cardiovascular-agents and zatebradine

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'

Bradycardic agents could limit the consequences of myocardial ischemia via two mechanisms: by decreasing myocardial oxygen demand (MVO2) and by increasing diastolic coronary blood flow (CBF). We investigated whether the benzazepinone UL-FS 49 affects only sinus node cells or also smooth muscle and/or myocardial cells. To avoid confounding interactions with the periphery, we performed experiments on 11 isolated, blood-perfused canine hearts. Injection of UL-FS 49 (1 mg/kg i.c.) significantly reduced heart rate (HR) from 104 +/- 7 to 93 +/- 7 min-1 (mean +/- SEM) and increased stroke volume (n = 6: 9.8 +/- 1.1 vs. 13.2 +/- 1.6 ml), so that cardiac output remained unchanged (n = 6: 1.1 +/- 0.1 vs. 1.2 +/- 0.1 l/min). The contractile state, assessed by isovolumic peak systolic pressure, was unaltered by UL-FS 49 (n = 5: 72 +/- 6 vs. 72 +/- 6 mmHg). At a constant coronary arterial pressure (CAP) of 80 mmHg, mean CBF was slightly decreased (102 +/- 11 vs. 97 +/- 10 ml/[min.100 g]) by UL-FS 49, such that mean coronary resistance remained unchanged (0.9 +/- 0.1 vs 1.0 +/- 0.1 mmHg.min.100 g/ml). The slight decreases in arteriovenous oxygen content difference (n = 6: 6.6 +/- 0.7 vs. 6.5 +/- 0.7 ml/100 ml) and in CBF lead to a calculated, significant decrease in MVO2 (n = 6: 6.9 +/- 0.5 vs. 6.0 +/- 0.4 ml.100 g/min). In conclusion, UL-FS 49 at the dose used decreases MVO2 by reducing HR in isolated canine hearts. In the absence of negative inotropic and vasodilating effects, cardiac output is maintained via increased stroke volume, and CAP will likely be preserved in situ. Thus, this specific bradycardic agent could be useful in treating ischemic myocardial disease.

Topics: Animals; Benzazepines; Cardiovascular Agents; Coronary Circulation; Dogs; Female; Heart; Heart Rate; Hemodynamics; In Vitro Techniques; Infusion Pumps; Male; Oxygen Consumption; Research Design; Ventricular Function

We examined the antianginal and anti-ischemic effects of oral zatebradine, a direct sinus node inhibitor that has no blood pressure-lowering or negative inotropic effects in patients with chronic stable angina pectoris taking extended-release nifedipine.. Heart rate reduction is considered an important pharmacologic mechanism for providing anginal pain relief and anti-ischemic action in patients with chronic stable angina, suggesting a benefit for sinus node-inhibiting drugs.. In a single-blind placebo run-in, randomized double-blind, placebo-controlled, multicenter study, patients already receiving extended-release nifedipine (30 to 90 mg once a day) were randomized to receive zatebradine (5 mg twice a day [n = 64]) or placebo (n = 60). All subjects had reproducible treadmill exercise-induced angina at baseline, and after randomization they performed a serial exercise test 3 h after each dose for 4 weeks.. Zatebradine reduced rest heart rate both at 4 weeks ([mean +/- SEM] 12.9 +/- 1.23 vs. 2.3 +/- 1.6 [placebo] beats/min, p < 0.0001) and at the end of comparable stages of Bruce exercise (16.7 +/- 1.2 vs. 3.4 +/- 1.2 [placebo] beats/min, p < 0.0001). Despite the significant effects on heart rate at rest and exercise, there were no additional benefits of zatebradine from placebo baseline in measurements of total exercise duration, time to 1-mm ST segment depression or time to onset of angina. Subjects taking zatebradine also had more visual disturbances as adverse reactions.. Zatebradine seems to provide no additional antianginal benefit to patients already receiving nifedipine, and it raises questions regarding the benefit of heart rate reduction alone as an antianginal approach to patients with chronic stable angina.

Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Benzazepines; Blood Pressure; Cardiovascular Agents; Chronic Disease; Delayed-Action Preparations; Double-Blind Method; Drug Therapy, Combination; Exercise Test; Female; Heart Rate; Humans; Male; Middle Aged; Nifedipine; Treatment Outcome

Zatebradine, a member of a novel class of drugs called 'sinus node inhibitors', is a specific heart rate lowering drug suitable for the treatment of stable angina pectoris. Animal studies showed that relatively high intravenous doses of zatebradine contracted guinea-pig airways by a histamine-like mechanism. Therefore, the objective of the present study was to assess the bronchopulmonary effects in asthmatic patients who showed a moderate to severe bronchial hyperreactivity towards histamine (PC20 FEV1 < or = 1 mg/ml). Moreover, it had to be established to what extent the bronchial responsiveness to inhaled salbutamol was retained and whether pulmonary effects were related to the severity of bronchial hyperreactivity. By means of a double-blind cross-over design, single oral doses of zatebradine (10 mg) or placebo were administered on two occasions with a washout phase of at least 3 days. Sixteen patients, four female and 12 male, with stable mild to moderate bronchial asthma (FEV1 less than 80% predicted) were selected. Their mean age was 54 years and the mean FEV1 was 1.831 (59% predicted). They showed a mean improvement in FEV1 of 27% 15 min after inhaling 200 micrograms salbutamol; the mean PC20 was 0.35 mg/ml. Following test drug intake, the respiratory and cardiac effects were assessed at regular time intervals up to 6 h after administration. In comparison to placebo, zatebradine induced small, but significant (P < 0.05), mean falls of 128 ml and 168 ml in FEV1 at 3 h and 6 h after drug intake. A large inter-individual variation in response was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Albuterol; Asthma; Benzazepines; Bronchial Hyperreactivity; Cardiovascular Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Forced Expiratory Volume; Histamine; Humans; Lung; Male; Middle Aged; Respiratory Function Tests; Sinoatrial Node

We investigated the effects of hypothermia (25 degrees C) on the chronotropic and inotropic effects of zatebradine (a blocker of hyperpolarization-activated inward current, I(f)), E-4031 (a blocker of the rapid type of the delayed rectifier K+ current, I(Kr)) and verapamil, and on the positive cardiac responses to isoproterenol after treatment with zatebradine and E-4031 in isolated, blood-perfused dog atria. Hypothermia shifted the dose-response curves to the right for the negative chronotropic and inotropic effects of verapamil and for the negative chronotropic and positive inotropic effects of zatebradine, but not for the negative chronotropic and positive inotropic effects of E-4031. Hypothermia attenuated the positive chronotropic response to isoproterenol or Bay k 8644 (an L type Ca2+ channel agonist) and was attenuated more than the inotropic one. Zatebradine selectively inhibited the positive chronotropic response to isoproterenol at a normal temperature, but in hypothermia, it inhibited neither the chronotropic nor inotropic responses. E-4031 did not affect the positive responses to isoproterenol. These results suggest that verapamil and zatebradine but not E-4031 influence the atrial rate and contractile force much less in hypothermia than in normothermia and that the I(f) and inward Ca2+ current are sensitive to hypothermia in the heart.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Benzazepines; Calcium Channel Agonists; Cardiovascular Agents; Cold Temperature; Dogs; Dose-Response Relationship, Drug; Heart Atria; Hypothermia, Induced; In Vitro Techniques; Isoproterenol; Myocardial Contraction; Perfusion; Piperidines; Pyridines; Verapamil

1. Inhibition of I(f) or ICa by zatebradine has been reported in mammalian SA nodal cells. We thus investigated whether zatebradine differentially attenuates the positive chronotropic and inotropic responses to norepinephrine, isoproterenol, NKH 477 (an adenylyl cyclase activator), 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 (a calcium channel agonist) in the isolated, blood-perfused dog atrium. 2. When zatebradine (0.03-1 mumol) decreased sinus rate from 104 +/- 4.5 to 73 +/- 4.9 beats/min dose-dependently, it selectively attenuated the positive chronotropic but not inotropic responses to norepinephrine in a dose-related manner. Zatebradine decreased the norepinephrine-induced tachycardia (by approximately 80% from the control) more effectively than the spontaneous sinus rate (by approximately 30% from the control). 3. Zatebradine similarly attenuated the positive chronotropic but not inotropic responses to isoproterenol, NKH 477 and IBMX. Fifty per cent inhibition doses of zatebradine (0.10-0.18 mumol) for the chronotropic responses to each substance were not significantly different. 4. On the other hand, zatebradine attenuated neither positive chronotropic nor inotropic responses to Bay k 8644. 5. We therefore suggest that zatebradine selectively attenuates the positive chronotropic but not inotropic responses to cyclic AMP-related substances due to inhibition of I(f) but not ICa in the dog heart.

