Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
1.
Circulation ; 100(18): 1917-22, 1999 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-10545437

RESUMEN

BACKGROUND: To date, the lack of potent and selective inhibitors has hampered the physiological assessment of modulation of the cardiac slowly activating delayed rectifier current, I(Ks). The present study, using the I(Ks) blocker L-768,673, represents the first in vivo assessment of the cardiac electrophysiological and antiarrhythmic effects of selective I(Ks) blockade. METHODS AND RESULTS: In an anesthetized canine model of recent (8.5+/-0.4 days) anterior myocardial infarction, 0.003 to 0.03 mg/kg L-768,673 IV significantly suppressed electrically induced ventricular tachyarrhythmias and reduced the incidence of lethal arrhythmias precipitated by acute, thrombotically induced posterolateral myocardial ischemia. Antiarrhythmic protection afforded by L-768,673 was accompanied by modest 7% to 10% increases in noninfarct zone ventricular effective refractory period, 3% to 5% increases in infarct zone ventricular effective refractory period, and 4% to 6% increases in QTc interval. In a conscious canine model of healed (3 to 4 weeks) anterior myocardial infarction, ventricular fibrillation was provoked by transient occlusion of the left circumflex coronary artery during submaximal exercise. Pretreatment with 0.03 mg/kg L-768,673 IV elicited a modest 7% increase in QTc, prevented ventricular fibrillation in 5 of 6 animals, and suppressed arrhythmias in 2 additional animals. CONCLUSIONS: The present findings suggest that selective blockade of I(Ks) may be a potentially useful intervention for the prevention of malignant ischemic ventricular arrhythmias.


Asunto(s)
Acetamidas/uso terapéutico , Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Benzodiazepinonas/uso terapéutico , Bloqueo Cardíaco/terapia , Isquemia Miocárdica/tratamiento farmacológico , Disfunción Ventricular/tratamiento farmacológico , Animales , Arritmias Cardíacas/etiología , Modelos Animales de Enfermedad , Perros , Electrocardiografía , Isquemia Miocárdica/complicaciones , Sistema Nervioso Simpático/fisiología , Disfunción Ventricular/etiología
2.
J Am Coll Cardiol ; 34(3): 876-84, 1999 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10483973

RESUMEN

OBJECTIVES: The antiarrhythmic efficacies of the competitive angiotensin II (AII) antagonist losartan, losartan's more potent noncompetitive AII antagonist human metabolite EXP3174 and the angiotensin-converting enzyme inhibitor captopril were assessed in a canine model of recent myocardial infarction. BACKGROUND: Multiple hemodynamic and electrophysiologic effects of AII may contribute to cardiac electrical instability. In the recent Losartan Heart Failure Study, Evaluation of Losartan in the Elderly (ELITE), a 722-patient trial primarily designed to assess effects on renal function, an unexpected survival benefit was observed with losartan compared with captopril, with the lower mortality using losartan primarily confined to a reduction in sudden cardiac death. METHODS: Intravenous losartan (1 mg/kg + 0.03 mg/kg/min), EXP3174 (0.1 mg/kg + 0.01 mg/kg/min), captopril (1 mg/kg + 0.5 mg/kg/h) or vehicle were infused in anesthetized dogs with recent (8.1 +/- 0.4 days) anterior myocardial infarction. Electrolytic injury of the left circumflex coronary artery to induce thrombotic occlusion and posterolateral ischemia was initiated 1 h after the start of treatment. RESULTS: Losartan, EXP3174 and captopril elevated plasma renin activities and comparably and significantly reduced mean arterial pressure. No significant electrocardiographic or cardiac electrophysiologic effects were noted with any treatment. Incidences of acute posterolateral ischemia-induced lethal arrhythmias were: vehicle, 7/9 (77%); losartan, 6/8 (75%); EXP3174, 2/8 (25%; p < 0.05 vs. vehicle control); captopril, 7/10 (70%). There were no among-group differences in time to onset of acute posterolateral ischemia or underlying anterior infarct size. CONCLUSIONS: EXP3174, but not losartan nor captopril, reduced the incidence of lethal ischemic ventricular arrhythmia in this preparation. The antiarrhythmic efficacy of EXP3174 may be due to an attenuation of deleterious effects of local cardiac AII formed during acute myocardial ischemia or, alternatively, a non-AII-related activity specific to EXP3174. These findings suggest that in humans, metabolic conversion of losartan to EXP3174 may afford antiarrhythmic protection.


