cardiovascular-agents and falipamil

Several clinical studies demonstrate the importance of the heart rate for the cardiovascular morbidity and mortality. Over the last 50 years, some thought has been given to those substances that selectively reduce the heart rate. It is now recognized that I(f) ion channels of the sinus node play a major role in the automatism and modulation of the heart rate. Substances that selectively reduce the heart rate should decrease myocardial oxygen consumption and increase oxygen delivery via the prolonged diastolic coronary perfusion. Direct inotropic effects, however, are unlikely. In principle, anti-anginal and anti-ischemic effects of specific bradycardic substances can be expected. The clinical experience with some of the former bradycardic substances has not been sufficiently convincing. The more recent ivabradine (Procoralan presents an exception to this, as it successfully completed a clinical program for the treatment of chronically stable angina pectoris. In this review article, specific bradycardic substances (= I(f) channel inhibitors) are presented together with the corresponding experimental and clinical studies. The studies were selected against the background of the efficacy of I(f) channel inhibitors in the therapy of cardiovascular disease. As only ivabradine has completed a study on 5,000 patients, the discussion on that particular I(f) channel inhibitor is somewhat extensive. In addition, prospective possibilities and limitations of bradycardic substances are presented.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzazepines; Cardiotonic Agents; Cardiovascular Agents; Clonidine; Coronary Artery Disease; Humans; Isoindoles; Ivabradine; Phthalimides; Practice Guidelines as Topic; Practice Patterns, Physicians'

Falipamil (AQ-A 39) is a new verapamil derivative which exerts antitachycardic effects by a direct action on the sinus node. Its effects on heart rate (HR), blood pressure (BP) and ECG intervals were studied in 12 healthy volunteers, at rest and during bicycle exercise tests. In a double-blind, cross-over, single-dose study, the effects of falipamil (100 and 200 mg) during 8-h post-dosing were compared with those of placebo. Falipamil did not modify resting HR, BP, and electrocardiogram (ECG) intervals significantly. Maximal exercise HR significantly decreased by 5.3 +/- 2.9 (SD)% and 11.2 +/- 3.6% 2 h after the 100- and 200-mg dose respectively, whereas placebo had no effect. Exercise BP was not significantly modified by falipamil. The slopes of HR-workload relationships significantly decreased with falipamil. Peak plasma concentrations of falipamil occurred 1-1.5 h after absorption, and the falipamil-induced decrease in exercise HR over 8 h postdosing was proportional to falipamil plasma concentrations. These results suggest that falipamil decreases HR at exercise in normal subjects and may exert antianginal effects in patients with myocardial ischemia.

Topics: Adult; Blood Pressure; Cardiovascular Agents; Double-Blind Method; Exercise; Heart Rate; Humans; Isoindoles; Male; Phthalimides

Ten healthy male volunteers performed maximal exercise tests on a bicycle ergometer. A control reading was obtained; at a second session propranolol 80 mg was given, and then placebo, 100 mg or 200 mg AQ-A 39 were administered in a randomised double-blind manner. At peak exercise, the heart rate averaged 191.6 beats/min during the control test, 185.8 beats/min after placebo, 172.4 beats/min with 100 mg of AQ-A 39 (-10%), 166.0 (beats/min) with 200 mg of AQ-A 39 (-13.4%); with 80 mg of propranolol, the heart rate averaged 132.8 beats/min and the workload accomplished was substantially lower than that accomplished with AQ-A 39 and placebo which remained the same as in the control test. No effect on blood pressure was observed. The rate pressure product was significantly reduced with AQ-A 39.

Topics: Adult; Blood Pressure; Cardiovascular Agents; Cardiovascular System; Heart Rate; Humans; Isoindoles; Male; Phthalimides; Physical Exertion; Propranolol

We studied the cardiac electrophysiological effects of falipamil, a specific bradycardic agent, in conscious dogs, in comparison with those of alinidine. Sinus rate, corrected sinus recovery time, and Wenckebach point were measured in six intact dogs. Atrial rate, ventricular rate, and atrial effective refractory period were measured in six atrioventricular-blocked dogs. In both groups, blood pressure was also monitored. Each dog received, with at least a three-day interval, falipamil (hydrochloride) and alinidine (hydrobromide) in four successive intravenous injections, 30 min apart, at 0.5, 0.5, 1, and 2 mg kg-1. Falipamil increased sinus rate and atrial rate, but decreased ventricular rate, whereas alinidine decreased sinus rate and ventricular rate, but increased atrial rate. Falipamil shortened corrected sinus recovery time and increased Wenckebach point, whereas alinidine lengthened corrected sinus recovery time and decreased Wenckebach point. Falipamil and alinidine increased atrial effective refractory period. Neither falipamil nor alinidine modified mean blood pressure in either group. Overall, these results show that (a) falipamil exhibits effects on the electrical activity of the heart, reflecting the predominant direct vagolytic effect of this drug, (b) alinidine exhibits effects reflecting the marked antiarrhythmic potential of this agent, and (c) thus indicate that two drugs with almost identical specific bradycardic properties can produce quite different electrophysiological effects in the conscious dog.