Topics: 1-Methyl-3-isobutylxanthine; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Adrenergic Agonists; Animals; Benzazepines; Cardiovascular Agents; Colforsin; Dogs; Heart Atria; Heart Rate; Myocardial Contraction; Stimulation, Chemical

The effects of zatebradine on rate and contractile force and transmembrane action potentials were studied in isolated guinea pig atria and ventricular papillary muscles. In spontaneously beating right atria, zatebradine, 10(-7)-10(-4) M, produced a negative chronotropic effect (IC50 = 6.5 +/- 3.0 x 10(-6) M) and prolonged the recovery of the sinus function. In addition, it produced a biphasic effect on the atrial contractility, so that at concentrations up to 10(-5) M, it exerted a positive inotropic effect, whereas at higher concentrations, a negative inotropic effect was observed (IC50 = 9.0 +/- 0.3 x 10(-5) M). In electrically driven left atria, zatebradine produced a negative inotropic effect, though no changes were observed in the total contraction time or the time to peak tension. In papillary muscles, zatebradine > or = 5 x 10(-6) M caused a significant decrease in the maximum upstroke velocity (Vmax) without altering the resting membrane potential and exerted biphasic effects on the action potential duration (APD). At concentrations up to 5 x 10(-5) M, it prolonged the APD, whereas at higher concentrations, it shortened the APD. In addition, zatebradine, 10(-4) M, significantly reduced the amplitude and Vmax of the slow action potentials elicited by isoproterenol in K(+)-depolarized papillary fibres. In the presence of zatebradine, trains of stimuli at rates between 0.5 and 3 Hz led to an exponential decline in Vmax (frequency-dependent Vmax block), which was augmented at higher rates of stimulation. The time constant for the recovery of Vmax from the frequency-dependent block was 2.9 s.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Animals; Benzazepines; Cardiovascular Agents; Dose-Response Relationship, Drug; Electrophysiology; Female; Guinea Pigs; Heart Atria; In Vitro Techniques; Male; Membrane Potentials; Myocardial Contraction; Papillary Muscles; Sodium Channels

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

To investigate how to reduce the positive chronotropic response to sympathetic nerve activation selectively without affecting other cardiac actions, we studied the effects of zatebradine, an inhibitor of the hyperpolarization-activated current (I(f)), verapamil and parasympathetic nerve stimulation on the positive chronotropic, dromotropic and inotropic responses to sympathetic nerve stimulation in the autonomically decentralized heart of the open-chest anesthetized dog. Parasympathetic input was activated by stimulation of the cervical vagus (CV) or parasympathetic nerves to the sinoatrial (SA) nodal region (SAP). Zatebradine (0.1-3 mumol/kg i.v.) decreased the heart rate but not other cardiac responses to sympathetic nerve stimulation, i.e., a wave component of the right atrial pressure (RAP), the first derivative of the RAP (dRAP/dt), atrioventricular (AV) conduction time (AVCT), right ventricular pressure (RVP) and its first derivative (dRVP/dt). Zatebradine (1 mumol/kg) inhibited basal heart rate by 28% but inhibited the chronotropic response to sympathetic stimulation by 85%. Verapamil (0.06-0.6 mumol/kg i.v.) attenuated the increases in heart rate, RVP and dRVP/dt elicited by sympathetic stimulation but potentiated shortening of the AVCT from the prolonged basal AVCT. The SAP stimulation attenuated the heart rate and dRAP/dt responses to sympathetic stimulation without affecting other cardiac responses, whereas CV stimulation decreased the positive chronotropic and atrial and ventricular inotropic responses. Cervical vagus stimulation did not change the positive dromotropic response. These results demonstrate that in contrast to CV nerve activation or verapamil, zatebradine and SAP stimulation cause bradycardia but preserve the myocardial contractile force and AVCT in response to sympathetic nerve activation or sympathomimetic drugs in the heart in situ.

Topics: Animals; Benzazepines; Cardiovascular Agents; Dogs; Electric Stimulation; Heart Rate; Parasympathetic Nervous System; Sinoatrial Node; Sympathetic Nervous System; Verapamil

A class of pharmacologically active substances, known as "specific bradycardic agents", exerts a negative chronotropic influence on cardiac activity, which heavily relies upon a potent blockade of the hyperpolarization-activated cation current in Purkinje fibers. Since the cation conductance activated by hyperpolarization seems to represent an ubiquitous class of membrane channel in mammals, the present study was undertaken to evaluate the influence of specific bradycardic agents [UL-FS 49 (zatebradine) and its derivative DK-AH 268] on excitable cells of the central nervous system. Thalamocortical relay neurons of the dorsolateral geniculate nucleus, prepared from the guinea-pig thalamus as in vitro slices, were taken as model cells, because the significance of the hyperpolarization-activated cation current (Ih) for electrogenic activity is well documented in these neurons. Local application to relay neurons of the bradycardic agents at concentrations in the range 10(-5) to 10(-3) M resulted in a significant reduction in the amplitude of the Ih current, in the amplitude of the Ih activation curve, and in the slope of the fully activated Ih I/V-relationship. The bradycardic agents did not affect the instantaneous currents with no contribution of Ih, the time course of Ih activation, the voltage range of Ih activation, or the reversal potential of Ih. The inhibitory effect was critically dependent upon Ih activation with open Ih channels probably representing a sufficient condition for blockade. Significant recovery from block did not occur. Under current-clamp conditions, slow anomalous inward rectification of the membrane in the hyperpolarizing direction was blocked, and the resting input resistance increased by 30% associated with a negative shift (average 10 mV) of the membrane potential into a region of Ca(2+)-mediated burst activity. Parameters of electrophysiological activity outside the range of Ih activation were not significantly affected. These data indicate a selective and use-dependent blockade exerted by specific bradycardic substances on the conductance underlying Ih with no alteration in the gating properties. In view of the existence of hyperpolarization-activated cation conductances in neurons from various regions of the mammalian peripheral and central nervous systems, the results of the present study remind us of possible neuronal side-effects of bradycardia-producing agents.

Topics: Animals; Benzazepines; Cardiovascular Agents; Electric Conductivity; Guinea Pigs; Heart Rate; In Vitro Techniques; Ion Channel Gating; Ion Channels; Membrane Potentials; Neurons; Thalamus

Sinus tachycardia facilitates ventricular conduction delay and sustained ventricular tachyarrhythmias during tricyclic antidepressant overdose. We hypothesized that impeding sinus tachycardia with the specific bradycardia agent, UL-FS 49, would reduce the incidence of ventricular tachyarrhythmia caused by tricyclic antidepressant overdose and tested this hypothesis in a canine model of ventricular tachycardia (VT) induced by graded amitriptyline infusion (0.5-1.0 mg/kg/min) during continuous hemodynamic monitoring. Three groups were studied. A control group (group A, n = 8) received amitriptyline infusion alone. A pretreated group (group B, n = 8) received UL-FS 49 (1 mg/kg intravenously, i.v.) 45 minutes before amitriptyline infusion. A treatment group (group C, n = 5) received UL-FS 49 (1 mg/kg) during amitriptyline infusion after onset of ventricular tachyarrhythmia. Seven (88%) in group A had ventricular tachyarrhythmia at 35 +/- 6 min of amitriptyline infusion. Ventricular tachyarrhythmia did not occur in any (0%) animal in group B. Peak sinus heart rate (HR) was significantly higher in group A (160.0 +/- 9.8 beats/min) than in group B (92.8 +/- 5.3 beats/min; p < 0.0001). Unimpeded sinus tachycardia in group A was associated with a significantly longer QRS duration (158.8 +/- 7.4 ms) as compared with group B (101.0 +/- 2.3 ms; p < 0.0001). UL-FS 49 did not influence systolic blood pressure (SBP) at baseline or during amitriptyline infusion. In group C, 3 of 5 dogs with nonsustained VT (NSVT) had effective sinus rate slowing and suppression of all NSVT after UL-FS 49. UL-FS 49 did not terminate SVT in 2 of 5 group C dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amitriptyline; Animals; Benzazepines; Cardiovascular Agents; Dogs; Electrocardiography; Female; Male; Tachycardia, Ventricular

ZENECA ZD7288 (4-(N-ethyl-N-phenyl-amino)-1,2-dimethyl-6-(methylamino) pyrimidium chloride) is a novel compound which we compared with alinidine and UL-FS 49 (zatebradine) in guinea pig sinoatrial node (SAN) and papillary muscle preparations, using conventional microelectrode techniques. At low concentrations (1 x 10(-8)-1 x 10(-6) M), ZD7288 caused slowing of the diastolic depolarisation rate of SAN pacemaker cells, thus prolonging the diastolic interval and slowing the beating rate. Alinidine and UL-FS 49 also had qualitatively similar effects on diastolic depolarisation rate, but ZD7288 caused least prolongation of the action potential duration (APD) of SAN cells at the concentrations that had "selective bradycardic actions." ZD7288 affected the APs of ventricular cells in guinea pig papillary muscle only at relatively high concentrations (3 x 10(-6)M-1 x 10(-4) M), which reduced plateau potential duration, although total APD was less affected. Reduced force of contraction (FOC) was also observed at these high concentrations; significant effects on AP Vmax were noted only at concentrations > or = 3 x 10(-5)M. Alinidine also had negative inotropic effects on papillary muscle, but its effects were noted at concentrations similar to those with bradycardic actions; in contrast, UL-FS 49 had marked positive inotropic actions and also increased ventricular APD within the bradycardic concentration range. These data provide a basis for the selective actions of ZD7288 on heart rate (HR).