Asunto(s)
Angiotensina II/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/prevención & control , Captopril/uso terapéutico , Modelos Animales de Enfermedad , Imidazoles/uso terapéutico , Losartán/uso terapéutico , Infarto del Miocardio/complicaciones , Isquemia Miocárdica/prevención & control , Tetrazoles/uso terapéutico , Análisis de Varianza , Animales , Arritmias Cardíacas/etiología , Perros , Evaluación Preclínica de Medicamentos , Femenino , Ventrículos Cardíacos , Humanos , Masculino , Isquemia Miocárdica/etiología , Factores de Tiempo
3.
J Hypertens ; 2(5): 541-5, 1984 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-6442314

RESUMEN

The relaxation response to endothelium-dependent (acetylcholine and the calcium ionophore A23187) and independent (sodium nitroprusside) vasodilators was examined in isolated aortic ring segments from age-matched genetically hypertensive (GH) and normotensive (N) rats (New Zealand strain). Tissues were initially contracted with methoxamine to achieve similar levels of contractile force. The IC20, IC40 and IC50 values for acetylcholine, A23187 and sodium nitroprusside were shifted significantly to the right (P less than 0.05) in aortic rings from GH rats compared to the corresponding values in N rats. The maximal relaxation achieved by acetylcholine and A23187 was significantly depressed in aortas from GH rats (P less than 0.05). Sodium nitroprusside elicited the maximal relaxation in both groups of tissues. These results demonstrate that there exists a generalized defect in the relaxant ability of vascular smooth muscle from GH rats. In addition, our findings suggest that this defect is coupled with a decreased responsiveness to endothelium-dependent vasodilators in this particular animal model of hypertension.


Asunto(s)
Endotelio/fisiopatología , Hipertensión/fisiopatología , Vasodilatación/efectos de los fármacos , Acetilcolina/farmacología , Animales , Aorta , Calcimicina/farmacología , Relación Dosis-Respuesta a Droga , Metoxamina/farmacología , Contracción Muscular/efectos de los fármacos , Nitroprusiato/farmacología , Ratas , Ratas Endogámicas SHR
5.
J Cardiovasc Pharmacol ; 21(3): 397-404, 1993 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-7681500

RESUMEN

The antiarrhythmic efficacy and proarrhythmic potential of the class IC antiarrhythmic agent encainide were assessed in subacute and chronic postinfarction canine models, respectively. In conscious dogs with spontaneous premature ventricular complexes (PVCs) at 48 h after anterior myocardial infarction (MI), cumulative intravenous (i.v.) administration of 1.0 and 3 mg/kg encainide significantly reduced PVC frequency. However, in anesthetized dogs studied more chronically after anterior MI (range 8-44 days), i.v. administration of 0.3-3 mg/kg encainide resulted in induction of new ventricular tachyarrhythmias by programmed ventricular stimulation in 6 of 10 dogs with no inducible arrhythmias prior to encainide. Newly induced arrhythmias after encainide administration included unimorphic and polymorphic ventricular tachycardia (VT) as well as VT degenerating rapidly into ventricular fibrillation (VF). The incidences of new arrhythmia induction after cumulative i.v. administration of encainide were 3 of 9 after 0.3 mg/kg i.v. encainide, 4 of 9 after 1.0 mg/kg i.v. encainide, and 5 of 10 after 3.0 mg/kg i.v. encainide. Time elapsed between MI and electrophysiologic testing tended to predict proarrhythmic response to encainide, with the six preparations with newly induced arrhythmias tested earlier than the four preparations that remained nonresponsive to postencainide programmed stimulation (13.2 +/- 3.1 vs. 26.5 +/- 6.5 days postinfarction, respectively, p = 0.07). There was also a trend toward larger underlying anterior MIs in the six preparations with newly induced arrhythmias as compared with the four preparations that remained nonresponsive to postencainide programmed stimulation (13.2 +/- 2.9 vs. 7.5 +/- 2.1% of left ventricle, respectively, p = 0.19).(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Arritmias Cardíacas/inducido químicamente , Encainida/toxicidad , Infarto del Miocardio/complicaciones , Animales , Arritmias Cardíacas/etiología , Complejos Cardíacos Prematuros/tratamiento farmacológico , Complejos Cardíacos Prematuros/etiología , Modelos Animales de Enfermedad , Perros , Estimulación Eléctrica , Electrofisiología , Encainida/uso terapéutico , Femenino , Ventrículos Cardíacos/efectos de los fármacos , Inyecciones Intravenosas , Masculino , Infarto del Miocardio/tratamiento farmacológico
6.
Circ Res ; 76(1): 110-9, 1995 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8001268

RESUMEN

We compared the cardiac electrophysiological actions of two types of H1-receptor antagonists--the piperidines, astemizole and terfenadine, and the nonpiperidines, chlorpheniramine and pyrilamine-in vitro in guinea pig ventricular myocytes and in vivo in chloralose-anesthetized dogs. Astemizole and terfenadine significantly increased action potential duration of guinea pig myocytes. This concentration-dependent prolongation of action potential duration was reverse frequency dependent and led to development of early afterdepolarizations, which occurred more frequently at higher concentrations and slower pacing frequencies. Astemizole and terfenadine potently blocked the rapidly activating component of the delayed rectifier, IKr, with IC50 values of 1.5 and 50 nmol/L, respectively. At 10 mumol/L, terfenadine but not astemizole blocked the slowly activating component of the delayed rectifier, IKs (58.4 +/- 3.1%), and the inward rectifier, IK1 (20.5 +/- 3.4%). Chlorpheniramine and pyrilamine blocked IKr relatively weakly (IC50 = 1.6 and 1.1 mumol/L, respectively) and IKs and IK1 less than 20% at 10 mumol/L. Astemizole and terfenadine (1.0 to 3.0 mg/kg IV) significantly prolonged the QTc interval and ventricular effective refractory period in vivo. Chlorpheniramine and pyrilamine (< or = 3.0 mg/kg) did not significantly affect these parameters. Block of repolarizing K+ currents, particularly IK1, by astemizole and terfenadine produces reverse rate-dependent prolongation of action potential duration and development of early afterdepolarizations, delays ventricular repolarization, and may underlie the development of torsade de pointes ventricular arrhythmias observed with the use and abuse of these agents.


