Specific Bradycardic Agent Research Articles

Specific bradycardic agents. 1. Chemistry, pharmacology, and structure-activity relationships of substituted benzazepinones, a new class of compounds exerting antiischemic properties

Structural modification of the calcium-antagonist verapamil (1) by replacement of the lipophilic alpha-isopropylacetonitrile moiety by various heterocyclic ring systems has led to a new class of cardiovascular compounds which are characterized by a specific bradycardic activity. These agents reduce heart rate without binding to classical calcium channels or beta-adrenoceptors, interacting instead specifically with structures at the sino atrial node. Therefore they have also been termed sinus node inhibitors. The prototype falipamil (2) has been submitted to further optimization mainly by manipulation of the phthalmidine moiety. This has resulted in a second generation of specific bradycardic agents with increased potency and selectively and prolonged duration of action represented by the benzazepinone-derivative UL-FS 49 (4). Structure-activity relationships within this novel class of compounds have revealed a marked dependence of activity on the substitution pattern of the aromatic rings, the nature of the central nitrogen atom, and the length of the connecting alkyl chains. The crucial role of the benzazepinone ring for bradycardic activity can be best explained by its special impact on the overall molecular conformation.

Pharmacokinetics of Falipamil after Intravenous Administration to Humans

Falipamil (2-[3-[3-(3, 4-dimethoxyphenetylmethylamino]propyl]-5, 6-dimethoxyphthalamidine; 1) is a new specific bradycardic agent for the treatment of sinus tachycardia. Pharmacokinetics of falipamil in humans) (n = 6) was determined in plasma and urine after iv administration of 100mg (1.85 MBq) per person of 14C-labeled drug by liquid scintillation counting and by a specific, sensitive reversed-phase totally automated HPLC system with fluorimetric detection. Recovery of total radioactivity was 91.8 ± 3.7%, with 68.2 ± 4.3% in urine and 23.6 ± 2.5% in the feces. The majority of radioactivity was excreted within 24 to 48h. The parent drug, falipamil (1), and its N-desmethyl-metabolite (2), which is ∼100 times less active than 1, contributed 14.1 ± 1.6 and 4.5 ± 0.7%, respectively, of the dose to urinary excretion. Plasma protein binding of 1 and 2 was 87.9 ± 1.2 (concentration range: 2000–8000 ng/mL) and 89.7 ± 0.5% (concentration range: 62.5–1000 ng/mL), respectively. Plasma concentrations of 1 peaked at 2min at 724 ± 173 ng/mL, declined biphasically, and were fitted to a two-compartment open model. Plasma concentrations of 2 were very low, in all cases ranging from 0 to 35 ng/mL. The dominant terminal half-life (β-phase) of 1 from plasma was 1.8 ± 0.6h (range 1.4–2.9 h), mean residence time was 2.4 ± 0.4 h, total body clearance was 1108.5 ± 119mL/min, and renal clearance was 117 ± 20mL/min. All parameters demonstrated very low intersubject variability.

Alinidine Reduces the Incidence of Ischemic Ventricular Fibrillation in a Conscious Canine Model, a Protective Effect Antagonized by Overdrive Atrial Pacing

The antiarrhythmic and antifibrillatory effects of the specific bradycardic agent alinidine were evaluated in a conscious canine model of myocardial infarction and sudden death, and by determination of ventricular fibrillation thresholds (VFT) in anesthetized dogs. Programmed electrical stimulation (PES) was performed in conscious animals, 3-5 days after a 2-h occlusion/reperfusion of the left anterior descending coronary artery (LAD). Dogs in which PES resulted in a reproducible nonsustained or sustained ventricular tachycardia (VT) were randomized to receive either intravenous alinidine (1 mg/kg, n = 11) or intravenous vehicle (n = 10). Programmed electrical stimulation and measurement of electrophysiologic parameters were repeated after 30 min, and the animals were entered into the sudden death protocol by introducing a 150 microA anodal current to the lumen of the left circumflex coronary artery (LCX) via a surgically implanted silver wire electrode. A second alinidine-treated group (n = 3) had heart rates controlled by atrial pacing during this period. Alinidine failed to prevent the programmed electrical induction of VT in 10 of 11 animals, but significantly reduced both sudden (less than 1 h ischemia) and 24-h mortality as compared to the ventricle group. Infarct sizes were similar in the two groups, but the ischemia-related increase in heart rate was attenuated (p less than 0.05) by alinidine and the onset of ischemia tended to be delayed. All of the atrial-paced animals died acutely. Heart rate decreased after alinidine (p less than 0.01), but apart from a single index of refractoriness, the drug was without electrocardiographic or electrophysiologic effects. Neither alinidine nor vehicle demonstrated any effect upon VFT in two groups of five animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological mechanisms to attenuate sympathetically induced myocardial ischemia