Topics: Action Potentials; Animals; Benzazepines; Cardiovascular Agents; Clonidine; Dose-Response Relationship, Drug; Electrophysiology; Guinea Pigs; Heart Rate; Heart Ventricles; In Vitro Techniques; Male; Microelectrodes; Myocardial Contraction; Papillary Muscles; Pyrimidines; Sinoatrial Node

Heart rate, an important risk factor of coronary mortality, is highly correlated with numerous anthropometric and biochemical variables: height, body weight and hyperlipidemia; it varies, furthermore, with smoking and age and can be modified during pharmacotherapy for hypertension. From meta-analyses on different cardiovascular treatments, given after coronary events, only the efficacy of drugs significantly reducing heart rate is borne out (beta-blockers with sympathomimetic activity, or calcium-antagonists with a prevalent vasodilatory action do not provide a protective effect). Among calcium-antagonists, while the mechanism of action is similar at the cell level (delay of opening of voltage-operated slow channels), the distribution of activity within the vascular system varies markedly. Dihydropyridines (e.g., nifedipine) exert a dominant peripheral effect, with consequent vasodilation, whereas phenylalkylamines (verapamil) have both peripheral vasorelaxant and cardiac negative chronotropic activity, because of a reduced sinus node action potential. A relative tachycardia may occur with dihydropyridines, secondary to the activation of baroreceptors; the compensatory heart mechanism operated by verapamil antagonizes this reflex tachycardia. The activity of verapamil on the atrioventricular conduction allows both a slowing of functional recovery of the channel in hyperexcitable conditions (supraventricular tachycardia), and, moreover, increased diastolic intervals, with consequent improvement of coronary flow. New molecules can selectively reduce the sinus node activity without exerting other effects (hypotensive, anti-arrhythmic). From a comparative evaluation of these molecules with verapamil, it clearly emerges how this latter can provide a more acceptable pharmacodynamic profile, both for the hypotensive activity, and also for the control of reflex tachycardia, with a consequently improvement of coronary flow.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Animals; Benzazepines; Blood Pressure; Calcium Channel Blockers; Cardiovascular Agents; Coronary Circulation; Dihydropyridines; Electrocardiography; Female; Heart Rate; Humans; In Vitro Techniques; Male; Middle Aged; Nifedipine; Population Surveillance; Rabbits; Sinoatrial Node; Tachycardia; Verapamil

1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICI D7288) is a novel sino-atrial node function modulator which selectively slows sinus node rate. Its effects on haemodynamic function have been studied in pentobarbitone anaesthetized dogs, in comparison with zatebradine, atenolol and nitrendipine. 2. ZD7288 lowered heart rate in the dose-range 0.02 to 1.0 mg kg-1 i.v. from 152 to 77 beats min-1. Myocardial contractile function (measured as both dPLV/dtmax and right ventricular free wall developed force) decreased along with rate. Stroke volume increased as rate decreased. Cardiac output decreased at doses in excess of 0.2 mg kg-1, i.v. 3. These haemodynamic changes were reversed when heart rate reduction was reversed by atrial pacing and are, therefore, considered to be indirect consequences of heart rate changes induced by ZD7288. 4. The effects of zatebradine paralleled those of ZD7288 (heart rate reduced from 149 to 60.5 beats min-1 over the dose-range 0.02 to 1.0 mg kg-1, i.v.), except that dPLV/dtmax did not decrease with heart rate and increased during arial pacing. 5. Neither ZD7288 nor zatebradine had significant effects on atrio-ventricular conduction at intrinsic heart rates, but both significantly and dose-dependently prolonged the atrio-ventricular conduction interval during atrial pacing at 180 beats min-1. 6. The observed effects of atenolol were commensurate with removal of beta-sympathetic cardiac drive. Atrial pacing was found not to restore the pre-atenolol heamodynamic state completely. 7. Nitrendipine up to 0.2 mg kg- i.v. induced changes indicative of direct vasodilatation accompanied by reflex compensation, followed by cardiac depression at higher doses. Atrial pacing failed to compensate for the effects of vasodilatation, but caused atrio-ventricular conduction block at doses above 0.5mgkg-1, i.v.8.data show ZD7288 has marked heart rate slowing properties and that accompanying haemodynamic changes appear to be secondary to the rate changes, being reversed by atrial pacing even in the continued presence of the drug. Heart rate slowing without depression of contractile function should prove to be of benefit in the treatment of myocardial ischaemia, particularly in the presence of myocardial dysfunction.

Topics: Animals; Atenolol; Benzazepines; Cardiotonic Agents; Cardiovascular Agents; Dogs; Heart Rate; Hemodynamics; Nitrendipine; Pyrimidines; Sinoatrial Node

1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICI D7288) is a novel sino-atrial node function modulator which selectively slows heart rate. 2. The haemodynamic effects of ZD7288 (0.1, 0.3 and 1.0 mg kg-1, i.v.) have been evaluated and compared with those of placebo (physiological saline), zatebradine (ULFS 49, 0.1, 0.3 and 1.0 mg kg-1, i.v.) and propanolol (0.03, 0.1, and 0.3 mg kg-1, i.v.) in beagles chronically instrumented for measurement of heart rate, aortic pressure, aortic flow and dPLV/dtmax. The dogs were trained to run at 6.5 k h-1 on a level treadmill for 5 min at half hourly intervals over a period of 4 h. Drugs were dosed cumulatively after the second, fourth and sixth exercise periods. 3. Control experiments demonstrated a degree of accommodation to repeated exercise over a period of 4 h. Resting heart rate decreased by 21 beats min-1, but heart rate response to exercise was maintained, whereas dPLV/dtmax at rest remained steady while the response to exercise decreased significantly (by 25% after 2 h, P < 0.05). 4. ZD7288 and zatebradine both decreased heart rate during exercise in a dose-dependent manner, whilst heart rate at rest did not differ from resting heart rates in saline dosed control animals. In contrast, heart rate at rest and during exercise were lowered equally by the lowest doses of propranolol (approximately by 30 beats min-1), and additional doses caused only minor additional decreases. The exercise-induced tachycardia was maintained within 12% of pre-dose levels, presumably by withdrawal of vagal tone.5. Cardiac inotropism, as indicated by dPLv/dt max, was not affected by ZD7288 or zatebradine at rest,although the inotropic response to exercise decreased in proportion to the decreases in exercise-induced tachycardia. Propranolol caused a marked dose-dependent decrease in the exercise-induced inotropic response (by 85% at 0.3mg kg-1).6. Whilst the sino-atrial node modulators increased stroke volume at rest, and augmented increases in response to exercise, propranolol did not affect resting stroke volume and decreased the responses to exercise.7. Cardiac output at rest and cardiac output increases during exercise were well maintained in the presence of ZD7288 and zatebradine in contrast to propranolol which induced a significant depression of cardiac output, both at rest and during exercise. Propranolol also caused significant systemic vasoconstriction.8. In conclusio

Topics: Animals; Benzazepines; Cardiotonic Agents; Cardiovascular Agents; Dogs; Heart Rate; Hemodynamics; Physical Conditioning, Animal; Propranolol; Pyrimidines; Sinoatrial Node

A method has been developed for the measurement of zatebradine (UL-FS 49), a heart-rate lowering drug, suitable for the treatment of stable angina pectoris. The method comprises a fully automated liquid-solid extraction using a Zymark Benchmate, a capillary gas chromatography and ammonia chemical ionisation (CI) mass spectrometry using hexadeuterated zatebradine for the internal standard. The assay has a mean between-batch imprecision of 4.9% and a mean inaccuracy of 1.5%. The calibration curve covers the range of 1-30 ng/ml. About 60 samples can be handled per day. The assay has been successfully applied to human pharmacokinetic studies.

Topics: Ammonia; Autoanalysis; Benzazepines; Calibration; Capillary Action; Cardiovascular Agents; Chromatography, Gas; Deuterium; Drug Stability; Humans; Mass Spectrometry; Quality Control; Sensitivity and Specificity

The effects of the specific bradycardic agent, zatebradine (UL-FS 49), on ventricular arrhythmias occurring during an acute ischemia were compared to those of verapamil. Anesthetized rabbits were submitted to a ligation of the left circumflex coronary artery for 20 min. Zatebradine (150 and 750 micrograms/kg, i.v.) dose-dependently reduced heart rate, but changed neither the left ventricular pressure nor the (+)dp/dtmax. In comparison, verapamil (150 and 750 micrograms/kg, i.v.) reduced heart rate, systemic blood pressure, left ventricular pressure and (+)dp/dtmax. The incidence of ventricular premature beats occurring during acute ischemia was changed neither by zatebradine nor by verapamil. Ventricular fibrillation, occurring in 36% of the saline-treated rabbits, was reduced to 18% in the presence of 750 micrograms/kg of zatebradine and 0% with verapamil (750 micrograms/kg, p < 0.05). The action of zatebradine on ischemia-induced ventricular fibrillation, albeit limited, was completely reversed by atrial pacing to the predrug heart rate. To further investigate the mechanisms involved in the antiarrhythmic potential of both zatebradine and verapamil, their electrophysiological actions were compared in canine Purkinje fibers. Both zatebradine and verapamil induced a dose-dependent increase in action potential duration (APD) measured at 90% repolarization. The APDs measured during the plateau level (APD30) and at 50% of the repolarization (APD50) were shortened by verapamil and increased by zatebradine showing that at the concentrations used, zatebradine did not exhibit any calcium antagonistic activity when compared to verapamil. The results of the present study suggest that the specific bradycardic agent zatebradine showed a beneficial action mainly because of its anti-ischemic properties. However, the present studies performed in anesthetized rabbits suggest that in this species pure reduction in heart rate is not sufficient to entirely prevent ischemic arrhythmias.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Benzazepines; Cardiovascular Agents; Dogs; Dose-Response Relationship, Drug; Electrophysiology; Female; Heart Ventricles; Hemodynamics; Injections, Intravenous; Male; Myocardial Ischemia; Purkinje Fibers; Rabbits; Verapamil