Topics: Animals; Atrioventricular Node; Blood Pressure; Bundle of His; Cardiovascular Agents; Clonidine; Dogs; Electroencephalography; Electrophysiology; Female; Heart; Heart Rate; Isoindoles; Male; Phthalimides; Sinoatrial Node

The chronotropic cardiac effects of falipamil were studied in conscious dogs with chronic atrioventricular (AV) block. Falipamil (0.5-2 mg/kg) initially increased atrial rate dose dependently. After atropine and atropine-pindolol, falipamil (2 mg/kg) decreased atrial rate, but after pindolol, it did not modify atrial rate. After atropine-pindolol-phenoxybenzamine, atropine-pindolol-yohimbine, atropine-pindolol-verapamil, and atropine-pindolol-quinidine pretreatment, falipamil produced atrial bradycardia. Falipamil dose-relatedly decreased ventricular rate. Falipamil (2 mg/kg) decreased ventricular rate after atropine, pindolol, and atropine-pindolol more than under basal conditions. After the other four pretreatments, it also produced ventricular bradycardia. Falipamil did not affect mean blood pressure (MBP) at any dose. These results (a) show that the initial atrial cardio-acceleration produced by falipamil results from its direct vagolytic action; (b) show that absence of atrial bradycardia results from buffering by the vagolytic effect and/or a relatively low basal atrial rate; (c) suggest that the falipamil ventricular bradycardia is partly buffered by the vagolytic effect, norepinephrine (NE) release, and involvement of alpha 2-adrenoceptors; (d) exclude involvement of postsynaptic muscarinic, alpha- and beta-adrenoceptors, and of the slow calcium current in the mechanism(s) by which falipamil decreases cardiac automaticity; and (e) suggest possible involvement of a quinidine-sensitive current in this (these) mechanism(s).

Topics: Animals; Atropine; Autonomic Nervous System; Blood Pressure; Cardiovascular Agents; Dogs; Female; Heart Rate; Ion Channels; Isoindoles; Male; Phthalimides; Pindolol; Quinidine; Receptors, Adrenergic, beta; Receptors, Muscarinic; Stimulation, Chemical; Verapamil

Membrane currents were measured in single sino-atrial node cells of guinea pig and rabbit hearts as well as in guinea pig ventricular myocytes using the patch-clamp technique. UL-FS 49 blocked the L-type calcium current (ICa) in sino-atrial node cells at drug concentrations which had little or no effect on the amplitude of the hyperpolarization-activated current ih(f). In guinea pig ventricular myocytes UL-FS 49 also blocked ICa but not as strongly as in sino-atrial node cells. In a computer simulation of the sino-atrial node action potential the extent of rate reduction by block of either ih(f) or ICa was estimated. From the data obtained by single cell measurements and the computations we concluded that rate reduction in primary pacemaker cells by application of UL-FS 49 is mainly due to a use dependent block of the L-type calcium current. Voltage dependent unblock of iCa at potentials more negative than -50 mV together with the lower drug sensitivity of ventricular cells can explain the "specific bradycardic action" of UL-FS 49.

Topics: Action Potentials; Animals; Benzazepines; Cardiovascular Agents; Electric Stimulation; Electrophysiology; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Ion Channels; Isoindoles; Myocardial Contraction; Myocardium; Phthalimides; Rabbits; Sinoatrial Node; Verapamil

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.