Distal to a coronary stenosis, resting myocardial blood flow and function can be maintained by a compensatory dilation of the poststenotic vascular bed and an increased collateral blood flow from adjacent coronary vessels. Under this condition, electrical stimulation of cardiac sympathetic nerves, as well as their activation during sympathoexcitatory reflexes and exercise, induces a poststenotic alpha 2-adrenoceptor-mediated coronary constriction and a beta-adrenoceptor-mediated, tachycardia-related redistribution of blood flow away from the ischemia myocardium. Thus, activation of cardiac sympathetic nerves can precipitate poststenotic myocardial ischemia. In experimental studies in anesthetized, vagotomized dogs, as well as in conscious, chronically instrumented dogs, selective alpha 2-adrenoceptor antagonists and calcium-channel blockade with nifedipine were able to attenuate the sympathetically induced poststenotic myocardial ischemia. Beta-adrenoceptor blockade with atenolol was only proven beneficial as long as there was a heart-rate reduction. Conversely, a specific bradycardic agent (ULFS-49) also exerted beneficial effects. Myocardial ischemia can activate cardiac sympathetic afferents and then, by a spinal reflex, can in turn activate sympathetic efferents and aggravate the severity of myocardial ischemia. This vicious cycle could be interrupted by segmental epidural anesthesia with procaine as well as by blockade of sympathoexcitation at the central nervous level with clonidine in anesthetized dogs.

Binding of Two Specific Bradycardic Agents, Alinidine and AQ-A 39, to Muscarinic Receptors of Guinea Pig Atria and Ventricle

The mechanism of action of the two "specific bradycardic agents" alinidine and AQ-A 39 (falipamil) is still a matter of controversy. Their binding properties to atrial and ventricular myocardium of the guinea pig and rat were, therefore, investigated by the radioligand binding technique. In competition studies against the nonselective antagonists [125I]3-quinuclidinyl 4-iodobenzilate [( 125I]QNB) and 1-N-methyl-[3H]scopolamine methylchloride [( 3H]NMS), both alinidine and AQ-A 39 competitively displaced the radioligands with I50 values (corrected for radioligand concentration) of 1-2 microM (alinidine/[125I]QNB) and 4 microM (alinidine/[3H]NMS), respectively. The I50 values for AQ-A 39 were lower by a factor of two. Slope factors (pseudo Hill coefficients) were 0.7-0.8 (AQ-A 39) and 0.8-0.9 (alinidine), and significantly lower than unity in both atria and ventricle. The guanosine triphosphate (GTP) (100 microM) and 5'-guanylimido-di-phosphate [Gpp(NH)p] (100 microM) slightly creased [3H]QNB binding and produced no or only a small (factor 2-3) rightward shift of alinidine and AQ-A 39 competition curves. At high concentration (1 mM), AQ-A 39 drastically decreased [125I]QNB dissociation rate from both atrial and ventricular receptors (t1/2 control, 19 min; plus AQ-A 39, 75 min) while alinidine (1 mM) decreased dissociation half-life in ventricle with no change in atria. It is concluded that both bradycardic agents possess some but not all characteristics of weak agonists in binding studies, and that they also bind to an allosteric site of the muscarinic receptors. Association with this site could possibly activate a mixed Na+/K+ inward pacemaker current (if) resulting in bradycardia.