1. S 16257 is a new bradycardic agent. Its electropharmacological profile has been compared to that of the known bradycardic compound UL-FS 49 (Zatebradine). Intracellular recordings of action potentials (APs) were performed with conventional glass microelectrodes. 2. In the rabbit isolated sino-atrial node (SAN) tissue, S 16257 and UL-FS 49 (1 microM, 3 microM and 10 microM) were equipotent in slowing spontaneous APs firing predominantly by decreasing the rate of diastolic depolarization (at 3 microM, -23.8 +/- 3.9% and -27.9 +/- 2.6%, respectively). For the two compounds a maximal effect was obtained at 3 microM. In these preparations, action potential duration at 50% of total repolarization (APD50) was more affected by UL-FS 49 than S 16257 at any concentration tested (at 3 microM, +8.9 +/- 2.9% and +29.1 +/- 3.7% for S 16257 and UL-FS 49, respectively; P < or = 0.01). 3. To estimate the direct effects on AP duration, driven cardiac preparations were exposed to these agents. In guinea-pig papillary muscles, paced at a frequency of 1 Hz, increasing concentrations of S 16257 or UL-FS 49 (0.1 to 10 microM, 30 min exposure for each concentration) slightly prolonged AP repolarization. This prolongation was more marked for UL-FS 49 (at 1 microM, +6.1 +/- 0.6% and +11.2 +/- 1.3% elevation of APD50, for S 16257 and UL-FS 49, respectively). 4. Application of UL-FS 49 (3 microM) to rabbit Purkinje fibres, triggered at a frequency of 0.25 Hz, induced a marked prolongation of APD50 and APD90 (+149.4 +/- 51.2% and +86.0 +/- 15.4%, respectively). S 16257 (3 MicroM) induced only a weak prolongation of AP (+ 14.1 +/- 5.0% and + 14.8 +/- 3.3% for APD50 and APD90, respectively) significantly smaller than in the case of UL-FS 49.5. These results show that S 16257 slows the rate of spontaneous AP firing in isolated SAN mainly by a reduction of the diastolic depolarization of the cells, which suggests an inhibition of the pace-maker current (If). S 16257 and UL-FS 49 are equipotent in their bradycardic effect but S 16257 is more specific as it induces less increase in myocardial repolarization time.

Topics: Action Potentials; Animals; Benzazepines; Cardiac Pacing, Artificial; Cardiotonic Agents; Cardiovascular Agents; Electrophysiology; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Ivabradine; Male; Papillary Muscles; Purkinje Fibers; Rabbits; Sinoatrial Node

Myocardial stunning is characterized not only by a decreased regional postischemic function but also by a relatively high oxygen consumption (ie, decreased mechanical efficiency). Several lines of evidence suggest that the underlying mechanism may involve a decreased sensitivity of the myofibrils to calcium, but in vivo evidence is lacking. We therefore evaluated this hypothesis in vivo using EMD 60263, a calcium-sensitizing agent, which is devoid of any phosphodiesterase-inhibiting properties.. We first established the effect of two consecutive doses of EMD 60263 (0.75 and 1.5 mg/kg i.v., n = 7), administered at 15-minute intervals, on segment length shortening (SLS), external work index (EW; the area inside the left ventricular pressure-segment length loop), myocardial oxygen consumption (MVO2), and mechanical efficiency (EW/MVO2) in anesthetized pigs with normal myocardium. After the highest dose of EMD 60263, SLS in the distribution area of the left anterior descending coronary artery (LADCA) increased from 13 +/- 1% at baseline to 17 +/- 1% (P < .05). However, EW, MVO2, and EW/MVO2 were not significantly affected (123 +/- 10%, 98 +/- 9%, and 85 +/- 13% of baseline, respectively). In 14 other anesthetized pigs, myocardial stunning was induced by two sequences of 10 minutes of LADCA occlusion and 30 minutes of myocardial reperfusion. After induction of stunning, the two doses of EMD 60263 (n = 7) or saline (3 and 6 mL, n = 7) were infused. In the distribution area of the LADCA, the stunning protocol caused decreases in SLS from 16 +/- 1% to 8 +/- 1% (P < .05) and in EW to 49 +/- 5% of baseline (P < .05), whereas MVO2 was only minimally affected (P > .05). Consequently, mechanical efficiency decreased to 59 +/- 8% of baseline (P < .05). Saline infusion did not affect any of these regional myocardial variables, but after administration of EMD 60263 SLS recovered dose-dependently to 15 +/- 2% after the highest dose of the drug. EW and mechanical efficiency also recovered dose-dependently to 89 +/- 4% (P < .05 versus stunning) and to 88 +/- 7% (NS versus baseline) of baseline, respectively. In the not-stunned segment, SLS increased from 15 +/- 2% (at baseline) to 18 +/- 2% (after the highest dose), and EW per beat was not changed significantly. An adrenergic mode of action of EMD 60263 was excluded by blocking the alpha- and beta-adrenergic receptors with phentolamine and propranolol, respectively, 15 minutes before administration of EMD 60263 (ie, 15 minutes into the second reperfusion period) in five additional experiments. In these experiments the EMD 60263-induced increases in SLS and EW were not attenuated. Because EMD 60263 decreased heart rate from 106 +/- 4 to 76 +/- 3 beats per minute (P < .05) in the animals with stunned myocardium, we performed five experiments with the specific negative chronotropic compound zatebradine (UL-FS 49, 0.1 to 0.5 mg/kg) to rule out bradycardia as a factor contributing to the effects of EMD 60263. These zate. Calcium sensitization affects function and mechanical efficiency of stunned myocardium more profoundly than of not-stunned myocardium, lending support to the hypothesis that Ca2+ desensitization of the myofibrils is involved in myocardial stunning.

Topics: Animals; Benzazepines; Calcium; Cardiovascular Agents; Female; Hemodynamics; Male; Myocardial Contraction; Myocardial Stunning; Myocardium; Myofibrils; Oxygen Consumption; Swine; Thiadiazines

Block of the hyperpolarization-activated "pacemaker" current (i(f)) by the bradycardic agent UL-FS 49 was studied in isolated sino-atrial (SA) node myocytes. Using repetitive activation/deactivation protocols, micromolar concentrations of UL-FS 49 blocked i(f) in a dose-dependent fashion. Block development was slow, with time constants decreasing with drug concentration and ranging from 25.8 s at 10 microM to 75.5 s at 1 microM UL-FS 49. Block did not develop in cells held at -35 mV, at which voltage i(f) channels are closed, indicating that channels must open before blocking occurs. Apparently in contrast with the requirement of negative voltages for block development, block was relieved by hyperpolarization with a time course slower than current kinetics. Due to the hyperpolarization-induced block relief, current/voltage (I/V) relations in the presence of UL-FS 49 displayed inward-going rectification. Experimental data fitted the hypothesis that UL-FS 49 behaves as an "open channel" blocker of "single-ion" i(f) channels. Block occurs within the pore, at a distance of about 39% of the membrane thickness from its internal side.

Topics: Animals; Benzazepines; Cardiovascular Agents; Dose-Response Relationship, Drug; Electric Conductivity; Electrophysiology; Osmolar Concentration; Rabbits; Sinoatrial Node

Previous studies from our laboratory have shown pronounced augmentation of the force-frequency relation on myocardial contraction during exercise, but the influence of this effect on diastole has not been investigated.. Accordingly, the effect of changing heart rate on left ventricular (LV) relaxation, filling dynamics, and pressure-volume relations during exercise was studied in eight conscious dogs. The exercise heart rate was slowed from 208 +/- 21 (SD) to 163 +/- 11 beats per minute by injection of a specific sinus node inhibitor (UL-FS 49, or zatebradine, 0.6 mg/kg) during continuous exercise. Heart rate was then abruptly restored to the predrug level by atrial pacing during continued exercise. LV volume was calculated by use of implanted ultrasonic crystals, and LV pressure was determine with an implanted micromanometer. Comparing conditions after pacing back to a heart rate of 210 beats per minute with those obtained when the heart rate was slowed by atrial pacing, LV dP/dtmax was increased by 27% at the higher rate (P < .01), despite a marked decrease in LV end-diastolic pressure (24 +/- 4 versus 10 +/- 5 mm Hg, P < .01) and the time constant of isovolumic LV pressure decay (tau) was significantly shortened (19 +/- 5 versus 14 +/- 4 milliseconds, P < .01). The peak rapid filling rate in early diastole (PFR) was not significantly changed by increasing the heart rate, since it was maintained at the slower rate. During exercise, at the slowed heart rate the early portion of the diastolic pressure-volume curve was significantly shifted upward and to the right compared with that at the physiological heart rate, but the late portion of the curve was unchanged.. These data indicate that the negative inotropic effect of the force-frequency relation when heart rate was slowed during exercise caused pronounced impairment of LV relaxation and early filling dynamics. Conversely, an important component of the pronounced improvement of diastolic ventricular function during normal exercise was shown to result from exercise-induced enhancement of the positive inotropic effects of the force-frequency relation on myocardial contraction and relaxation.

Topics: Animals; Benzazepines; Cardiac Pacing, Artificial; Cardiovascular Agents; Dogs; Heart Rate; Myocardial Contraction; Physical Exertion; Ventricular Function, Left; Ventricular Pressure

This investigation determined whether attenuation of the tachycardia produced by dobutamine administration would improve perfusion and function distal to a severe coronary artery stenosis.. Tachycardia adversely affects perfusion and function distal to a coronary artery stenosis. It is not known whether a specific bradycardic agent can improve blood flow and function in an ischemic zone during administration of dobutamine.. The effects of dobutamine (2, 5 and 10 micrograms/kg body weight per min) alone and in combination with zatebradine (0.5 mg/kg), a specific bradycardic agent, on hemodynamic status, segment shortening (ultrasound length transducers) and myocardial perfusion (microspheres) were studied in anesthetized dogs with severe left circumflex coronary artery stenosis.. A 50% reduction in left circumflex coronary artery blood flow (58 +/- 4 to 29 +/- 2 ml/min [mean value +/- SEM]) produced a decrease in systolic shortening in the ischemic zone. Only a dose of dobutamine that did not elevate heart rate (2 micrograms/kg per min) produced an increase in segment shortening in the ischemic zone. High doses of dobutamine (10 micrograms/kg per min) caused an increase in heart rate without improvement in function and a reduction in the subendocardial/subepicardial flow ratio (0.74 +/- 0.06 to 0.48 +/- 0.05). Zatebradine administered in the presence of dobutamine caused a decrease in heart rate, an increase in subendocardial/subepicardial blood flow ratio (0.48 +/- 0.05 to 0.78 +/- 0.09) and allowed an increase in ischemic zone segment shortening. When normalized for changes in heart rate, ischemic zone subendocardial flow increased by 123 +/- 41% (0.39 +/- 0.09 to 0.71 +/- 0.12 ml/100 g per beat). Atrial pacing abolished the effects of zatebradine.. The present data suggest that the perfusion-contraction matching that accompanies a decrease in heart rate results in enhancement of inotropic stimulation of an ischemic zone. The actions of zatebradine are related to an increase in subendocardial blood flow per beat that allows improvement of regional contractile function.

