Specific Bradycardic Agent Research Articles

Beneficial effects of heart rate reduction on cardiac mechanics and energetics in patients with left ventricular dysfunction.

It has been shown recently that the force-frequency relationship is blunted in experimental heart failure models. Furthermore, tachycardia is thought to have adverse effects on the diseased heart for several reasons, one of which is an increase in myocardial oxygen consumption. Inversely, the oxygen-saving effects of bradycardia may be beneficial for the treatment of heart failure. The aim of this study was to elucidate how heart rate (HR) modulates cardiac mechanics and energetics in patients with left ventricular (LV) dysfunction. LV pressure-volume data and myocardial oxygen consumption (MVO2) was assessed using conductance and coronary sinus thermodilution catheters in 14 patients with moderate LV dysfunction (mean ejection fraction 34%) under 3 conditions: (a) basal, (b) HR increased by 20% using atrial pacing, and (c) HR decreased by 16% using a specific bradycardic agent, zatebradine (7.5 mg p.o.). Atrial pacing decreased external work (EW) (from 0.39 to 0.31 J beat(-1) m(-2), p<0.05) at a comparable MVO2 per beat with a marginal increase in LV contractility index (Ees) (from 2.34 to 2.76 mm Hg ml(-1) m(-2), p = 0.08), resulting in a decrease in mechanical efficiency (EW/MVO2) (from 25.9 to 22.1%, p<0.05). In contrast, zatebradine did not decrease Ees (from 2.34 to 2.24 mm Hg ml(-1) m(-2), NS), but increased EW (from 0.39 to 0.42 J beat(-1) m(-2), p<0.05 vs. basal level) without a change in MVO2 per beat, resulting in improved mechanical efficiency (from 25.9 to 29.7%, p<0.05 vs. basal level). These results suggest that mild bradycardia is energetically advantageous and does not decrease myocardial contractility and performance, whereas pacing-induced tachycardia worsens cardiac mechanics and energetics in patients with LV dysfunction. Thus, the oxygen-saving effect of bradycardia may be beneficial for the treatment of heart failure.

Pharmacologic heart rate reduction: effect of a novel, specific bradycardic agent on the heart.

Because heart rate (HR) is a major determinant of myocardial oxygen consumption (MVO2) a decrease in HR could prevent ischemia or reduce its consequences. We examined the effects of a novel bradycardic agent of the benzazepinone type, DK-AH 269 (DK), on ventricular function and perfusion in 12 isolated, blood-perfused rabbit hearts. HR was significantly reduced by 1mumol/L DK (160 +/- 28 vs. 124 +/- 23 min-1); diastole lengthened from 235 +/- 69 to 334 +/- 85 ms. Aortic flow tended to fall after DK (50.0 +/- 29.6 vs. 35.6 +/- 21.5 ml/min), but stroke volume remained unchanged (0.29 +/- 0.16 vs. 0.28 +/- 0.17 ml) following DK. Peak left-ventricular pressure (LVPmax) (106 +/- 29 vs. 92 +/- 35 mmHg) and dp/dtmax (1482 +/- 582 vs. 1247 +/- 644 mmHg/s) were decreased. dp/dtmin, as a measure of early relaxation, was also decreased (-1361 +/- 362 vs, -1125 +/- 488 mmHg/s), whereas the end-diastolic pressure (LVPed) was increased (20 +/- 12 vs. 25 +/- 17 mmHg). Coronary blood flow (CBF) per beat was not affected by DK: 0.07 +/- 0.02 vs. 0.07 +/- 0.02 ml. However, the coronary resistance increased with DK from 0.76 +/- 0.29 to 1.13 +/- 0.66 mmHg/(ml/min/100 g). The MVO2 was decreased (6.8 +/- 3.4 vs. 5.9 +/- 2.8 ml/min/100 g). The relation between subendocardial and subepicardial flow (colored microspheres) was unchanged after DK (1.12 +/- 0.22 vs. 1.13 +/- 0.16). Using electrical pacing to restore the control HR, dp/dtmax, LVPed, and MVO2 were nearly restored to predrug levels. In contrast, stroke volume, LVPmax, dp/dtmin and CBF per beat were less than control. In summary: DK effectively reduces heart rate and increases diastole. In parallel with the moderately reduced contractile function, MVO2 is reduced whereas CBF per beat is preserved. These results suggest that this novel bradycardic agent could be useful in treating unwanted tachycardia in the experimental setting, postoperative tachycardia in patients with heart disease or be useful even in treating coronary heart disease.