Binding of Two Specific Bradycardic Agents, Alinidine and AQ-A 39, to Muscarinic Receptors of Guinea Pig Atria and Ventricle

Summary: The mechanism of action of the two “specific bradycardic agents” alinidine and AQ-A 39 (falipamil) is still a matter of controversy. Their binding properties to atrial and ventricular myocardium of the guinea pig and rat were, therefore, investigated by the radioligand binding technique. In competition studies against the nonselective antagonists [125I]3-quinuclidiny1 4-iodoben-zilate ([125I]QNB) and 1-N-methyl-[3H]scopolamine methylchloride ([3H]NMS), both alinidine and AQ-A 39 competitively displaced the radioligands with I50 values (corrected for radioligand concentration) of 1-2 μM (alinidine/[125I]QNB) and 4 μM (alinidine/[3H]NMS), respectively. The I50 values for AQ-A 39 were lower by a factor of two. Slope factors (pseudo Hill coefficients) were 0.7-0.8 (AQ-A 39) and 0.8-0.9 (alinidine), and significantly lower than unity in both atria and ventricle. The Guanosine triphosphate (GTP) (100 μM) and 5′-guanylimido-di-phosphate [Gpp(NH)p] (100 μM) slightly creased [3H]QNB binding and produced no or only a small (factor 2-3) rightward shift of alinidine and AQ-A 39 competition curves. At high concentration (1 mM), AQ-A 39 drastically decreased [125I]QNB dissociation rate from both atrial and ventricular receptors (t1/2control, 19 min; plus AQ-A 39, 75 min) while alinidine (1 mM) decreased dissociation half-life in ventricle with no change in atria. It is concluded that both bradycardic agents possess some but not all characteristics of weak agonists in binding studies, and that they also bind to an allosteric site of the muscarinic receptors. Association with this site could possibly activate a mixed Na+/K+ inward pacemaker current (if) resulting in bradycardia.

Specific bradycardic agents--a novel pharmacological class?

Data have been reviewed and presented which suggest that substances from two different chemical groups, congeners of alinidine and falipamil, respectively, can be described as representatives of a novel and distinct pharmacological class: specific bradycardic agents (SBAs). They are characterized by a slowing of the sinus rate within physiological limits as the prominent cardiovascular effect. Involvement of alpha-adrenoceptors, beta-adrenoceptors and cholinergic receptors as mediators of the bradycardic effects have been excluded. Experiments in isolated atrial preparations suggested that drugs of the same type as alinidine or as falipamil have a similar mode of rate lowering action which is different from that of Ca-channel blockers: low external Ca2+ increased and low Na+ as well as high K+ decreased the bradycardic effect of SBA; verapamil behaved in the opposite way. Combination of different SBAs did not result in excessive additive rate-lowering effects; in contrast, addition of verapamil to maximally acting concentrations of SBAs resulted in a further significant reduction in rate. SBAs were much more potent in reducing spontaneous sinus rate than in reducing BaCl2 induced automaticity, whereas Ca-channel blockers behaved in the opposite way. Differences in the cardiovascular profile against other drugs with rate lowering effects have been pointed out: beta-adrenoceptor blocking agents more markedly decrease contractility and Ca-channel blocking agents more markedly decrease contractility, slow down AV conduction and have vasorelaxing properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Alinidine as a model of the mode of action of specific bradycardic agents on SA node activity.

Three different bradycardic agents, alinidine, AQ-A39 and UL-FS49 increase the intrinsic cycle length of the isolated SA node preparation of the rabbit. This increase is mainly caused by a decrease in rate of diastolic depolarization. One of these agents, alinidine, was used to study the underlying ionic mechanism of the decrease in the diastolic depolarization rate in isolated cells and small cell clusters of the rabbit SA node. In these preparations alinidine slowed down the rate of spontaneous activity at higher concentrations (80 microM). At lower concentrations (10 microM) the decrease in rate of spontaneous activity was variable, but injection of a hyperpolarizing current slowed the spontaneous rate more in the presence of alinidine, indicating an increase in membrane resistance. In voltage clamp experiments we found that the main effect of alinidine was a block of the hyperpolarization activated current if. The block was potential dependent and was maximal in the potential range in which diastolic depolarization occurs. These results are discussed in relation to previous findings of others.