Topics: Animals; Benzazepines; Cardiovascular Agents; Coronary Circulation; Dobutamine; Dogs; Drug Synergism; Female; Heart Rate; Hemodynamics; Male; Myocardial Contraction; Myocardial Ischemia; Stimulation, Chemical

1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyridinium chloride) is a sinoatrial node (SAN) modulating agent which produces a selective slowing of the heart rate. Its effects have been studied in single, freshly dissociated guinea-pig SAN cells, by standard patch clamp procedures. 2. Whole-cell inward currents were evoked by hyperpolarizing voltage clamp steps from a holding potential of -40 mV. ZD7288 inhibited the hyperpolarization activated cationic current (If) in a concentration-dependent manner. The 'selective bradycardic agents' alinidine and UL-FS 49 (zatebradine) both also inhibited If. 3. The activation of If was investigated by measuring tail current amplitudes at +20 mV after hyperpolarizing steps to different potentials to activate the current. The reduction in If resulted from both a shift in the If current activation curve in the negative direction on the voltage axis, and also a reduction in the activation curve amplitude. 4. ZD7288 did not affect the ion selectivity of the If channel, since the tail current reversal potential was unchanged in the presence of the drug. 5. With ZD7288 the inhibition of If was not use-dependent, whereas UL-FS 49 displayed use-dependence in the block of the If current. 6. Whereas ZD7288 had no significant effect on the delayed rectifier current (Ik) in these cells, both alinidine and UL-FS 49 significantly reduced Ik at the same concentrations which reduced If. 7. The data show that ZD7288 reduces If by affecting the activation characteristics of the If current; this inhibition may account for this agent's selective bradycardiac properties.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Benzazepines; Cardiovascular Agents; Clonidine; Electrophysiology; Guinea Pigs; In Vitro Techniques; Ion Channels; Membrane Potentials; Pyrimidines; Sinoatrial Node

Zatebradine (UL-FS 49) is a drug with a specific bradycardiac electrophysiological profile. It reduces heart rate by lengthening the duration of diastolic depolarization in the sinoatrial (SA) node. The ionic basis of this action, however, is not clarified.. We used the whole-cell patch-clamp technique to study the effects of zatebradine on ionic currents underlying diastolic depolarization of isolated rabbit SA node cells. Low concentrations of zatebradine simultaneously reduced diastolic depolarization rate and the pacemaker current I(f). The drug blocked the pacemaker current, I(f), in a use-dependent manner without causing a shift of its activation curve. At hyperpolarized potentials, unblock of I(f) occurred. Clinically relevant concentrations of the drug have little effect on the L-type calcium current or delayed rectifier potassium current.. This use-dependent block of the If channel can account for most of the pharmacological characteristics of zatebradine and is probably the mechanism of heart rate reduction caused by this agent. Thus, the sinus node inhibitor zatebradine belongs to a new class of "I(f) blockers" with possible advantages over currently available drugs for the treatment of ischemic heart disease.

Topics: Animals; Benzazepines; Calcium; Cardiac Pacing, Artificial; Cardiovascular Agents; Diastole; Electric Conductivity; Female; Kinetics; Male; Membrane Potentials; Potassium; Rabbits; Sinoatrial Node

We have generated transgenic animals that heritably develop atrial tumors composed of differentiated proliferating cardiomyocytes. Experiments were initiated to characterize the electrical properties of these cells.. We show that the primary atrial tumors are composed of discrete foci that exhibit spontaneous automatic activity. A direct correlation was observed between tumor size and firing rate of these foci. In addition to the primary atrial tumors, we examined the properties of cultured cardiomyocytes isolated from a transplantable transgenic tumor lineage (designated AT-1 cells). Cultured AT-1 cells are also spontaneously automatic. The action potential configuration from these preparations is similar to that observed in nontransgenic atrial cardiomyocytes, albeit somewhat more depolarized and of longer duration. As would be expected for cardiomyocytes of atrial origin, the transgenic cardiomyocyte preparations hyperpolarize during muscarinic stimulation due to increased K+ conductance mediated by a pertussis toxin sensitive G-protein. Assessment of pharmacologic blockage of the "if" pacemaker current suggests that the automaticity of both transgenic cardiomyocyte preparations may be of novel origin. In this context, the cultured AT-1 cells showed spontaneous behavior that was clearly of cellular origin; this activity was manifest as transient bursts of electrical activity followed by periods of electrical quiescence. This bursting pattern is unusual for normal adult cardiomyocytes, but has been observed in several other cell types. In the primary tumors, automatic behavior may arise from a similar cellular origin or alternatively from a microreentrant phenomena.. Primary tumors and AT-1 cells show essential atrial electrophysiology with important novel features.

Topics: Acetylcholine; Action Potentials; Animals; Antigens, Polyomavirus Transforming; Atrial Natriuretic Factor; Benzazepines; Calcium Channels; Carbachol; Cardiovascular Agents; Cell Communication; Cell Division; GTP-Binding Proteins; Heart; Heart Atria; Heart Neoplasms; Membrane Potentials; Mice; Mice, Inbred DBA; Mice, Transgenic; Myocardium; Potassium; Tumor Cells, Cultured; Verapamil

The purpose of this study was to compare the effects of zatebradine on heart rate, contractility and relaxation with those of its structural analog verapamil. We used isoproterenol, a potent beta-agonist, to see how these effects were modulated by sympathetic activation. We also compared the effects of zatebradine and verapamil on coronary blood flow and coronary blood flow reserve.. Zatebradine, previously called UL-FS 49, is a new bradycardic agent believed to act selectively at the sinoatrial node.. Isolated isovolumetric pig hearts were prepared and left ventricular pressure, its first derivative (dP/dt), tau and heart rate were measured both before and after administration of either 0.975 mg of zatebradine (Group I, n = 8) or 125 micrograms of verapamil (Group II, n = 8). After the effects of each drug reached a plateau, a continuous infusion of isoproterenol was started and measurements were obtained again and compared with a third group of measurements from control hearts infused with isoproterenol after receiving only saline solution (n = 8). We also assessed the effects of zatebradine and verapamil on coronary vascular tone by measuring flow in the left anterior descending coronary artery in intact anesthetized open chest pigs both before and after the intracoronary administration of these drugs (n = 8 for each). All preparations were atrially paced to negate any bradycardiac effects of the drugs.. In the group that received zatebradine, mean (+/- SE) heart rate decreased from 143 +/- 8 to 99 +/- 4 beats/min (p < 0.01) and there was no significant change in either peak left ventricular systolic pressure, dP/dt or tau. In contrast, verapamil produced a lesser decrease in heart rate (136 +/- 7 to 120 +/- 7 beats/min, p < 0.05) but produced substantial decreases in peak left ventricular pressure (100 +/- 3 to 45 +/- 4 mm Hg, p < 0.01) and dP/dt (68% decrease, p < 0.01) and an increase in tau (+26%, p < 0.05). Isoproterenol restored these variables toward normal values in the hearts treated with verapamil, although left ventricular systolic pressure and dP/dt were restored to control values only at the highest isoproterenol concentrations. In the hearts treated with zatebradine, isoproterenol significantly increased left ventricular pressure and contractility and decreased tau; however, heart rate remained unchanged at peak effect. Zatebradine had no effect on coronary blood flow and there was a 100% increase in flow with reactive hyperemia. Conversely, verapamil increased coronary flow by 100%, with no subsequent further increase by reactive hyperemia compared with control values.. Although structurally similar to verapamil, zatebradine is a highly specific bradycardic agent. It has little direct effect on left ventricular developed pressure, contractility, relaxation and coronary vascular tone. Furthermore, the bradycardic effect of zatebradine unlike that of verapamil, is not overcome by doses of isoproterenol that increase developed pressure and contractility and improve relaxation. Because of its highly specific bradycardic effect, this drug may potentially be useful in treating patients with ischemic heart disease or congestive heart failure.