Topics: Animals; Anti-Arrhythmia Agents; Benzazepines; Calcium Channel Blockers; Cardiovascular Agents; Chemical Phenomena; Chemistry; Coronary Disease; Guinea Pigs; Heart Rate; Isoindoles; Molecular Conformation; Muscle, Smooth, Vascular; Myocardial Contraction; Nifedipine; Phthalimides; Rabbits; Rats; Structure-Activity Relationship; Verapamil

Tachycardia caused by surgical stimulation can compromise the myocardial oxygen balance and may also lead to a reduction of cardiac output. Conventional drugs with negative chronotropic effects also cause reduction of inotropy. Recent so-called specific bradytropic agents are expected to act merely upon chronotropy without affecting pressure of the systemic or coronary circulation. The goal of this study was to investigate the effects of a calcium channel blocker. Falipamil, on the circulation controlling excessive intraoperative tachycardia. PATIENTS AND METHODS. In this study 15 patients, aged 32 to 73 years, mean 55 +/- 12 were investigated. The cardiac risk classes included classification I-III, according to Goldman. The patients underwent major abdominal or thoracoabdominal operations. Monitoring consisted of a radial arterial cannula, as well as a 7 French Swan-Ganz catheter, which was introduced via the internal jugular vein. Determination of cardiac output was done using the thermodilution technique with a Kimray Medical Association Oklahoma City model 3500; related indexes were calculated. Electrophysiological data were read from the ECG. The recorded QT interval was corrected for heart rate according to the formula of Hegglin and Holzmann. Anesthesia consisted of premedication with diazepam, 0.1 mg/kg, 1 h preoperatively. Anesthesia was induced with thiopentone, 5 mg/kg, and fentanyl, 1.5 micrograms/kg. After giving 1 mg alcuronium, succinylcholine, 1 mg/kg, was used for intubation. Anesthesia was continued using ventilation with O2: N2O 1:2 and intermittent doses of fentanyl and alcuronium. When tachycardia occurred at a rate higher than 100 beats per minute, a dose of 2 micrograms/kg fentanyl was administered to deepen the anesthesia. If this had no influence, control readings were taken and subsequently falipamil 2 mg/kg was injected. After that the hemodynamic parameters were monitored for 1, 2, 3, 5, 10, and 20 min. Statistical analysis was performed using the analyses of variance, followed by the Newman-Keuls test. The level of significance was p less than 0.05. RESULTS. The means and standard deviations of the hemodynamic parameters following induction of anesthesia (0) and at the peak rate are shown in Table 1. The mean increase in heart rate at that time was 38 +/- 18% and the QT and RR interval were reduced concomitantly. Both times the QT measured and the QT corrected for rate did not significantly differ from each other. (ABSTRACT TR

Topics: Adult; Aged; Anti-Arrhythmia Agents; Calcium Channel Blockers; Cardiovascular Agents; Female; Hemodynamics; Humans; Intraoperative Complications; Isoindoles; Male; Middle Aged; Phthalimides; Tachycardia

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 100 mg (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 48 h. The parent drug, falipamil (1), and its N-desmethyl-metabolite (2), which is approximately 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 2 min 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 (beta-phase) of 1 from plasma was 1.8 +/- 0.6 h (range 1.4-2.9 h), mean residence time was 2.4 +/- 0.4 h, total body clearance was 1108.5 +/- 119 mL/min, and renal clearance was 117 +/- 20 mL/min. All parameters demonstrated very low intersubject variability.

Topics: Adult; Cardiovascular Agents; Humans; Injections, Intravenous; Isoindoles; Male; Phthalimides

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.

Topics: Animals; Binding, Competitive; Cardiovascular Agents; Clonidine; Guanosine Triphosphate; Guinea Pigs; In Vitro Techniques; Isoindoles; Myocardium; Phthalimides; Quinuclidines; Quinuclidinyl Benzilate; Radioligand Assay; Rats; Receptors, Muscarinic

The cardiovascular effects of a specific bradycardic agent, AQ-A 39, were investigated in intact donor dogs and isolated and cross-perfused dog heart preparations. Intravenous administration of AQ-A 39 (10-1000 micrograms/kg) to the donor dog caused a dose-dependent heart rate decrease in the donor dog and a decreased atrial rate in the isolated atrium perfused by the donor's blood. The arterial blood pressure of the donor dog and contractile force of the atrial preparation were unchanged or slightly decreased. The direct injection of AQ-A (1-300 micrograms) into the sinus node artery of the isolated atrium caused dose-dependent negative chronotropic and slight, transient positive inotropic responses. Alinidine and verapamil caused marked negative chronotropic and inotropic responses. The negative chronotropic effect of AQ-A 39 was not modified by atropine. However, it was enhanced slightly but significantly by propranolol, indicating that AQ-A 39-induced bradycardia was antagonized partly by beta-adrenoceptor function. These results confirmed that AQ-A 39 selectively reduced sinus rate by a direct action on the sinus node. Furthermore, the potency of the bradycardiac action, compared with the decrease in contractility, was greater than for alinidine or verapamil. AQ-A 39 (300 micrograms) tended to depress norepinephrine (NE)-induced positive chronotropic but not inotropic effects in isolated atria. By contrast, verapamil (3-10 micrograms) significantly depressed the NE-induced positive inotropic but not the chronotropic effect, and propranolol (10 micrograms) suppressed both cardiac effects of NE. These data suggest that the AQ-A 39-induced, selective attenuation of the NE-induced chronotropic effect is not due to either calcium channel blockade or beta-adrenoceptor antagonism.