Zatebradine inhibits tachycardia induced by bronchodilators without affecting respiratory resistance in dogs

Bronchodilators used for bronchial asthma reduce respiratory resistance but also increase heart rate to some extent. It is often difficult to use such bronchodilators with elderly patients and patients with heart disease. The object of our study was to investigate whether a specific bradycardic agent, zatebradine, inhibited the heart rate increased by bronchodilators without affecting respiratory resistance. We evaluated the effects of zatebradine on the increases in heart rate and inhibition of the respiratory resistance in response to the bronchodilators, isoproterenol, procaterol (a β 2-adrenoceptor agonist), 6-(3-dimethylaminopropionyl)-forskolin, NKH 477 (an adenylyl cyclase activator) and aminophylline in the anesthetized and artificially ventilated dog. When zatebradine in doses of 0.05–1.5 mg/kg i.v. decreased heart rate without affecting arterial blood pressure, it dose dependently attenuated the increase in heart rate in response to isoproterenol, procaterol, NKH 477 and aminophylline but did not affect the inhibition by these substances of the increase in respiratory resistance induced by histamine. Propranolol (0.01–0.3 mg/kg i.v.) dose dependently inhibited not only the increase in heart rate but also the inhibition of the respiratory resistance induced by isoproterenol and procaterol. The present results indicate that zatebradine selectively inhibits the increase in heart rate in response to cyclic AMP-dependent bronchodilators without affecting their bronchodilator effects in anesthetized dogs and suggest that zatebradine may be a useful drug for prevention of the tachycardia induced by bronchodilators used for patients with bronchial asthma.

Increases in inotropic state without change in heart rate: Combined use of dobutamine and zatebradine in conscious dogs

The cardiovascular and left ventricular functional effects of dobutamine (5, 10 and 20 μg kg −1 min −1) were examined in conscious, chronically instrumented dogs in the presence and absence of control of heart rate with the specific bradycardic agent, zatebradine. Dobutamine increased heart rate, cardiac output, stroke volume, diastolic coronary blood flow velocity and pressure-work index (calculated myocardial oxygen consumption) and decreased systemic vascular resistance and diastolic coronary vascular resistance. Mean arterial pressure and left ventricular systolic and end-diastolic pressures were unchanged. Dobutamine-induced increases in heart rate and pressure-work index were attenuated by zatebradine. Dobutamine alone increased preload recruitable stroke work slope (63 ± 6 to 116 ± 11 mmHg) and + dP dt . These positive inotropic effects were unaffected by zatebradine. Dobutamine decreased the time constant of isovolumic relaxation (30 ± 3 to 25 ± 2 ms). Dobutamine-induced decreases in the time constant of isovolumic relaxation were not altered by zatebradine, indicating that changes in the time constant occurred independent of heart rate. Dobutamine also increased the maximal segment lengthening velocity to a similar degree in zatebradine-treated versus untreated dogs. Control of dobutamine-induced tachycardia by zatebradine decreases myocardial oxygen consumption but does not alter the positive inotropic and lusitropic effects of dobutamine.

Cardiac electrophysiological effects of falipamil in the conscious dog: comparison with alinidine

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

Specific Bradycardic Agents Lower Purkinje Fibers aNa1 and Slow Ectopic Rhythms 24 Hours after Coronary Ligation in Canine Heart

Specific Bradycardic Agents Lower Purkinje Fibers aNa1 and Slow Ectopic Rhythms 24 Hours after Coronary Ligation in Canine Heart

Prevention of Tricyclic Antidepressant-Induced Ventricular Tachyarrhythmia by a Specific Bradycardic Agent in a Canine Model

Prevention of Tricyclic Antidepressant-Induced Ventricular Tachyarrhythmia by a Specific Bradycardic Agent in a Canine Model

Prevention of Tricyclic Antidepressant-Induced Ventricular Tachyarrhythmia by a Specific Bradycardic Agent in a Canine Model

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)

Specific bradycardic agents block the hyperpolarization-activated cation current in central neurons

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 ( I h ) 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 −3M resulted in a significant reduction in the amplitude of the I h current, in the amplitude of the I h activation curve, and in the slope of the fully activated I h I/V-relationship. The bradycardic agents did not affect the instantaneous currents with no contribution of I h , the time course of I h activation, the voltage range of I h activation, or the reversal potential of I h . The inhibitory effect was critically dependent upon I h activation with open I h 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 I h activation were not significantly affected. These data indicate a selective and use-dependent blockade exerted by specific bradycardic substances on the conductance underlying I h 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.

Zatebradine, a specific bradycardic agent, enhances the positive inotropic actions of dobutamine in ischemic myocardium

Objectives. This investigation determined whether attenuation of the tachycardia produced by dobutamine administration would improve perfusion and function distal to a severe coronary artery stenosis.Background. 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.Methods. The effects of dobutamine (2, 5 and 10 μg/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.Results. 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 μg/kg per min) produced an increase in segment shortening in the ischemic zone. High doses of dobutamine (10 μ/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.Conclusions. 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.

ChemInform Abstract: Synthesis and Cardiovascular Activity of Phenylalkylamine Derivatives. Part 1. Potential Specific Bradycardic Agents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Effect of zatebradine on contractility, relaxation and coronary blood flow

Objectives. 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.Background. Zatebradine, previously called UL-FS 49, is a new bradycardic agent believed to act selectively at the sinoatrial node.Methods. 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 μg 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 bradycardic effects of the drugs.Results. 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 veatricular 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 vestricular systolic pressure and dP/dt were restored to control values only at the highest isoproterenol concentrations. In the hearts treated with zatebradine, isoproterenol sagnificantly increased left ventricular pressure and contractility and decreased tau; however, beast rate remained unchanged at peak effect. Zatebradine had no effect on coronary blood flow and there was a 100% increase in flow with reactive heyperemia, Conversely, verapamil increased coromry flow by 100%, with no subsequent further increase by reactive hyperemia compared with control values.Conclusions. Although structurally similar to verapamil, zatebradine is a nighty specific bradycardic agent. It has little direct effect on left ventricular developed pressare, 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.