Topics: Animals; Benzazepines; Cardiovascular Agents; Coronary Circulation; Depression, Chemical; Heart Rate; Isoproterenol; Myocardial Contraction; Swine; Verapamil

Zatebradine (1; UL-FS 49 CL; 1,3,4,5-[tetrahydro-7,8-dimethoxy-3-[3-[ [2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-2H-3-benzazepin- 2-on- hydrochloride) is the proposed INN name for a nonchiral, novel, specific heart-rate-lowering drug that is suitable for the treatment of stable angina pectoris. The pharmacokinetics of 1 and of total radioactivity in healthy volunteers (n = 6) were determined after intravenous infusion and oral administration of an experimental drug solution containing 7.5 mg (1.85 MBq) of 14C-labeled drug. Concentrations in plasma and urine were measured by a specific, sensitive, reversed-phase automated high-performance liquid chromatography system with fluorimetric detection at 285 nm Ex, 315 nm Em and by liquid scintillation counting. Recovery of total radioactivity was 89.8 +/- 2.3% (infusion) and 92.2 +/- 3.0% (oral). Renal elimination of total radioactivity was 62.5 +/- 2.0% (infusion) and 48.8 +/- 3.1% (oral). After intravenous infusion and oral administration, 27.3 +/- 2.4 and 43.4 +/- 3.9%, respectively, of the administered dose was eliminated in the feces. Absorption, based on renal excretion of total radioactivity following oral and intravenous dosing, was 79.2 +/- 15.3% (mean +/- standard deviation). Unchanged parent drug contributed 28.4 +/- 5.8% (infusion) and 12.4 +/- 3.7% (oral) of the dose to renal excretion. Zero to three minutes after cessation of the 20-min infusion, the maximum concentration of parent drug in plasma was 161.9 +/- 70.9 ng/mL. After oral administration, a mean peak concentration in plasma of 24.3 +/- 6.7 ng/mL (0.5-3 h postadministration) was reached. Data regarding levels of 1 in plasma could be adequately fitted with an open, two-compartment model.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Benzazepines; Biological Availability; Cardiovascular Agents; Chromatography, High Pressure Liquid; Eating; Feces; Half-Life; Humans; Infusions, Intravenous; Male; Models, Biological

Topics: Animals; Benzazepines; Cardiovascular Agents; Heart Conduction System; Heart Rate; In Vitro Techniques; Myocardial Ischemia; Rabbits; Sheep

We investigated the effects of a bradycardic agent, 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), on the sinus rate and atrial contractile force and the ventricular force in the isolated, blood-perfused right atrial and left ventricular preparations of the dog and the inhibition by UL-FS 49 of the negative cardiac responses to acetylcholine, adenosine and cromakalim. UL-FS 49 (0.003-3 mumol) decreased sinus rate, increased atrial force and decreased ventricular force in a dose-dependent manner. The threshold doses of UL-FS 49 (0.03 mumol) for atrial responses were smaller than that (1 mumol) for a ventricular response. The duration of bradycardia induced by UL-FS 49 was longer than the intropic one. Propranolol and atropine did not block the positive inotropic and negative chronotropic responses to UL-FS 49, respectively, in isolated atria. UL-FS 49 (0.1-3 mumol) dose-dependently inhibited the negative chronotropic and inotropic responses to parasympathetic nerve stimulation and acetylcholine exogenously administered. UL-FS 49 at higher doses (1 and 3 mumol) attenuated the negative inotropic but not chronotropic responses to adenosine and cromakalim.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholine; Adenosine; Animals; Atrial Function; Benzazepines; Benzopyrans; Cardiovascular Agents; Cromakalim; Dogs; Heart Atria; Heart Ventricles; In Vitro Techniques; Myocardial Contraction; Perfusion; Potassium Channels; Pyrroles; Sinoatrial Node; Ventricular Function

The influence of changes in heart rate on myocardial contractility (the force-frequency effect) differs under various experimental conditions, including the anesthetized versus the conscious state.. To assess the influence of beta-adrenergic stimulation on force-frequency effects on myocardial contraction and relaxation, seven instrumented conscious dogs were studied in which heart rate could be controlled by atrial pacing after the intrinsic rate was slowed with a bradycardiac agent (UL-FS 49 0.5-0.75 mg/kg). Left ventricular (LV) pressure was measured with a micromanometer under resting conditions and during dobutamine infusion at low, intermediate, and high doses (2.7, 5.4, and 10.7 micrograms/kg/min). At each dose, heart rate was progressively increased from 100 to 210 beats per minute. In the absence of dobutamine (control), no significant positive force-frequency effect was detected on LV dP/dtmax; this was probably due to the known effect of the observed decrease in preload to reduce LV dP/dtmax, thereby offsetting an effect of the force-frequency response to increased dP/dt. However, during dobutamine infusions, the force-frequency effect was observed to increase significantly in a dose-dependent manner with increases in heart rate. An increase in heart rate from 100 to 210 beats per minute increased LV dP/dtmax by 12.4 +/- 12.5% with low-dose, 22.7 +/- 13.1% with intermediate-dose, and 27.5 +/- 8.9% with high-dose dobutamine. Changes in preload and aortic pressure were within the same ranges under control conditions and at each of the three dobutamine doses. The time constant of LV pressure fall (tau) was significantly shorter with increases in heart rate during control, but only the highest dobutamine dose caused further significant shortening in tau with increased heart rate.. These data indicate that there is a pronounced dose-dependent action of beta-adrenergic stimulation to enhance force-frequency-induced contractile responses in normal conscious dogs.

Topics: Adrenergic beta-Agonists; Animals; Benzazepines; Cardiac Pacing, Artificial; Cardiovascular Agents; Consciousness; Dobutamine; Dogs; Female; Heart Rate; Male; Myocardial Contraction; Receptors, Adrenergic, beta; Ventricular Function, Left

UL-FS 49 is a sinus node inhibitor that has been reported to reduce heart rate and may be useful in improving myocardial oxygen supply vs. demand. However, previous studies performed in a variety of preparations have produced mixed results regarding the independent inotropic effect of UL-FS 49. To determine whether UL-FS 49 has an inotropic effect, we measured both steady-state hemodynamic responses and transient hemodynamic responses to random preload and afterload changes, both with and without UL-FS 49. We found that under steady-state conditions, the effect of UL-FS 49 is so small that it would be of doubtful physiologic significance: a 3% increase in stroke volume (p = 0.007) and 7% increase in peak positive dP/dt (p = 0.051), in the presence of no statistically significant differences in end-diastolic pressure, end-diastolic volume, peak systolic pressure, end-systolic pressure, or heart rate. The more powerful multiple linear regression modeling of hemodynamic transient sequences resulting from random preload and afterload changes showed that UL-FS 49 is without a statistically significant direct effect on left ventricular function. We conclude that UL-FS 49 has no physiologically important direct effect on left ventricular pump function.

Topics: Algorithms; Animals; Benzazepines; Cardiovascular Agents; Dogs; Female; Hemodynamics; Male; Myocardial Contraction; Stimulation, Chemical; Ventricular Function, Left

UL-FS 49 (Zatebradine) and its quaternary derivative, UL-AH 99, were injected by iontophoresis in shortened sheep cardiac Purkinje fibres. The i(f) pacemaker current changes were analyzed using the two-microelectrode voltage-clamp technique. Injection of either drug resulted in a decrease of the maximal diastolic depolarization rate as a consequence of a reduction in i(f) amplitude, with no changes in the kinetics of this current or in voltage dependence. The i(f) blockade was proportional to the total charge injected. After drug iontophoresis under conditions where no i(f) current was activated, an exponential use-dependent decline in i(f) tail current was observed during the application of a voltage-clamp pulse train activating i(f). A slow recovery from blockade, measured after prolonged hyperpolarizations, followed exponential kinetics. Recovery rate and extent of steady state recovery increased with more negative potentials. This suggests that bradycardiac agents interact with the i(f) channel in cationic form from the inside of the cell.

Topics: Action Potentials; Animals; Benzazepines; Cardiovascular Agents; In Vitro Techniques; Iontophoresis; Microelectrodes; Purkinje Fibers; Sheep

The effects of N-]4-(2-(2-[4-(methanesulphonamide)phenoxy]-N- methylethylamino)ethyl)phenyl]methanesulphonamide, free base (UK-68,798) (30 and 100 micrograms/kg i.v.), a class III antiarrhythmic with potassium channel blocking activity, on regional ventricular function during exercise-induced ischemia in conscious dogs were compared to those of 1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-(]2-ad3,4- dimethoxyphenyl]ethyl)methylamino)propyl]-2H-3-benzazepin-2-one, hydrochloride (UL-FS 49) (500 micrograms/kg, i.v.), a specific bradycardic agent. Studies were performed in chronically instrumented dogs trained to run on a motor-driven treadmill. After stenosis of the left anterior descending coronary artery, dogs were submitted to a submaximal exercise. UK-68,798 did not change the resting heart rate, but reduced exercise heart rate by 6.5 and 13.5% at 30 and 100 micrograms/kg, respectively (P less than .05). In a normal area, both doses of UK-68,798 slightly increased regional function. In an ischemic area, the lower dose of UK-68,798 (30 micrograms/kg) was without effect. At the higher dose (100 micrograms/kg), the ischemic dysfunction was worsened, because the percent systolic shortening was reduced from 22.6 +/- 2.6% in the control exercise to 11.1 +/- 5.6% in the presence of UK-68,798 (P less than .05). UL-FS 49 (500 micrograms/kg) reduced heart rate before and during exercise. At rest, UL-FS 49 slightly increased systolic shortening in normal and ischemic areas. In the ischemic area, UL-FS 49 reversed the exercise-induced dysfunction. Before and during exercise, UL-FS 49 (500 micrograms/kg) prolonged diastolic time significantly more than UK-68,798 (100 micrograms/kg; P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Benzazepines; Cardiovascular Agents; Coronary Disease; Dogs; Electrocardiography; Female; Heart; Heart Rate; Male; Myocardial Contraction; Phenethylamines; Physical Conditioning, Animal; Potassium Channels; Sulfonamides