Antiarrhythmic action of specific bradycardic agents.

Antiarrhythmic action of specific bradycardic agents Get access E. M. Vaughan Williams E. M. Vaughan Williams Hertford College, Oxford UniversityOxford, U.K. Search for other works by this author on: Oxford Academic PubMed Google Scholar European Heart Journal, Volume 8, Issue suppl_L, December 1987, Pages 17–18, https://doi.org/10.1093/eurheartj/8.suppl_L.17 Published: 01 December 1987

Acute haemodynamic effects of a specific bradycardic agent in patients with coronary heart disease and impaired left ventricular function.

Alinidine is a bradycardic agent, which appears to be of potential value in the therapy of coronary heart disease. It might be useful in patients with impaired left ventricular function, where use of other bradycardic agents such as beta-blockers is limited due to their negative inotropy. To assess if alinidine has the potential to worsen haemodynamics in patients with strongly reduced left ventricular function we have examined acute haemodynamic changes after alinidine (0.5 mg kg-1 i.v.) both in a group of patients with mildly and in a group with strongly reduced left ventricular function. A significant reduction of resting heart rate and cardiac index was observed in both groups. All other haemodynamic parameters, especially left ventricular filling pressures (LVEDP, PC) and enddiastolic volume index did not show any significant change; dp/dtmax was not significantly influenced by alkinidine, when the influence of heart rate lowering was eliminated by pacing. We conclude that administration of alinidine in the dosage used does not lead to a significant deterioration even in patients with strongly impaired left ventricular function.

Specific Bradycardic Agents, A New Therapeutic Modality for Anesthesiology

A "specific bradycardic agent" has direct negative chronotropic actions without producing other systemic or coronary hemodynamic alterations. UL-FS 49, a recently synthesized structural analog of verapamil without classical slow channel calcium blocking activity, is proposed as such an agent. The purpose of this investigation was to characterize the hemodynamic and electrocardiographic actions of UL-FS 49 (0.25, 0.50, and 1.0 mg/kg) and compare its effects with those of propranolol (0.25, 0.50, and 1.0 mg/kg) in conscious or isoflurane-anesthetized (with and without neuromuscular blockade by pancuronium) chronically instrumented dogs. In six groups, comprising 52 experiments, UL-FS 49 was found to be more efficacious than propranolol in reducing heart rate, although this agent did not block the hemodynamic response to isoproterenol. UL-FS 49 produced 45-50% reductions in heart rate in dogs with isoflurane-induced tachycardia as compared to 15 and 30% reductions following propranolol. Furthermore, few other hemodynamic alterations were produced by UL-FS 49 indicating the remarkable specificity of this drug for reducing heart rate. A "specific bradycardic agent" such as UL-FS 49 may be useful clinically during the perioperative period. Such a drug may be especially advantageous for patients with documented or suspected ischemic heart disease, those who cannot tolerate the side effects of beta adrenergic blockade, as well as patients requiring a greater reduction in heart rate than can be obtained with beta adrenergic receptor antagonists.

Alinidine modifies the pacemaker current in sheep Purkinje fibers.

(1) The "specific bradycardic agent" alinidine reduces the slope of the diastolic depolarization in sinoatrial tissue and Purkinje fibers. In short Purkinje fibers of sheep, alinidine (28 microM) decreased the pacemaker current by a dual action. The voltage dependence of if activation was shifted in the hyperpolarizing direction by 7.8 +/- 0.6 mV (n = 18, p less than 0.001) and the conductance of the fully activated if current was reduced to 73 +/- 2% (n = 18, p less than 0.001) of its control value. These effects were reversible and dose-dependent. (2) Ionophoretic injections of alinidine caused reversible reductions of the diastolic depolarization rate and simultaneous transient hyperpolarizing shifts of the if activation range. (3) Some prolongation of the action potential duration was observed at 28 microM and more pronounced at higher concentration. This was presumably the consequence of a reduction by alinidine of outward repolarizing current carried by the background inward rectifier and plateau current ix. (4) The action of alinidine on if resulted in a slower activation of a reduced fraction of the pacemaker current at the maximal diastolic potential level. This explains the decrease of the diastolic depolarization rate observed in Purkinje fibers.