Asunto(s)
Astemizol/farmacología , Clorfeniramina/farmacología , Corazón/efectos de los fármacos , Pirilamina/farmacología , Terfenadina/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Electrocardiografía , Cobayas , Corazón/fisiología , Técnicas In Vitro , Canales de Potasio/efectos de los fármacos , Periodo Refractario Electrofisiológico/efectos de los fármacos
7.
J Pharmacol Exp Ther ; 277(2): 671-8, 1996 May.
Artículo en Inglés | MEDLINE | ID: mdl-8627544

RESUMEN

Class III activity has been proposed as a potential mechanism for the treatment of reentrant arrhythmias. The purpose of the present study was to assess the concordance in antiarrhythmic efficacy of MK-499, a selective blocker of IKr, the rapidly activating component of cardiac delayed rectifier K+ current, against programmed ventricular stimulation (PVS)-induced ventricular tachycardias and thrombotically induced lethal ischemic arrhythmias, and to characterize the electrophysiologic determinants of antiarrhythmic efficacy in the canine model of previous myocardial infarction. Single i.v. doses of 1.0, 3.0 and 10.0 micrograms/kg MK-499 were administered to anesthetized dogs with anterior myocardial infarctions. Protection (suppression + stabilization/slowing) vs. PVS-induced ventricular tachycardias occurred in 5/11 (45%) preparations at 1.0 microgram/kg, in 9/12 (75%) preparations at 3.0 micrograms/kg and in 10/11 (91%) preparations at 10.0 micrograms/kg i.v. MK-499. The incidences of lethal ventricular arrhythmias developing in response to thrombotically induced posterolateral myocardial ischemia were 34/40 (85%) in vehicle controls, 7/11 (64%) at 1.0 microgram/kg, 6/12 (50%, P < .05) at 3.0 micrograms/kg and 4/11 (36%, P < .01) at 10.0 micrograms/kg i.v. MK-499. Low-dose i.v. MK-499 prolonged ECG QT interval and increased noninfarct zone and infarct zone ventricular refractoriness. However, there was a poor concordance (56%) between response to PVS with MK-499 and response to thrombotically induced acute myocardial ischemia. Furthermore, different trends of association between site and magnitude of Class III effect and antiarrhythmic efficacy were observed for PVS- vs. ischemia-induced arrhythmias. Hence, although low-dose i.v. MK-499 provided significant protection against both electrically and ischemically triggered arrhythmias in the setting of previous myocardial infarction, protection against PVS-induced ventricular tachycardias was not highly predictive of protection against lethal ischemic arrhythmias in this preparation.


Asunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Benzopiranos/uso terapéutico , Infarto del Miocardio/fisiopatología , Piperidinas/uso terapéutico , Animales , Benzopiranos/farmacología , Perros , Electrocardiografía , Femenino , Corazón/efectos de los fármacos , Corazón/fisiopatología , Masculino , Piperidinas/farmacología
8.
J Cardiovasc Pharmacol ; 18(5): 687-95, 1991 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-1723765

RESUMEN

The effects of cumulative intravenous (i.v.) administration of potent and selective methanesulfonanilide class III antiarrhythmic agents on cardiac electrophysiologic and hemodynamic parameters were compared with those of D-sotalol in chloralose-anesthetized dogs. The new class III agents tested were E-4031 [1-(2-(6-methyl-2-pyridyl)ethyl)-(4-methanesulfonamidobenzoyl)pipe ridine]; UK-66,914 [N-(4-(1-hydroxy-2-(4-(4-pyridinyl)-1-piperazinyl)ethyl)phenyl) methanesulfonamide], and UK-68,798 [1-(4-methanesulfonamidophenoxy)-2-(N- (4-methanesulfonamidophenethyl)-N-methylamino)ethane]. The class III agents produced significant and dose-dependent increases in ventricular refractoriness, with effective doses required to increase ventricular relative refractory period 20 ms above baseline (ED20, micrograms/kg i.v., with 95% confidence limits) of 5.2 (4.2-6.6) for UK-68,798, 17 (13-23) for E-4031, 75 (58-99) for UK-66,914, and 3,700 (2,600-5,800) for D-sotalol. Significant increases in the electrocardiographic QT and QTc intervals paralleled the increases in ventricular refractoriness for the four class III agents. Significant increases in left ventricular (LV) + dP/dt also paralleled increases in ventricular refractoriness and QT intervals for E-4031 (10-1,000 micrograms/kg i.v.), UK-66,914 (100-1,000 micrograms/kg i.v.), and UK-68,798 (30-1,000 micrograms/kg i.v.), but not for D-sotalol. No concomitant alterations in LV-dP/dt were observed for the new and potent methanesulfonanilide class III agents, resulting in significant increases in the ratio of LV + dP/dt/-dP/dt for E-4031, UK-66,914, and UK-68,798. Potent and selective methanesulfonanilide class III agents therefore may augment cardiac contractility in addition to prolonging ventricular refractoriness.