The effects of UL-FS 49, a specific bradycardic agent, on systemic hemodynamics, regional myocardial function (sonomicrometry, percentage of segment shortening), and regional coronary blood flow (radioactive microspheres) were studied in open-chest, anesthetized dogs with severe left circumflex coronary artery (LCX) stenosis. UL-FS 49 was administered as two sequential bolus injections of 0.25 mg/kg. Heart rate decreased from 149 +/- 13 beats/min to 102 +/- 6 and 77 +/- 4 beats/min after 0.25 and 0.5 mg/kg cumulative doses of UL-FS 49, respectively. The reduction in heart rate was not associated with any significant change in left ventricular pressure or mean arterial pressure, left ventricular dp/dt, or coronary vascular resistance. Similarly no hemodynamic changes occurred with atrial pacing to the initial heart rate. Application of an LCX stenosis of sufficient severity to produce a 50% reduction in mean LCX blood flow (44 +/- 4 to 22 +/- 2 ml/min) resulted in a significant reduction in the percentage of segment shortening in the ischemic zone (9.8 +/- 1.6% to 6.5 +/- 1.1%). The percentage of segment shortening in the ischemic zone progressively improved to 8.4 +/- 1.2% and 9.4 +/- 0.5% after 0.25 and 0.5 mg/kg UL-FS 49, respectively. Subepicardial perfusion in the ischemic zone was decreased and subendocardial perfusion was increased after administration of UL-FS 49. Consequently the ischemic zone endocardial/epicardial ratio increased from 0.43 +/- 0.08 to 1.12 +/- 0.22 and 1.48 +/- 0.32 with low and high doses of UL-FS 49.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzazepines; Cardiovascular Agents; Coronary Circulation; Coronary Disease; Depression, Chemical; Dogs; Female; Heart Rate; Hemodynamics; Male; Myocardial Contraction; Myocardium; Oxygen Consumption

This study was designed to test whether the selective bradycardic effects of zatebradine (UL-FS 49) were altered in the setting of chronic mild left ventricular dysfunction secondary to a myocardial infarction. We therefore administered four doses of UL-FS 49 at 15-min intervals (cumulative doses of 10, 30, 100, and 300 micrograms/kg) to eight normal conscious pigs and to seven pigs in which the left circumflex coronary artery was occluded 3 weeks previously. Left ventricular dysfunction in this second group of animals was manifested by an increase in left ventricular end-diastolic pressure (LVEDP, 11 +/- 2 mmHg vs. 7 +/- 1 mmHg, respectively; p less than 0.05) and a decrease in LVdP/dtmax (3020 +/- 210 mmHg vs. 3720 +/- 210 mmHg, respectively; p less than 0.05). The results showed that UL-FS 49 was equally effective in reducing heart rate in both groups of animals [from 126 +/- 4 to 95 +/- 2 beats/min and from 140 +/- 5 to 98 +/- 6 beats/min for the normal animals and for the animals with a chronic myocardial infarction (MI), respectively]. The duration of left ventricular systole was not affected, but the duration of diastole was prolonged from 290 +/- 10 msec to 420 +/- 20 msec in the normal animals and from 250 +/- 10 msec to 430 +/- 30 msec in the animals with MI (both p less than 0.05). Up to 100 micrograms/kg UL-FS 49 did not affect arterial blood pressure, whereas LVdP/dtmax and cardiac output decreased by less than 10% in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzazepines; Cardiovascular Agents; Female; Hemodynamics; Male; Myocardial Infarction; Swine; Ventricular Function, Left

The magnitude of the force-frequency effect on myocardial contractility in the conscious animal has been studied at rest, but it has not been assessed during exercise.. The influence of heart rate (HR) changes were evaluated during treadmill exercise in eight preinstrumented, conscious dogs in which high-fidelity left ventricular (LV) pressure, LV volume (by sonomicrometry), and aortic pressure were measured. Under resting conditions, end-systolic pressure-volume relations were obtained using inferior vena caval occlusion. Dogs were run on a treadmill, and the intrinsic exercise HR was reduced by infusion of a specific bradycardic drug (UL-FS 49 0.5 mg/kg) during continuing exercise while HR was maintained at 240 beats per minute by atrial pacing. At 6 minutes of running at a fixed, paced HR when a stable drug effect had been achieved, no effects of UL-FS 49 on measures of LV contractility were detected compared with exercise before drug administration. HR was then reduced stepwise from 240 to 210, 180, or 150 beats per minute in a random manner, returning to 240 beats per minute between steps. Progressive reductions in measures of myocardial contractility occurred as the HR was slowed, and reduction of rate from 240 to 150 beats per minute reduced the LV maximum positive dP/dt by 31% and (dP/dt)DP40 by 21% despite increases in LV end-diastolic pressure. The entire end-systolic pressure-volume could not be determined during exercise, but beat-averaged end-systolic pressure-volume points during exercise were progressively shifted to the right and downward by slowing the exercise HR. Thus, a pronounced negative inotropic influence of slowing the heart was observed during exercise, and the rate of ventricular relaxation (tau) was also significantly prolonged.. These findings indicate that force-frequency effects on the inotropic state of the intact LV are markedly enhanced by exercise.

Topics: Animals; Benzazepines; Cardiac Pacing, Artificial; Cardiovascular Agents; Consciousness; Dogs; Electrocardiography; Exercise Test; Heart Rate; Myocardial Contraction; Physical Exertion; Ventricular Function, Left

The effects of ULFS-49, a new calcium channel blocker, on right ventricular (RV) systolic and diastolic performance were evaluated in nine anesthetized, closed-chest dogs by load-insensitive indexes. ULFS-49 (0.3 mg/kg) decreased heart rate (HR) from 76 +/- 25 to 47 +/- 11 beats/min (p less than 0.01) and cardiac output (CO) from 1.89 +/- 0.62 to 1.42 +/- 0.72 L/min (p less than 0.01), as RV free wall end-diastolic area increased from 486 +/- 126 to 581 +/- 45 mm2 (p less than 0.01) and RV end-diastolic volume increased from 66.6 +/- 26.4 to 85.3 +/- 28.5 ml (p less than 0.05). Pacing at 100 beats/min ablated these hemodynamic and dimensional changes. RV free wall contractility was assessed by the slope and midrange intercept values of the relation between RV end-systolic pressure (Pes) and end-systolic free wall area (Aes) and between RV free wall segmental work (SW) and end-diastolic area (Aed). RV free wall stiffness was measured by exponential fit of the RV end-diastolic pressure (Ped)-Aed points during caval occlusion. With pacing at 100 beats/min, the slope of the Pes-Aes relationship was unchanged by ULFS-49 (0.52 +/- 0.29 vs. 0.60 +/- 0.35 mm Hg/mm2) as was the midrange intercept (382.3 +/- 114.7 vs. 387.1 +/- 121.5 mm2). After administration of ULFS-49, the slope of the SW-Aed relation increased from 31.8 +/- 14.4 to 37.3 +/- 17.7 mm Hg.mm2 (p less than 0.05) without changing the midrange intercept (410.5 +/- 108.1 mm2 vs. 413.0 +/- 107.0 mm2). Similarly, neither the position nor curvature of the Ped-Aed relation was changed by ULFS-49. These data demonstrate that ULFS-49 causes significant bradycardia and increases the size of the right ventricle without directly depressing RV free wall systolic or diastolic performance.

Topics: Animals; Benzazepines; Blood Pressure; Cardiac Output; Cardiovascular Agents; Dogs; Female; Heart; Heart Rate; Hemodynamics; In Vitro Techniques; Male; Myocardial Contraction; Ventricular Function, Right

Compound 1 (UL-FS 49) has recently been described as the representative of a novel class of antiischemic compounds termed "specific bradycardic agents". In search of specific bradycardic agents with different pharmacokinetic profiles, heteroaromatic analogues of 1 have been synthesized and evaluated for their bradycardic activity, selectivity, and duration of action. The chain length n and the nature of the heteroaromatic system of compounds 2 strongly determine the biological activities. Unsubstituted benzothiophenes and benzofurans in combination with a chain length of n = 2 give the most active bradycardic compounds. Some of the new compounds combine high bradycardic potency and selectivity with a short duration of action and may thus be useful for the development of short-acting specific bradycardic drugs.

Topics: Animals; Benzazepines; Blood Pressure; Cardiovascular Agents; Chemical Phenomena; Chemistry; Heart Rate; Male; Molecular Structure; Rats; Structure-Activity Relationship

Previous studies of the beat-to-beat regulation of left ventricular performance in the intact cardiovascular system have shown that the performance of the left ventricle on any one beat is influenced by the mechanical events of the previous beat, so-called previous beat contraction history. The general hypothesis investigated in this study is that previous beat contraction history occurs because of the perturbation of one or more biochemical processes with time courses that are long relative to one cardiac cycle. If this is true, then previous beat contraction history should depend on the interval between beats and, therefore, should extend beyond the previous beat to two, or even three, previous beats as heart rate is increased. Hemodynamic responses to random preload and afterload changes were measured in 11 anesthetized open-chest dogs on right heart bypass at three paced heart rates. Multiple linear regression was used to analyze these hemodynamic sequences and identify variables from the previous one, two, or three beats that were important in the mechanical history dependence of left ventricular function. The results of this analysis showed that under baseline conditions, all 11 hearts showed one beat of history dependence, with only two of 11 hearts showing a dependence on the previous two or three beats. At the highest heart rate, all 11 hearts still showed one beat of history dependence, but 10 of 11 hearts showed two beats of history dependence, and four of 11 showed three beats of history dependence (p less than 0.05). A general framework for the mechanism underlying these findings, which relates previous beat contraction history to the interval-dependent mechanical restitution phenomenon, is proposed and discussed.