Topics: Animals; Cardiovascular Agents; Clonidine; Dogs; Dose-Response Relationship, Drug; Heart; Heart Atria; Heart Rate; Isoindoles; Myocardial Contraction; Phthalimides; Verapamil

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

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.

Topics: Animals; Cardiovascular Agents; Female; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Isoindoles; Isoproterenol; Male; Myocardial Contraction; Phthalimides; Receptors, Adrenergic, beta; Verapamil

AQA39 is a new cardioactive agent with, at low dosages, a minute positive inotropic action on ventricular myocardial tissue probably mediated through the calcium sequestering membraneous systems. At higher concentrations AQA39 depressed myocardial performance probably due to inhibition of the slow calcium channels.

Topics: Animals; Calcium Channel Blockers; Cardiovascular Agents; Cats; In Vitro Techniques; Isoindoles; Myelin Sheath; Myocardial Contraction; Myocardium; Papillary Muscles; Phthalimides

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%, EC30 = 0.030 microgram/ml) than it decreased the contractility (2.5 Hz; EC30 = 108 micrograms/ml) and maximal driving frequency (EC30 = 11 micrograms/ml) in electrically driven atria. In comparable experiments AQ-A 39 was much less effective, the EC30 for the negative chronotropic effect being 0.61 microgram/ml. In rabbit aortic strips in the presence of 43 mM K+ and 1.8 mM Ca2+, UL-FS 49 relaxed contraction by 30% at 15 micrograms/ml. In contrast to UL-FS 49, several "Ca2+-antagonists" elicited aortic relaxation at lower concentrations than 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 (CA10) was achieved with 11.3 micrograms/ml and the CA10 for AQ-A 39 was 1.7 micrograms/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 rate 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 preparations 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.

Topics: Animals; Aorta, Thoracic; Benzazepines; Blood Pressure; Cardiovascular Agents; Cats; Dogs; Electric Stimulation; Electrocardiography; Female; Guinea Pigs; Heart Rate; Hemodynamics; In Vitro Techniques; Isoindoles; Male; Muscle, Smooth, Vascular; Myocardial Contraction; Parasympatholytics; Phthalimides; Potassium; Rabbits

The cardiac and coronary vasodilator actions of AQ-A 39 were investigated in various isolated, blood-perfused dog-heart preparations. AQ-A 39 was injected i.a. In sinoatrial (SA) node preparations, AQ-A 39 (3 micrograms-3 mg) decreased sinus rate but rarely produced atrial standstill even in large doses (1-3 mg). In paced atrioventricular (AV) node preparations, AQ-A 39 injected into the posterior septal artery (which supplies the AV node) increased AV conduction time (i.e., AV nodal conduction time) in rather large doses (100 micrograms-1 mg), but produced neither second-nor third-degree AV block even with the largest dose examined (1 mg). In the same preparations, AQ-A 39 injected into the anterior septal artery (which supplies the His-Purkinje-ventricular system) prolonged AV conduction time (i.e., intraventricular conduction time) in rather large doses (0.3-1 mg). In paced papillary muscle preparations, AQ-A 39 reduced force of contraction only in large doses (1-3 mg). In spontaneously beating papillary muscle preparations, AQ-A 39 (10 micrograms-3 mg) decreased rate of automaticity and force of contraction only with large doses (1-3 mg). In all preparations, AQ-A 39 (30 micrograms-3 mg) increased blood flow. The order of effectiveness of AQ-A 39 on the above cardiovascular variables is as follows: ventricular automaticity not equal to SA nodal automaticity much greater than AV nodal conduction not equal to intraventricular conduction not equal to coronary blood flow not equal to ventricular muscle contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cardiovascular Agents; Coronary Circulation; Dogs; Heart; Heart Conduction System; Heart Rate; In Vitro Techniques; Isoindoles; Male; Myocardial Contraction; Papillary Muscles; Perfusion; Phthalimides; Vasodilation