Asunto(s)
Antiarrítmicos/farmacología , Corazón/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Animales , Perros , Relación Dosis-Respuesta a Droga , Electrocardiografía/efectos de los fármacos , Electrofisiología , Femenino , Hemodinámica/efectos de los fármacos , Masculino , Fenetilaminas/farmacología , Piperidinas/farmacología , Pirazinas/farmacología , Piridinas/farmacología , Periodo Refractario Electrofisiológico/efectos de los fármacos , Sotalol/farmacología , Sulfonamidas/farmacología
9.
J Cardiovasc Pharmacol ; 15(5): 764-75, 1990 May.
Artículo en Inglés | MEDLINE | ID: mdl-1692937

RESUMEN

The antiarrhythmic efficacy of a new and potent class III agent E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4- methylsulfonylaminobenzoyl)piperidine] was evaluated in several canine models of recent myocardial infarction. In anesthetized dogs with baseline inducible ventricular arrhythmias studied 4-10 days after anterior myocardial infarction, 30-300 micrograms/kg i.v. E4031 suppressed induction of ventricular tachyarrhythmias by programmed ventricular stimulation in 7 of 10 animals tested, while significantly prolonging refractoriness in both noninfarcted and infarcted ventricular myocardium. The incidence of lethal ischemic ventricular arrhythmias developing in response to acute posterolateral myocardial ischemia in the presence of previous anterior infarction was reduced from 10 of 10 (100%) in a vehicle pretreatment group to 3 of 10 (30%, p less than 0.01) in an E4031 (300 micrograms/kg intravenously, i.v.) pretreatment group. Neither the sizes of the underlying anterior myocardial infarctions (26.9 +/- 3.7 vs. 33.2 +/- 2.1% of left ventricle) nor the times to development of acute posterolateral myocardial ischemia (43 +/- 11 vs. 40 +/- 8 min) differed significantly between the vehicle and E4031 pretreatment groups, respectively, suggesting that the reduction in the incidence of lethal ischemic arrhythmias in the E4031 pretreatment group was not due to smaller underlying, electrically unstable myocardial substrates nor to a delay in onset of the acute ischemic insult. In conscious dogs with spontaneous ventricular ectopy at 48 h after myocardial infarction and in anesthetized dogs with no baseline inducible arrhythmias at 4-10 days after myocardial infarction, E4031 (30-3,000 micrograms/kg i.v.) produced no facilitation or aggravation of spontaneous or inducible ventricular arrhythmias. These findings suggest that pharmacologic agents such as E4031 that increase ventricular refractoriness (class III electrophysiologic activity) may provide significant protection against development of malignant ischemic ventricular arrhythmias in the setting of previous myocardial infarction.


Asunto(s)
Antiarrítmicos/farmacología , Infarto del Miocardio/tratamiento farmacológico , Piperidinas/farmacología , Piridinas/farmacología , Anestesia , Animales , Presión Sanguínea/efectos de los fármacos , Cloralosa , Perros , Estimulación Eléctrica , Electrocardiografía , Electrofisiología , Femenino , Corazón/fisiología , Masculino , Infarto del Miocardio/fisiopatología , Periodo Refractario Electrofisiológico/efectos de los fármacos
10.
J Cardiovasc Pharmacol ; 16(1): 41-9, 1990 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-1696665

RESUMEN

The antiarrhythmic actions of high-dose intravenous (i.v.) lidocaine infusions were assessed in conscious dogs with spontaneous ventricular ectopy subacutely (48 h) after anterior myocardial infarction and in anesthetized dogs with ventricular tachyarrhythmias inducible by programmed ventricular stimulation at 4-11 days after anterior myocardial infarction. In conscious dogs administered cumulative doses of lidocaine at 48 h after myocardial infarction, a significant reduction in the frequency of spontaneous ventricular ectopic complexes (from 61 +/- 12 to 11 +/- 9% of total complexes) occurred only after administration of 10 mg/kg i.v. lidocaine. In anesthetized postinfarction dogs responding to baseline programmed stimulation with ventricular tachyarrhythmias, lidocaine administration (6 mg/kg i.v. loading dose + 100 micrograms/kg/min i.v. maintenance infusion) resulted in a selective increase in infarct zone conduction time (53.0 +/- 5.6 to 60.5 +/- 6.2 msec; p less than 0.05), increases in infarct zone relative refractory periods (RRPs 182 +/- 5 to 193 +/- 5 ms; p less than 0.05), and effective refractory periods (ERPs 156 +/- 4 to 165 +/- 3 ms; p less than 0.05), and an increase in noninfarct zone ERP (154 +/- 5 to 166 +/- 8 ms; p less than 0.05). The induction of ventricular arrhythmias by programmed stimulation was suppressed by lidocaine (6 mg/kg + 100 micrograms/kg/min i.v.) in 5 of 10 postinfarction animals tested, with an additional 3 animals displaying favorable stabilizations of induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Arritmias Cardíacas/tratamiento farmacológico , Enfermedad Coronaria/complicaciones , Lidocaína/uso terapéutico , Infarto del Miocardio/complicaciones , Anestesia , Animales , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Enfermedad Coronaria/fisiopatología , Perros , Estimulación Eléctrica , Electrocardiografía , Electrofisiología , Femenino , Masculino , Infarto del Miocardio/fisiopatología , Periodo Refractario Electrofisiológico/efectos de los fármacos
11.
Am Heart J ; 121(5): 1413-21, 1991 May.
Artículo en Inglés | MEDLINE | ID: mdl-1708198