Effect of the New Specific Bradycardic Agent AQ-A39 (Falipamil) on Coronary Collateral Blood Flow in Dogs

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.

Investigations differentiating the mechanism of specific bradycardic agents from that of calcium channel blockers.

The effects of two "specific bradycardic agents", falipamil (AQ-A 39) and the alinidine-congener STH 2148 (2-[N-(cyclopropylmethyl)-N-(2,6-dibromophenyl)amino]-2-imidazolin e), on the spontaneous electrical discharge rate of intact guinea-pig sinus node preparations were investigated in comparison to that of the "calcium channel blocker" verapamil. Addition of falipamil (10 micrograms/ml) to a maximally rate lowering concentration of STH 2148 (30 micrograms/ml) exerted no further bradycardic effect. In contrast, verapamil (0.1 microgram/ml) added to either STH 2148 (30 micrograms/ml) or a maximally effective concentration of falipamil (30 micrograms/ml) resulted in a further, significant reduction of sinus rate. The results are compatible with the idea of a common mechanism of the two specific bradycardic agents, different from that of calcium channel blockers.

Effects of a specific bradycardic agent (AQ-A39) and verapamil on beta-adrenergic responses in isolated guinea pig atria.

AQ-A39 (5,6-dimethoxy-2-[3-[(3,4-dimethoxy)phenylethyl)methylamino]propyl)- phthalimidine), a specific bradycardic agent, and verapamil, a calcium channel blocker, were studied for their ability to alter rate and force of contraction in the presence and absence of isoproterenol, a beta-adrenergic stimulant, using isolated guinea pig atria. Both compounds (10(-7)-10(-4) M) produced dose-related decreases in frequency of spontaneously beating right atria. Verapamil decreased, while AQ-A39 increased, the force of contraction of electrically stimulated (1.0 Hz) left atria. At equal negative chronotropic concentrations, AQ-A39 was more effective than verapamil in reducing the maximum isoproterenol-induced tachycardia. Verapamil, but not AQ-A39, antagonized positive inotropic responses to isoproterenol. Therefore, AQ-A39 differed from verapamil in that (i) AQ-A39 was a more selective bradycardic agent in both beta-adrenergically stimulated and nonstimulated preparations and (ii) AQ-A39 was more effective in reducing isoproterenol-elevated heart rate compared with basal heart rate. This profile of activities suggests that AQ-A39 will be beneficial in cardiac pathologies where sympathetic nervous system activity is elevated and a lowering of heart rate without a reduction in cardiac contractility is desired.

AQ-A 39 (falipamil), a new specific bradycardic agent, improves cardiac performance in dogs

AQ-A 39 (falipamil), a new specific bradycardic agent, improves cardiac performance in dogs

Effects of AQ-AH 208, a New Specific Bradycardic Agent, on Myocardial Ischemia–Reperfusion Injury in Anesthetized Dogs