5,6-Dimethoxy-2-((3[(alpha-(3,4-dimethoxy) phenylethyl)-methylamino]propyl))-phthalimidine hydrochloride (AQ-A 39 Cl, in the following briefly called AQ-A 39) is a new compound with a structure similar to that of verapamil and which exhibits a specific bradycardic effect by a direct action on the sinus node. In nine anesthetized pigs the compound produced a dose-dependent decrease in heart rate up to 35%. For concentrations less than 1500 ng . ml-1, the drug exerted only minor effects on myocardial contractility (less than 5%), but for concentrations greater than 2000 ng . ml-1 negative inotropic properties became apparent and cardiac output decreased up to 25%, in spite of an increase in stroke volume. Left ventricular filling pressure and systemic vascular resistance were not affected. Myocardial O2-consumption also decreased dose-dependently up to 35%. The reduction in heart rate was not the only factor in determining the magnitude of this decrease as substantial decreases (25-30%) were also observed when, during drug administration, the heart rates were raised to 120 and 150 beats . min-1, respectively by means of coronary sinus pacing. The decrease in myocardial O2-consumption was reflected by decreases in both coronary blood flow and myocardial O2-extraction, while coronary vascular resistance did not change. The cardiovascular profile of AQ-A 39 indicated that, especially for arterial plasma concentrations lower than 1500 ng . ml-1, the drug may be useful in the treatment of tachycardias and in lowering myocardial O2-demand, without adverse effects on cardiovascular performance.

Topics: Anesthesia; Animals; Cardiovascular Agents; Coronary Circulation; Depression, Chemical; Electrocardiography; Heart Rate; Hemodynamics; Isoindoles; Phthalimides; Pulmonary Circulation; Swine

The effects of two drugs that apparently block slow inward current--nifedipine and the new compound AQ-A 39--were studied on the isolated sinoatrial (SA) and atrioventricular (AV) nodes of the rabbit heart using intracellular microelectrodes. Nifedipine and AQ-A 39 both slowed the sinus rate associated with a decrease in the rate of diastolic depolarisation. Conduction through the AV node was consistently impaired; this effect was enhanced with increasing atrial rates or with decreasing coupling intervals of premature beats. The action potential amplitude was significantly reduced in SA nodal and upper (AN) AV nodal fibres but was not significantly affected in lower (NH) AV nodal and in atrial fibres. The maximum diastolic potential showed little or no alteration. In all fibre types studied, the action potential duration was shortened with nifedipine but was significantly prolonged with AQ-A 39. Prevention of AV nodal reentrant tachycardia by nifedipine was related to an increase in the effective refractory period of the AV node. AQ-A 39 prevented the tachycardia by both slowing of AV nodal conduction and by prolongation of action potential duration in the AV nodal and atrial compartments of the reentrant circuit associated with the appearance of different gap phenomena of the AV conduction. The maximum possible A-H interval was, however, not shortened by either drug and single atrial echo beats could still be initiated. The results suggest that nifedipine and AQ-A 39 both have a direct depressant action on the slow inward current-dependent electrical activity of the SA and AV node but have opposite effects on the repolarisation phase resulting in different antiarrhythmic mechanisms.

Topics: Action Potentials; Animals; Atrioventricular Node; Cardiovascular Agents; Heart Conduction System; Isoindoles; Nifedipine; Phthalimides; Pyridines; Rabbits; Sinoatrial Node; Tachycardia

Topics: Action Potentials; Animals; Calcium; Cardiovascular Agents; Cats; Dose-Response Relationship, Drug; Gallopamil; Heart; In Vitro Techniques; Ion Channels; Isoindoles; Phthalimides; Verapamil

An isolated perfused hearts as well as in papillary muscles and in Purkinje fibres, the influence of 5,6-dimethoxy-2(3[alpha-(3,4-dimethoxy)phenylethyl)-methylamino]propyl)phthalimidine hydrochloride (AQ-A 39) on the electrical activity was examined (concentration range of AQ-A 39 2.15--10.7 x 10-(5) mol/l). In the isolated heart AQ-A 39 (2.15 x 10(-5) mol/l) reduced the sinus frequency by about 50%. Higher concentrations (up to 10.7 x 10(-5) mol/l) exerted only little additional influence. Similar effects of AQ-A 39 were observed in Ba2+ induced pacemakers in the ventricular myocardium. In Purkinje fibres (K+e 2.7 x 10(-3) mol/l) AQ-A 39 (2.15 x 10(-5) mol/l) reduced the rate of spontaneous discharge to a considerable extent. In papillary muscles as well as in Purkinje fibres the terminal phase of repolarization of the action potential was markedly prolonged without a detectable influence on the resting potential or the maximal rate of rise (Vmax). In the Ba2+ treated depolarized myocardium Vmax was considerably reduced by AQ-A 39. The effects of AQ-A 39 are discussed in view of their ionic mechanisms as well as of the therapeutic application of the drug.