RESUMEN

The antiarrhythmic and antifibrillatory efficacies of the class IB antiarrhythmic agent tocainide were characterized in conscious dogs in the early subacute phase of anterior myocardial infarction (48 hours after infarction) and in anesthetized dogs with ventricular tachyarrhythmias that were inducible by programmed stimulation more chronically (10.8 +/- 1.0 days) after anterior myocardial infarction. The frequency of spontaneous premature ventricular complexes in the early subacute postinfarction phase was reduced significantly from 48.4% +/- 10.5% to 8.2% +/- 5.0% of total complexes (p less than 0.01) by the cumulative intravenous administration of 10 mg/kg tocainide. In the late postinfarction setting, the intravenous administration of tocainide (6 mg/kg intravenous loading dose + 100 micrograms/kg/min intravenous maintenance infusion) suppressed the initiation of ventricular tachyarrhythmias by programmed stimulation in 5 of 12 animals that were tested and slowed the rate of tachycardia in 3 additional animals. However, the incidence of ventricular fibrillation and of the total number of arrhythmia-related deaths that resulted from the occurrence of a secondary ischemic insult in the presence of previous infarction did not differ significantly between tocainide (75% [9 of 12] incidence of both ventricular fibrillation and of total number of arrhythmia-related deaths) and saline-vehicle control groups (80% [12 of 15] incidence of ventricular fibrillation; 93.3% [14 of 15] incidence of total number of arrhythmia-related deaths). These findings suggest that although class I agents such as tocainide may be efficacious in the suppression of spontaneous premature ventricular complexes and ventricular arrhythmias immediately after myocardial infarction, they may be of limited value in the prevention of malignant ischemic arrhythmias that occur later after myocardial infarction.


Asunto(s)
Antiarrítmicos/uso terapéutico , Complejos Cardíacos Prematuros/prevención & control , Lidocaína/análogos & derivados , Infarto del Miocardio/complicaciones , Taquicardia/prevención & control , Animales , Complejos Cardíacos Prematuros/etiología , Estimulación Cardíaca Artificial , Perros , Femenino , Sistema de Conducción Cardíaco/efectos de los fármacos , Sistema de Conducción Cardíaco/fisiopatología , Lidocaína/uso terapéutico , Masculino , Taquicardia/etiología , Factores de Tiempo , Tocainida
12.
Basic Res Cardiol ; 95(3): 186-98, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10879620

RESUMEN

The clinical use of positive inotropic agents has been associated with increased mortality, with proarrhythmia speculated to be a contributing factor. This study compares the arrhythmogenic potentials of six positive inotropic agents representing different mechanistic classes: the beta-adrenergic agonist dobutamine, the adenylyl cyclase activator forskolin, the phosphodiesterase-III inhibitor milrinone, the cardiac glycoside ouabain, and the sodium channel agonists DPI 201-106 and BDF 9148. These agents were studied in dogs with anterior myocardial infarction using lower and higher dose i.v. regimens targeted to elicit 20-40% and 70-90% increases in LV+dP/dt, respectively. Precipitation of new ventricular arrhythmia by programmed ventricular stimulation was observed in all treatment groups. Incidences of new arrhythmia were comparable in the lower dose regimens, ranging from 16.7% (3/18 animals with BDF 9148) to 31.6% (6/19 animals with DPI 201-106), and in the higher dose regimens, ranging from 10.0% (1/10 animals with milrinone) to 27.7% (5/18 animals with DPI 201-106). The overall incidence of new ventricular arrhythmia ranged from 27.3% (3/11 animals with ouabain) to 47.4% (9/19 animals with DPI 201-106). No differences were observed in underlying infarct size or time from infarction to electrophysiologic study between subgroups of animals in which new arrhythmias were precipitated vs. those remaining non-responsive in any treatment group. The positive inotropic agents tested displayed diverse total group effects on heart rate, electrocardiographic intervals including QTc and ventricular refractoriness. Within individual treatment comparisons revealed a general but not universal pattern of greater ventricular refractory period values in newly inducible vs. non-inducible subgroups in the DPI 201-106, BDF 9148 and ouabain (low and high dose); milrinone and dobutamine (high dose) treatment groups. These findings indicate that regardless of underlying cellular mechanism of action, the six positive inotropic agents tested all displayed comparable proarrhythmic potentials unrelated to underlying infarct size and time from infarction. This observation suggests the general shared property of increased myocardial contractility, potentially adversely affecting myocardial oxygen balance, myocardial perfusion and electrical stability in the setting of previous myocardial infarction, to be a common underlying cause for arrhythmogenesis. Additionally, alterations in ventricular refractoriness and repolarization may contribute significantly to proarrhythmia with some positive inotropic interventions.


