter from the ABC transporter superfamily, P-glycoprotein, was found to be overexpressed in tumor cells and associated with an acquired resistance to several anticancer drugs. P-glycoprotein, thought at first to be confined to tumor cells, was subsequently recognized to be expressed in normal tissues such as the liver, kidney, intestine, and heart. Even though information remains rather limited on the functional role of ABC transporters in the myocardium, it is hypothesized that they may modulate efficacy and toxicity of cardioactive agents. This review addresses recent progress on knowledge about the ABC transporters in drug disposition and more precisely their role in drug distribution to the heart.

Optimized strategy for rapid cytochrome P450 2D6 genotyping by real-time long PCR.

Because of genetic polymorphisms, cytochrome P450 2D6 (Cyp2D6) activity in humans varies widely and alters the metabolism of commonly used drugs such as antidepressants, neuroleptics, and cardioactive agents. Severe adverse effects or resistance to therapy may result. We performed long PCR on the LightCycler(TM) and used the product as a template for a previously validated multiplex PCR that examines the *3, *4, *6, *7, and *8 alleles of Cyp2D6. We used real-time PCR to identify the *5 null allele and duplication of Cyp2D6 with detection by either hybridization probes or SYBR Green((R)). The *2 -1584 C/G polymorphism and the *35 allele were identified by PCR with detection by hybridization probes. Products of all PCRs were visualized with gel electrophoresis using a 0.7-1.5% agarose gel and ethidium bromide. Samples containing the *35 allele were analyzed in parallel by digestion with NlaIII, MslI, and BstXI and SmaI. We analyzed samples from volunteers and patients (105 samples for deletion and duplication and 116 samples for preamplification). Of those samples, 59 were from depressive inpatients taking part in a trial not yet published. Identical genotyping results for both real-time and conventional PCR were obtained and verified by gel electrophoresis. Use of long-PCR methods on the LightCycler enabled comprehensive analysis of all relevant polymorphisms of the Cyp2D6 gene in 1 working day with a hands-on time of approximately 3-4 h. This is the first description of a successful long-PCR application on the LightCycler and the fastest technique for amplification and specific detection of a PCR product of comparable length. The method appears suitable for large clinical and epidemiologic studies.

Molecular mechanisms in endothelial regulation of cardiac function.

Endothelium is now recognized as a massive, regionally specific, multifunctional organ. Given its strategic anatomic location between the circulating blood components and the vascular smooth muscle or the cardiac muscle, it is a biologically significant interface whose dysfunction can be a critical factor in various pathological conditions. Two types of endothelial cells are recognized in the heart, the endocardial endothelial (EE) cells and the microvascular endothelial cells (MVE). Both produce common autacoids and share similar roles in signal transduction induced by neurotransmitters, hormones or mechanical stimuli. They are however two distinct cell populations with dissimilar embryological origin, cytoskeletal organization, receptor mediated functions and electrophysiological properties. Both the MVE and EE are modulators of cardiac performance. Myocardial contraction may be modulated by cardioactive agents such as nitric oxide, prostanoids, endothelin, natriuretic peptides, angiotensin II, kinins, reactive oxygen species and adenyl purines released from the cardiac endothelium. Two mechanisms have been proposed for the signal transduction from EE to the underlying myocytes: stimulus-secretion-contraction coupling and blood-heart barrier. Nitric oxide, bradykinin and myofilament desensitizing agent are probably important in short-term regulation of myocardial functions. Endothelin and Angiotensin II are probably involved in long-term regulation. Besides its sensory function and paracrine modulation of myocardial performance, EE as a blood-heart barrier could be of significance for the ionic homeostasis of the cardiac interstitium. In cardiac diseases, the damage to EE or MVE leading to failure of the endothelial cells to perform its regulatory and modulator functions may have serious consequences. A better understanding of the endothelial signaling pathways in cardiac physiology and pathophysiology may lead to the development of novel therapeutic strategies.

Arrhythmogenic activity of cardiac muscle in pulmonary veins of the dog: implication for the genesis of atrial fibrillation.

Pulmonary veins are important foci of ectopic beats to initiate paroxysmal atrial fibrillation. The purpose of this study were to investigate the electrophysiological characteristics of excitable cells in canine pulmonary veins obtained from healthy and chronic rapid atrial pacing dogs and their responses to cardioactive agents. Transmembrane action potentials (APs) were recorded from multiple sites of pulmonary veins isolated from 17 healthy dogs and 14 dogs with chronic (6-8 weeks) rapid atrial pacing (780 bpm). In normal superfusate, several types of electrical activities were identified, including silent electrical activity, fast response APs driven by electrical stimulation, and spontaneous fast or slow response APs (with or without early afterdepolarizations). The incidences of AP with an early afterdepolarization (93% versus 41%) was greater in chronic pacing dogs. The spontaneous activities were depressed by beta-adrenoceptor blocker, calcium channel blocker, adenosine and acetylcholine. High frequency (>8 Hz) irregular rhythms occurred spontaneously or were induced by cardioactive agents or electrical stimuli. The incidence of spontaneously occurring tachyarrhythmias was much higher in preparations from chronic pacing dogs (93%) than from control (12%). The tachyarrhythmias were suppressed by sodium channel blocker, potassium channel blocker or magnesium. Pulmonary veins have arrhythmogenic ability through spontaneous activities or high-frequency irregular rhythms. The higher incidence of spontaneously occurring high-frequency irregular rhythms in chronic rapid atrial pacing dogs may account for the increased risk of atrial fibrillation in these dogs.

Cardiac capillary cells release biologically active nitric oxide at an early stage of in vitro development.