Topics: Action Potentials; Animals; Barium; Cardiovascular Agents; Electric Stimulation; Electrophysiology; Guinea Pigs; Heart; In Vitro Techniques; Isoindoles; Membrane Potentials; Papillary Muscles; Phthalimides; Purkinje Fibers

1. v. administration of 5,6-dimethoxy-2-(3-[(alpha-(3,4-dimethoxy) phenylethyl) methylamino] propyl)- phthalimidine (AQ-A 39) to anaesthetized animals induced dose dependents bradycardia. A comparison of the cardiovascular actions of AQ-A 39 to those of the chemically related Ca2+-antagonist verapamil in anaesthetized cats revealed that AQ-A 39 reduced heart rate more that arterial blood pressure of left ventricular dpldtmax, whereas verapamil was more active in decreasing blood pressure and myocardial contractility that in reducing heart rate. The corresponding ED20% (mg/kg i.v.) for AQ-A 39 were 0.5 (heart rate), 2.9 (mean arterial blood pressure) and 1.8 (dp/dt max). The respective ED20% for verapamil were 1.2, 0.06 and 0.08 mg/kg i.v. Decrease in dp/dt max following injection of AQ-A 39 but not of verapamil could be abolished or diminished by cardiac pacing. So the inotropic effect following i.v. administration of AQ-A 39 were mainly due to interval-strength relationship. Cardiac output was much less decreased than heart rate since there was a significant increase in stroke volume in both anaesthetized cats and dogs. Peripheral resistance was not significantly influenced by systemic administration of AQ-A 39. In anaesthetized dogs AQ-A 39 (0.5 and 2.0 mg/kg i.v.) reduced myocardial oxygen consumption without impairing cardiac work output (i.e., mean aortic pressure X cardiac output). AQ-A 39 induces cardiovascular actions which might be of benefit in the treatment of ischaemic heart disease.

Topics: Animals; Cardiovascular Agents; Cats; Coronary Circulation; Dogs; Female; Guinea Pigs; Heart Rate; Hemodynamics; Isoindoles; Male; Mice; Myocardial Contraction; Myocardium; Oxygen Consumption; Phthalimides; Rabbits; Rats; Species Specificity; Verapamil

In isolated guinea-pig atria AQ-A 39 (5,6-dimethoxy-2[3[[alpha-(3,4-dimethoxy)-phenylethyl]methylamino]propyl]phtalimidine) decreased the rate of spontaneously beating preparations, the contraction amplitude and maximal driving frequency of electrically driven preparations. However, the concentrations which reduced the parameters by 30% were different: 1.4 microgram/ml, 110 microgram/ml and 19 microgram/ml respectively. The bradycardic action was not affected by atropine (0.05 microgram/ml). In the ECG of anaesthetized cats (0.1-10 mg/kg i.v.) the prominent effect of AQ-A 39 was the increase in heart period (PP') and QT in contrast to the chemically related verapamil which mainly increased PQ. Blood pressure and ejection time were slightly affected whereas the diastolic period was markedly prolonged (5 mg/kg i.v.). The 'triple product' of heart rate X ejection time X blood pressure was decreased by AQ-A 39. In cats with acute occlusion of a coronary artery branch, AQ-A 39 diminished the elevation of the ST-segment of the epicardial electrogram. AQ-A 39 decreased the heart rate in conscious dogs (5 mg/kg i.v.), provided the initial heart rate was higher than approximately 130 beats/min, but increased the heart rate when the initial rates were lower. The drug revealed an anticholinergic effect by antagonising the bradycardic action of carbachol on isolated atria from guinea pigs. The prevalent effect on heart rate differentiated AQ-A 39 from other drugs with direct action on the heart such as antiarrhythmics, the so-called 'calcium antagonists' and cholinergic drugs. The profile resembled that of alinidine (St 567) and indicated a decrease in myocardial oxygen demand.

Topics: Animals; Blood Pressure; Cardiovascular Agents; Cats; Coronary Vessels; Dogs; Electrocardiography; Female; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Isoindoles; Male; Myocardial Contraction; Myocardium; Oxygen Consumption; Parasympathetic Nervous System; Phthalimides