Asunto(s)
Arritmias Cardíacas/inducido químicamente , Cardiotónicos/efectos adversos , Animales , Perros , Electrocardiografía , Electrofisiología , Corazón/efectos de los fármacos , Corazón/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Infarto del Miocardio/patología , Taquicardia Ventricular/inducido químicamente , Función Ventricular Izquierda/efectos de los fármacos
13.
J Pharmacol Exp Ther ; 230(1): 103-9, 1984 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-6747822

RESUMEN

Cyproheptadine was compared with nifedipine, verapamil and diltiazem for calcium entry blocker activity in isolated cardiovascular preparations. Using rat aortic strips, all compounds (10(-7) M) inhibited both the contraction caused by the readdition of calcium (1.0 mM) into regular buffer or buffer containing potassium (130 mM) or norepinephrine (10(-5) M) and the potassium-stimulated uptake of 45Ca. The rank order of potency for these experiments was in general nifedipine greater than cyproheptadine greater than or equal to verapamil greater than diltiazem. The same order of potency also was found for the four compounds in relaxing potassium (40 mM)-contracted aortic strips (IC50 values: nifedipine, 2.6 X 10(-9) M; cyproheptadine, 6.3 X 10(-8) M; verapamil, 7.6 X 10(-8) M; and diltiazem, 2.1 X 10(-7) M), but cyproheptadine was the least potent agent in antagonizing the spontaneous contractions of the rat portal vein (IC50 values: nifedipine, 6.6 X 10(-9) M; verapamil 7.7 X 10(-8) M; diltiazem 9.6 X 10(-8) M; and cyproheptadine 3.9 X 10(-7)M). None of the compounds (10(-7) M) inhibited the contraction to norepinephrine (10(-5) M) in rabbit aortic strips bathed in calcium-free buffer (1 mM ethylene glycol bis(beta-aminoethyl ether)-N, N'-tetraacetic acid). Nifedipine, verapamil and diltiazem were more potent in inhibiting the restoration of contractility by isoproterenol in potassium-depolarized rabbit papillary muscles than decreasing force in normally polarized muscles; cyproheptadine was equipotent when tested in these two preparations. Cyproheptadine was the least potent of the four compounds in lowering perfusion pressure in the perfused canine hindlimb.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Ciproheptadina/farmacología , Músculo Liso Vascular/efectos de los fármacos , Animales , Diltiazem/farmacología , Femenino , Corazón/efectos de los fármacos , Masculino , Contracción Muscular/efectos de los fármacos , Nifedipino/farmacología , Norepinefrina/farmacología , Músculos Papilares/efectos de los fármacos , Cloruro de Potasio/farmacología , Conejos , Ratas , Ratas Endogámicas , Verapamilo/farmacología
14.
J Cardiovasc Pharmacol ; 18(3): 406-14, 1991 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-1720841

RESUMEN

The effects of the new and potent methanesulfonanilide class III antiarrhythmic agents (E-4031, UK-66,914, and UK-68,798) on myocardial refractoriness and contractility were compared to those of d-sotalol in ferret isometrically contracting right ventricular papillary muscle preparations. During 1 Hz pacing at 37 degrees C, the four class III agents elicited concentration-dependent increases in ventricular effective refractory period (ERP), with a relative order of potency of UK-68,798 greater than E-4031 greater than UK-66,914 much greater than d-sotalol. EC25 values (effective concentration required to increase ERP 25% above baseline) were (in microM) UK-68,798, 0.018; E-4031, 0.058; UK-66,914, 0.501; and d-sotalol, 43.76. Maximal increases in ERP relative to baseline (% of baseline value) for the class III agents at 37 degrees C (range of 44.5 +/- 4.5 to 63.0 +/- 3.1%) were greater than the maximal increases observed at 27 degrees C (range of 15.0 +/- 3.3 to 31.2 +/- 4.8%), whereas the maximal absolute (ms) increases in ERP above baseline were comparable for the class III agents at both temperatures. Increases in ERP produced by the four class III agents at 37 degrees C were significantly greater at a pacing frequency of 1 Hz (range of 70.0 +/- 7.6 to 102.0 +/- 2.3 ms) than at 3 Hz (range of 18.3 +/- 4.4 to 31.BBB/- 4.8 ms). During a temporary period of hypoxic perfusion at 37 degrees C, increases in ERP produced by the four class III agents were reversed, such that "hypoxic" ERP values approximated pretreatment, baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Antiarrítmicos/farmacología , Corazón/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Periodo Refractario Electrofisiológico/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Estimulación Cardíaca Artificial , Hurones , Hipoxia/fisiopatología , Técnicas In Vitro , Masculino , Fenetilaminas/farmacología , Piperidinas/farmacología , Pirazinas/farmacología , Piridinas/farmacología , Sotalol/farmacología , Sulfonamidas/farmacología , Temperatura
15.
J Pharmacol Exp Ther ; 248(1): 149-56, 1989 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-2464055