The effects of a new specific bradycardic agent, AQ-AH 208--3,4-dihydro-6,7-dimethoxy-2-[3-( [ 2-(3,4-dimethoxyphenyl)-ethyl]-aminoethyl)-propyl ]-1(2H)isochinolinon--on ischemia-reperfusion-induced myocardial infarct size following a 2-h occlusion and 30-min reperfusion period of the left anterior descending coronary artery (LAD) were determined in anesthetized dogs. Regional myocardial blood flow was measured by use of radioactive microspheres (15 micron), and tissue injury was determined by use of the triphenyltetrazolium chloride histochemical stain. In two groups of dogs, vehicle (saline) or AQ-AH 208 (500-micrograms/kg bolus followed by 25 micrograms/kg/min) was administered intravenously 10 min prior to LAD occlusion and infused throughout the occlusion and reperfusion periods. In a third group, AQ-AH 208 was given 10 min after LAD occlusion and infused throughout the remainder of the experiment. AQ-AH 208 treatment resulted in a significant reduction in heart rate and heart rate-systolic pressure product during occlusion and reperfusion. AQ-AH 208 produced variable increases in collateral blood flow as compared with the saline-treated group 20 min and 2 h following LAD occlusion. These increases in collateral perfusion were primarily to the midmyocardium and subendocardium, as reflected by increases in the endocardial/epicardial blood flow ratio (endo/epi). During reperfusion, subendocardial flow was significantly elevated and subepicardial flow reduced in both AQ-AH 208-treated groups, as compared with control, and the endo/epi was markedly increased. In all three groups, left ventricular weight, area at risk, percent of the left ventricle at risk, and retrograde flow and pressure prior to drug treatment were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular characterisation of UL-FS 49,1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylimino]propyl]-2H-3-benzazepin- 2-on hydrochloride, a new “specific bradycardic agent”

UL-FS 49, a chemical congener of AQ-A 39 with structural similarities to verapamil, decreased the rate of spontaneously beating guinea-pig atria at much lower concentrations (effective concentration 30%, EC 30 = 0.030 μg/ ml) than it decreased the contractility (2.5 Hz; EC 30 = 108 μg/ ml) and maximal driving frequency (EC 30 = 11 μg/ ml) in electrically driven atria. In comparable experiments AQ-A 39 was much less effective, the EC 30 for the UL-FS 49 relaxed contraction by 30% at 15 μg/ml. In contrast to UL-FS 49, several “Ca 2+-antagonists” elicited aortic relaxation at lower concentrations tham bradycardia. In anaesthetized cats (n = 6) 0.3 mg/kg i.v., UL-FS 49 increased the cardiac cycle length by 56±3.5% (S.E.), there were slight or no changes in blood pressure and ECG intervals PQ and QRS . ST and the effective refractory period (ERP), as determined by R-triggered extrastimuli in the right ventricle, were prolonged by 28±3.1% and 24±2.5% respectively. At comparable increases in cycle length AQ-A 39 prolonged ST and ERP significantly more than UL-FS 49. In isolated guinea-pig atria UL-FS 49 antagonized the carbachol-induced bradycardia; a 10-fold shift of the dose-response curve (CA 10) was achieved with 11.3 μg/ml and the CA 10 for AQ-A 39 was 1.7 μg/ml. In conscious dogs UL-FS 49, 1 mg/kg i.v., decreased the heart rate without changes in blood pressure. This was observed in dogs with both genuine sinus rate and heart elevated by either atropine or hydralazine. The bradycardic effect was positively correlated with the control heart rate. In conclusion, sinus bradycardia was the most prominent action of UL-FS 49 in isolated preparation as well as in intact animals. In comparison to its congener AQ-A 39, UL-FS 49 was more potent in lowering heart rate but less effective in prolonging repolarization time and in anticholinergic activity. It thus represents a new specific bradycardic agent.

Comparison of the bradycardic effects of alinidine (St 567), AQ-A 39 and verapamil on guinea-pig sinoatrial node superfused with different Ca 2+ and NaCl solutions

Two new substances, alinidine (St 567) and AQ-A 39, previously described as ‘specific bradycardic agents’ were investigated with respect to their effects on the rate of electrical discharges from sinus nodes of isolated right guinea-pig atria. Both substances decreased the discharge rate concentration dependently within a wide range (3–100 μg/ml). Low external Ca 2+ (0.18 mM) increased and low external NaCl (62 mM) decreased the rate lowering effect of alinidine as well as of AQ-A 39. In contrast, the reference compound verapamil (an inhibitor of slow inward current) was less effective in low Ca 2+ and more effective in low NaCl. The similar reactions of alinidine and AQ-A 39 are discussed with respect to their different chemical structure and different electrophysiological action patterns as described so far.