Coronary microvascular endothelial cells (EC) may regulate the myocardial contractile function by releasing cardioactive agents such as nitric oxide (NO). However, understanding of these regulatory mechanisms is complicated by the fact that EC exhibit marked phenotypic changes, such as the loss of endothelial NO synthase (eNOS), when they are placed into culture. Recently, it has been shown that eNOS gene expression is regulated by specific cell-cell interactions with mural cells depending on vascular beds. Since EC and pericytes (PL) are closely associated in capillaries, we have enzymatically isolated these cells from rat hearts to develop a primary culture of capillary cells favoring the re-establishment of cell interactions in vitro. Expression of transcripts for both eNOS and the inducible isoform (iNOS), was evaluated by using reverse transcription, polymerase chain reaction and Southern blot analysis. Expression of NOS proteins was detected with specific rhodamine-labeled antibodies. Production of NO was assessed (i) from nitrite measurements in culture supernatants by the Griess reaction, and (ii) from its antiproliferative action on cardiac fibroblasts (FIB) in non-contacted cocultures (reporter-cell bioassay) compared to that of sodium nitroprusside in homotypic FIB cultures. Fura-2 fluorescence was used to measure agonist-induced changes in cytosolic free calcium levels. In our heterotypic cultures, EC firstly proliferated to form spots of monolayers (i.e. first phase) before to be covered by PL on the following days (i.e. second phase). The data from RT-PCR analysis demonstrate the presence of mRNAs of both eNOS and iNOS at all developmental stages of the culture. However, eNOS protein was only detected and restricted to EC. During the first phase of cell growth (5-8 days), cells released nitrite and a labile factor, clearly identified as NO, that inhibited the FIB proliferation in reporter-cell bioassay. These effects, not observed during the second phase of cell growth (15-20 days), were prevented by hemoglobin (50 microM) and by N omega-nitro-L-arginine methyl ester (L-NAME; 100 microM). At the two periods of culture, EC increased rapidly their cytosolic Ca(2+) concentration in response to bradykinin (10 nM). However, this calcium response was associated with an increase in nitrite production only in older cultures. Our data indicate that heterotypic cultures of native capillary cells preserve the eNOS expression by EC. This enzyme is basally active at an early stage of in vitro development, and then becomes activatable by a Ca(2+)-mobilizing agonist. NO released by growing EC downregulates the proliferation of cardiac FIB, an effect which could be important in the cardiovascular plasticity.

Animal models of cardiovascular disease for pharmacologic drug development and testing: appropriateness of comparison to the human disease state and pharmacotherapeutics.

For proper drug development, targeting and testing the use of suitable animal models that are well controlled with regard to duration, degree, and stage of the disease are vitally needed. Furthermore reliable phenotyping and genotyping with regard to functional physiology as well as cellular biochemistry and molecular biology are vital to early decision making in drug discovery, development, and successful clinical development. The use of animal models allows the design of clinical trials without the complication of having to impose "accepted treatment modalities" on top of investigative agents. With the availability of human myocardium for study as a result of cardiac transplantation programs, experimental findings previously reported in several animal models of heart disease have been questioned with regard to suitability for comparison to the human condition. With the development and application of sophisticated techniques and biochemical assays to the study of heart tissue several adaptive changes have been identified and labeled "markers of heart failure." Several animal models share some of these adaptive changes in common with failing human myocardium, but not others. The goal of this report is to point out similarities and differences reported to date in failing and nonfailing human myocardium to that reported in animal models of human heart disease. This discussion indicates important dissimilarities found in several key animal models that have resulted in the development of cardioactive agents and therapeutic interventions for the treatment of human heart disease and the unexpected outcomes. Although focusing on heart failure, a vital goal of this report is to emphasize some key principles supporting the need for clear, comprehensive, and unbiased evaluation of animal models currently in use to study any disease condition, as well as the need for further model development and study in open collaborative efforts.

The effect of insulin-like growth factor-1 on adult rat cardiac contractility.

There is increasing evidence that insulin-like growth factor-1 (IGF-1) may play a role in both physiological and pathophysiological events in the mammalian myocardium. The present study investigated the acute effects of IGF-1 on isometric force development in isolated rat cardiac muscle and on intracellular calcium (Ca2+) handling in isolated cardiac myocytes. IGF-1 had a positive inotropic effect on rat ventricular papillary muscles increasing force development by 17.8 +/- 4.6%, 18.5 +/- 5.8% and 11.9 +/- 4.9% (n = 12-20) at concentrations of 1, 10 and 100 ng/ml respectively. Isoprenaline increased tension in these papillary muscles by 56.7 +/- 7.7% at a concentration of 100 nM (n = 22). In comparison, insulin increased papillary muscle force development by 11.6 +/- 3.2%, 17.7 +/- 4.1% and 19.7 +/- 5.6% at concentrations of 1, 10 and 100 nM respectively (n = 16-20). In the single cardiac myocyte IGF-1 increased, the peak cytosolic free Ca2+ concentration, the amplitude of the Ca2+ transient and the time to peak Ca2+ as measured with the fluorescent bioprobe Indo-1 AM. The positive inotropic response to IGF-1 by rat ventricular muscle is therefore associated with a rise in free, peak cytosolic Ca2+ in isolated cardiac myocytes. Increasing insulin concentrations (1-1000 nM) elicited a progressive elevation in isometric force and free, cytosolic Ca2+. In contrast, in the presence of IGF-1, the maximal rise in isometric force and free cytosolic Ca2+ were both observed at 10 ng/ml. Recent reports have suggested that IGF-1 may act on the mammalian myocardium when administered chronically, but this study is amongst the first to demonstrate an acute effect of IGF-I on the mammalian heart. IGF-1 may prove then to be a novel cardioactive agent in both normal and pathophysiological states.