RESUMEN

BRL 34915 [6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl) 2H-benzo(b) pyran-3-ol], minoxidil sulfate and diazoxide may relax vascular smooth muscle via hyperpolarization due to an opening of membrane potassium channels. We therefore examined the effects of several potassium channel antagonists on the relaxation response to these vasodilators in isolated rat portal venous strips which were mounted in vitro for detecting changes in isometric force. BRL 34915 (IC50 = 4.7 X 10(-8) M), minoxidil sulfate (IC50 = 1.4 X 10(-7) M) and diazoxide (IC50 = 5 X 10(-6) M) elicited concentration-dependent relaxations of the spontaneous, myogenic contractions in venous strips. The relatively nonselective potassium channel antagonists tetraethylammonium ion (0.3-10 X 10(-3) M) and 4-aminopyridine (1-10 X 10(-3) M) caused concentration-dependent shifts (5- to 50-fold) in the relaxation responses to each vasodilator. Charybdotoxin (up to 10(-7) M) and apamin (up to 10(-7) M), known to be antagonists of high and low conductance calcium-activated potassium channels, respectively, had no inhibitory effect on the relaxation-response curves to BRL 34915, minoxidil sulfate or diazoxide. Glyburide (10(-7) to 3 X 10(-5) M), a sulfonylurea which has been shown to block the ATP-modulated potassium channel in insulin-secreting cells, caused concentration-dependent shifts to the right (up to 100-fold) of the IC50 value for BRL 34915 and diazoxide, and at 10(-6) M, abolished the relaxation response to minoxidil sulfate.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Antihipertensivos/farmacología , Benzopiranos/farmacología , Diazóxido/farmacología , Gliburida/farmacología , Minoxidil/análogos & derivados , Músculo Liso Vascular/efectos de los fármacos , Pirroles/farmacología , Vasodilatación/efectos de los fármacos , 4-Aminopiridina , Adenosina Trifosfato/farmacología , Aminopiridinas/farmacología , Animales , Caribdotoxina , Cromakalim , Masculino , Minoxidil/farmacología , Canales de Potasio/efectos de los fármacos , Ratas , Ratas Endogámicas , Venenos de Escorpión/farmacología , Tetraetilamonio , Compuestos de Tetraetilamonio/farmacología
16.
J Pharmacol Exp Ther ; 269(2): 541-54, 1994 May.
Artículo en Inglés | MEDLINE | ID: mdl-7802864

RESUMEN

The cardiac electrophysiologic and antiarrhythmic actions of two Class III ketone- and alcohol-containing spirobenzopyran piperidine analogs, L-702,958 and L-706,000 [MK-499], respectively, were assessed in vitro and in vivo. L-702,958 and L-706,000 [MK-499] selectively blocked the rapidly activating component of the delayed rectifier K+ current in guinea pig isolated ventricular myocytes (IC50 values, 14.6 and 43.9 nM, respectively), and prolonged effective refractory period in ferret isolated papillary muscles (EC25 values, 10.5 and 53.8 nM, respectively). In anesthetized dogs, L-702,958 and L-706,000 [MK-499] increased ventricular refractory periods (ED20 values, 3.3 and 9.2 micrograms/kg i.v., respectively) and concomitantly increased ECG QT interval and left ventricular+dP/dt. Cumulative i.v. administrations of up to 100 micrograms/kg of L-702,958 and 300 micrograms/kg L-706,000 [MK-499] in anesthetized dogs increased atrial and ventricular refractoriness and prolonged the ECG QT interval, but did not alter atrial, atrioventricular nodal, His-Purkinje or ventricular conduction indices. In anesthetized dogs studied chronically (9.2 +/- 1.1 days) after anterior myocardial infarction, the cumulative i.v. administrations of 100 micrograms/kg of L-702,958 and 300 of micrograms/kg L-706,000 [MK-499] suppressed the induction of ventricular tachyarrhythmia by programmed ventricular stimulation (suppression rates: 8 of 10, 80% and 9 of 11, 82%, respectively) and reduced the incidence of lethal ventricular arrhythmias (incidence of lethal ischemic arrhythmias: 4 of 10, 40% and 1 of 11 9%, respectively, compared to 34 of 40, 85%, in vehicle controls. L-702,958 and L-706,000 [MK-499] (cumulative 100 and 300 micrograms/kg i.v., respectively) did not facilitate the induction of arrhythmias by programmed ventricular stimulation in postinfarction dogs. After equivalently effective p.o. doses in conscious dogs, L-702,958 (10 micrograms/kg) and L-706,000 [MK-499] (30 micrograms/kg) increased ECG QT interval with long durations of action of approximately 9 and 14 hr, respectively. L-706,000 [MK-499] elicited a more consistent and sustained prolongation of the QT interval than L-702,958. These findings show that both L-702,958 and L-706,000 [MK-499] are potentially useful agents for the prevention of malignant ventricular arrhythmias in the setting of myocardial ischemic injury.