Topics: Animals; Benzazepines; Cardiovascular Agents; Cardiovascular Physiological Phenomena; Dogs; Female; Heart; Heart Rate; Male; Myocardial Contraction; Regression Analysis

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

The mechanism by which the bradycardiac agent UL-FS 49 blocks the if pacemaker current was investigated in sheep Purkinje fibres using the two microelectrode voltage-clamp technique. If was activated by 1 s pulses applied between -30 mV and -120 mV at 0.4 Hz in a modified Tyrode solution containing BaCl2 and MnCl2, and with TRIS replacing most of the Na+. UL-FS 49 caused an exponential decline of the if current amplitude during a train of pulses. Both the rate and extent of the if reduction increased with drug concentration, without there being a resting blockade. Recovery from blockade followed a single exponential time course during prolonged hyperpolarizations. The recovery rate was extremely slow and increased with more negative voltages, as did the extent of steady state recovery from blockade. A frequency-dependent reduction of the diastolic depolarization rate resulted from a use-dependent blockade of the pacemaker current.

Topics: Animals; Barium; Barium Compounds; Benzazepines; Cardiovascular Agents; Chlorides; Dose-Response Relationship, Drug; Electrophysiology; Heart; In Vitro Techniques; Magnesium Chloride; Membrane Potentials; Microelectrodes; Purkinje Fibers; Sheep

In anesthetized swine, the left anterior descending coronary artery was cannulated and perfused at constant blood flow levels during two grades of ischemia. In one group (n = 10), moderate ischemia reduced percent systolic wall thickening (by sonomicrometry) from 25 +/- 7% to 6 +/- 2%, whereas in the other group (n = 7), severe ischemia reduced percent wall thickening from 24 +/- 6% to -0.5 +/- 4%. Heart rate was paced in both groups at 91 beats/min. After reperfusion and complete return to control conditions, administration of the bradycardic agent UL-FS 49 (0.37 mg/kg i.v.) decreased the heart rate to 55 +/- 5 beats/min. During subsequent ischemia at the same coronary inflow as before bradycardia, percent wall thickening in the ischemic zone during moderate ischemia was increased from 6 +/- 2% to 25 +/- 6% (p less than 0.01) (not significantly different from control without ischemia), and during severe ischemia, percent wall thickening increased from -0.5 +/- 4% to 13 +/- 7% (p less than 0.01). During moderate ischemia, bradycardia caused an increase in the subendocardial blood flow from 0.24 +/- 0.60 to 0.42 +/- 0.17 (ml/min)/g (p less than 0.009) and during severe ischemia, bradycardia caused an increase from 0.14 +/- 0.08 to 0.2 +/- 0.1 (ml/min)/g (p less than 0.001). At each level of ischemia, a more marked improvement occurred in subendocardial blood flow per beat ([(ml/min)/g]/heart rate). The relation between myocardial blood flow and wall function at a heart rate of 55 beats/min (n = 14) was plotted and compared with that studied at a heart rate of 122 beats/min in another group of pigs (n = 14). The increase in subendocardial blood flow per minute during bradycardia was not sufficient to explain the striking increase in function; thus, an independent relation (p less than 0.05) between blood flow per minute and contractile function (percent wall thickening) was found for for each heart rate. In contrast, when myocardial blood flow was normalized for heart rate and expressed per beat, data from both heart rate groups could be described by a single relation. Thus, the subendocardial blood flow per beat predicted wall function independently of heart rate and accounted for changes in both oxygen supply and demand.

Topics: Animals; Benzazepines; Biomechanical Phenomena; Cardiovascular Agents; Coronary Circulation; Coronary Disease; Depression, Chemical; Heart; Heart Rate; Swine

1. To clarify whether the bradycardic agent UL-FS 49 exhibits a positive inotropic effect even in the absence of improvement in regional myocardial function of an underperfused myocardial area, this study was undertaken in dogs with unimpaired coronary flow. 2. We also investigated the haemodynamic and functional effects of the negative chronotropic and inotropic beta-adrenoceptor blocker propranolol. 3. UL-FS 49 did not depress total or regional myocardial performance. Moreover, an increase in positive left ventricular dp/dt max at rest suggests a positive inotropic effect of UL-FS 49. 4. Propranolol, in contrast to UL-FS 49, led to a marked reduction in positive dp/dt max, stroke volume and systolic wall thickening at rest and during exercise. Additionally, propranolol decreased the exercise values of cardiac output, left ventricular work and left ventricular power to a far greater extent than UL-FS 49. 5. In contrast to propranolol, the selective bradycardic agent UL-FS 49 did not decrease total or regional ventricular performance and caused less reduction in cardiodynamic parameters during exercise. 6. These results suggest that patients with moderate coronary insufficiency or patients with coronary vessel disease and mild left ventricular failure may attain a higher exercise limit under selective bradycardia with UL-FS 49 in comparison to that possible with a beta-adrenoceptor antagonist, such as propranolol.

Topics: Animals; Benzazepines; Blood Pressure; Cardiac Output; Cardiovascular Agents; Coronary Vessels; Dogs; Female; Heart Rate; Hemodynamics; In Vitro Techniques; Male; Myocardial Contraction; Physical Exertion; Propranolol; Stroke Volume

The effects of the bradycardic agent UL-FS 49 on hemodynamic and segmental parameters were studied in a canine model of exercise-induced myocardial dysfunction which mimics exercise-induced angina pectoris. Ten dogs, trained to subunit to five treadmill exercise cycles consisting of 4 min of running and 11 min of recovery, were chronically instrumented with a microtip manometer in the left ventricle, two pairs of crystals for sonomicrometry, a hydraulic occluder around the circumflex branch of the left coronary artery and arterial and venous catheters. Control experiments with coronary stenosis clarified the reproducibility of exercise-induced regional contractile dysfunction and recovery of function in the intervening resting periods. In each individual dog, a similar degree of stenosis was used in the subsequent experiments with UL-FS 49. After two control runs, which exhibited regional contractile dysfunction of comparable magnitude, UL-FS 49 was administered intravenously at a dosage of 0.5 mg/kg/5 min (6 dogs) or 0.25 mg/kg/5 min (4 dogs). Both doses of UL-FS 49 markedly reduced heart rate without alteration of left ventricular positive dp/dtmax at rest and during exercise. A marked improvement of regional function in the area perfused by the stenosed coronary artery was also observed during exercise. This beneficial effect of selective bradycardia, here observed with UL-FS 49, remains to be confirmed in clinical trials.

Topics: Angina Pectoris; Animals; Benzazepines; Blood Pressure; Cardiovascular Agents; Disease Models, Animal; Dogs; Exercise Test; Female; Heart Rate; Hemodynamics; Male; Myocardial Contraction

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.

Topics: Anesthesia, Inhalation; Animals; Benzazepines; Cardiovascular Agents; Dogs; Electrocardiography; Female; Heart Rate; Hemodynamics; Isoflurane; Male; Propranolol

We have previously demonstrated that the beneficial effect of cardioselective beta-blockade on exercise-induced ischemia is due entirely to negative chronotropism. Therefore we studied the effect of a new bradycardiac agent (UL-FS 49) in 10 dogs with chronic coronary artery stenosis produced by an ameroid constrictor. Regional myocardial function (sonomicrometers, wall thickness) and blood flow (microspheres) were measured during a control treadmill exercise bout and an identical run 3 hr later after the administration of UL-FS 49 (1.0 mg/kg iv). In the control run, heart rate increased from 114 +/- 20 to 230 +/- 19 beats/min and systolic wall thickening (%WT) in the poststenotic myocardium decreased from 23.3 +/- 5.2% at rest to 9.3 +/- 5.0%, a 60% reduction. Subendocardial blood flow in the ischemic area decreased from 1.04 +/- 0.30 to 0.55 +/- 0.40 ml/min/g, blood flow per beat decreased from 9.1 X 10(-3) to 2.5 X 10(-3) ml/g, and mean transmural flow failed to increase (1.06 +/- 0.30 vs 1.08 +/- 0.39 ml/min/g). During exercise with UL-FS 49, heart rate increased from 89 +/- 10 to only 139 +/- 10 beats/min. End-diastolic left ventricular pressure was increased compared with that during the control run (35.7 +/- 3.0 vs 28.9 +/- 5.5 mm Hg) but left ventricular peak systolic pressure and dP/dt were unchanged. %WT in the ischemic zone did not change significantly during exercise with UL-FS 49 (23.3 +/- 7.9% at rest, 21.5 +/- 8.4% during the run), and in the nonischemic zone it increased to the same extent as during the control run.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzazepines; Cardiovascular Agents; Coronary Circulation; Coronary Disease; Depression, Chemical; Dogs; Heart Rate; Myocardial Contraction; Physical Exertion

Propranolol (0.5 mg X kg-1 X 5 min-1), alinidine (1 mg X kg-1 X 5 min-1) and the benzazepinon UL-FS 49 (0.5 mg X kg-1 X 5 min-1) were investigated in a canine model of exercise-induced transient myocardial dysfunction, mimicking exercise-induced functional impairment during angina pectoris in man. Each drug was infused intravenously, after two control treadmill exercise runs had shown comparable, ultrasonically assessed regional contractile dysfunction in an area supplied by a partly stenosed branch of the left coronary artery. All three drugs abolished exercise-induced regional contractile dysfunction. Propranolol and alinidine comparably decreased heart rate and positive dp/dtmax during exercise. UL-FS 49 showed a marked negative chronotropic effect without affecting positive dp/dtmax. Thus, prevention of exercise-induced regional contractile dysfunction has been shown for the first time using a selective bradycardic agent.

Topics: Animals; Arrhythmias, Cardiac; Benzazepines; Cardiovascular Agents; Clonidine; Dogs; Hemodynamics; Male; Myocardial Contraction; Physical Exertion; Propranolol

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