O-137 - Differential inhibition of positive chrono- and inotropic responses to cardiotonics by UL-FS 49, a specific bradycardic agent in the isolated dog atrium.

O-137 - Differential inhibition of positive chrono- and inotropic responses to cardiotonics by UL-FS 49, a specific bradycardic agent in the isolated dog atrium.

Regional redistribution of myocardial perfusion by UL-FS 49, a selective bradycardic agent

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. Atrial pacing to the control heart rate abolished the effects of UL-FS 49 on regional myocardial blood flow and percentage of segment shortening. These data indicate that UL-FS 49 is a selective bradycardic agent that can improve ischemic myocardial function distal to severe coronary stenosis. The data suggest that UL-FS 49 improves the relationship between myocardial oxygen supply and demand by negative chronotropic actions and by favorably redistributing ischemic blood flow.

Synthesis and cardiovascular activity of phenylalkylamine derivatives. I. Potential specific bradycardic agents.

A series of acyclic amide derivatives of N-(omega-aminoalkyl)-N-methylhomoveratrylamine was synthesized and evaluated for their bradycardic activity in isolated guinea pig right atria. Among these compounds, (E)-N-[3-[N'-[2-(3,4-dimethoxyphenyl)ethyl]-N'-methylamino]propyl]- 4-[3,4-(methylenedioxy)phenyl]-3-butenamide (35) was the most potent in vitro and was also found to show dose-dependent bradycardia without remarkable reduction of left ventricular dp/dtmax or mean aortic pressure in anesthetized dogs.

Effect of the ‘Specific Bradycardic Agent’ Alinidine on the Function of Ischemic Myocardium

In patients with coronary artery disease, the reduction of heart rate (HR) by beta-blockers can further impair myocardial function by reducing the contractility and coronary perfusion. This is possibly not the case for "specific bradycardic agents" like alinidine (ALI). The effect of ALI on ischemic myocardium, therefore, was studied in anesthetized open-chest dogs measuring left ventricular end-diastolic pressure (LVedP), dP/dt, aortic pressure (AoP) by catheter tip manometers, coronary blood flow (Q) electromagnetically, end-diastolic length (edL) and systolic shortening (sdL in %edL) of ischemic (RISC) and non-ischemic (NISC) wall segments by sonomicrometry. Group A (n = 11): Left coronary artery constriction to reduce Q (-53%) and poststenotic sdL (-54%), then i.v. injection of ALI (0.25 + 0.25 + 0.5 + 1.0 mg/kg), thereafter atrial pacing at HR before ALI. Group B (n = 9): Installation of an aorto-coronary bypass, pump-perfused at 50% of free flow, infusion of ALI into the bypass. The results showed that ALI iv dose-dependently reduced HR from 135/min to 90/min, LVedP rose from 8.6 to 10.0 mmHg and NISC-edL from 14.1 to 14.6 mm indicating increased ventricular filling. Non-ischemic systolic shortening did not change. Ischemic systolic shortening was improved from 9.2% to 17.5%, which was not due to an increase in RISC-edL (14.8 versus 14.7 mm), enhanced RISC-Q (13 versus 12 ml/min), reduced AoP (86 versus 84 mmHg) or change in inotropy (dP/dtmax: 2290 versus 2240 mmhg/s), but the increase in RISC-sdl correlated closely (r greater than 0.85) to the reduction in HR (oxygen-demand).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of a bradycardic agent on the isolated blood-perfused canine heart

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.

Specific bradycardic agents. 2. Heteroaromatic modifications in the side chain of specific bradycardic benzazepinones: chemistry, pharmacology, and structure-activity relationships

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.

Specific bradycardic agents. 1. Chemistry, pharmacology, and structure-activity relationships of substituted benzazepinones, a new class of compounds exerting antiischemic properties [Erratum to document cited in CA112(21):198106m

Specific bradycardic agents. 1. Chemistry, pharmacology, and structure-activity relationships of substituted benzazepinones, a new class of compounds exerting antiischemic properties [Erratum to document cited in CA112(21):198106m

Effects of alinidine and falipamil, two new specific bradycardic agents, on the atrial effective refractory period in conscious dogs. Comparison with quinidine: M. Boucher, E. Chapuy, P. Ducheˆne-Marullaz. U195 INSERM, Faculty of Medicine,63001 Clermont-Fd Cedex

Effects of alinidine and falipamil, two new specific bradycardic agents, on the atrial effective refractory period in conscious dogs. Comparison with quinidine: M. Boucher, E. Chapuy, P. Ducheˆne-Marullaz. U195 INSERM, Faculty of Medicine,63001 Clermont-Fd Cedex