Asunto(s)
Antiarrítmicos/farmacología , Benzopiranos/farmacología , Corazón/efectos de los fármacos , Piperidinas/farmacología , Animales , Perros , Electrocardiografía/efectos de los fármacos , Femenino , Hurones , Cobayas , Corazón/fisiología , Hemodinámica/efectos de los fármacos , Técnicas In Vitro , Masculino , Estructura Molecular , Isquemia Miocárdica/fisiopatología
17.
J Pharmacol Exp Ther ; 273(1): 168-75, 1995 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-7714763

RESUMEN

The Class III electrophysiologic and antiarrhythmic actions of the bradycardic agent tedisamil were assessed in vitro and in vivo. In ferret isolated right ventricular papillary muscles, tedisamil increased effective refractory period (ERP) in a concentration-dependent manner, with a 25% ERP increase achieved with 3.0 microM tedisamil, and a 133.4% +/- 28.8% increase in ERP achieved at the high 100 microM concentration tested. In anesthetized dogs, the cumulative i.v. administration of tedisamil significantly increased ventricular relative refractory period (VRRP) and ventricular effective refractory period (VERP) as well as electrocardiographic QTc intervals (100-1000 micrograms/kg i.v.). A 20msec increase in VRRP was achieved with 45.0 micrograms/kg i.v. tedisamil, and a 56.1 +/- 9.8 msec (40.1% +/- 8.1%) increase in VRRP was achieved at the highest dose tested (1000 micrograms/kg i.v.). In the same dosage range in anesthetized dogs, tedisamil produced significant hemodynamic effects, including reduction in HR (100-1000 micrograms/kg i.v.) and elevations in mean arterial pressure (1000 micrograms/kg i.v.), left ventricular developed pressure (1000 micrograms/kg i.v.) and the maximum rate of LV pressure development (100-1000 micrograms/kg i.v.). In anesthetized dogs studied chronically (8.2 +/- 0.6 days) after anterior myocardial infarction, tedisamil suppressed programmed stimulation-induced ventricular tachyarrhythmias (8/10, 80% suppression at 100-1000 micrograms/kg i.v.) and reduced the incidence of lethal ischemic arrhythmias developing in response to acute posterolateral myocardial ischemia (arrhythmic mortality 5/10, 50% tedisamil vs. 34/40, 85% vehicle control cohort; P = .027). The latter findings suggest that tedisamil might be useful in the prevention of malignant ventricular arrhythmias in the setting of myocardial ischemic injury.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Antiarrítmicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes , Compuestos Bicíclicos con Puentes/farmacología , Ciclopropanos/farmacología , Corazón/efectos de los fármacos , Animales , Perros , Electrocardiografía , Femenino , Hurones , Corazón/fisiología , Hemodinámica/efectos de los fármacos , Técnicas In Vitro , Masculino , Isquemia Miocárdica/fisiopatología , Músculos Papilares/efectos de los fármacos , Músculos Papilares/fisiología , Canales de Potasio/efectos de los fármacos , Periodo Refractario Electrofisiológico/efectos de los fármacos
18.
J Pharmacol Exp Ther ; 265(2): 720-30, 1993 May.
Artículo en Inglés | MEDLINE | ID: mdl-8496818

RESUMEN

The cardiac electrophysiologic and antiarrhythmic actions of 3,4-dihydro-1'-[2-(benzofurazan-5-yl)ethyl]-6-methyl-sulfonamid ospiro [(2H)-1-benzopyran-2,4'-piperidin]-4-one HCl (L-691,121), a novel spirobenzopyran piperidine class III agent, were assessed in vitro and in vivo. In ferret isolated papillary muscles, L-691,121 significantly prolonged effective refractory period (EC25 = 13 nM) and elicited a modest positive inotropic effect. In guinea pig isolated ventricular myocytes, L-691,121 prolonged action potential duration by selectively blocking (IC50 = 4.4 nM) a rapidly activating and rectifying component of the delayed rectifier K+ current, Ikr. The class III activity of L-691,121 in isolated papillary muscles was reverse frequency-dependent, and reversed by hypoxic perfusion. L-691,121 modestly depressed spontaneous beating rate (-14%) in guinea pig isolated right atria at concentrations up to 3 microM. In anesthetized dogs, the i.v. administration of 10 to 100 micrograms/kg of L-691,121 significantly increased atrial and ventricular refractoriness and prolonged the electrocardiographic Q-T interval, but did not alter atrioventricular nodal, His-Purkinje, atrial or ventricular conduction. In conscious dogs with spontaneous premature ventricular complexes at 48 hr after myocardial infarction, 10 to 1000 micrograms/kg i.v. of L-691, 121 failed to reduce premature ventricular complex frequency. However, in anesthetized dogs studied chronically (7.9 +/- 0.3 days) after infarction, 10 and 100 micrograms/kg i.v. of L-691,121 suppressed the induction of ventricular tachyarrhythmia by programmed stimulation in 8/14 (57%) and 11/14 (79%) dogs tested, respectively, and reduced the incidence of lethal ventricular arrhythmias triggered by a secondary myocardial ischemic event from 14/15 (93%) in vehicle controls to 5/14 (36%; P < .01) in L-691,121-treated (100 micrograms/kg i.v.) animals. The latter findings suggest the potential for L-691,121 to prevent the development of malignant ventricular arrhythmias in the setting of previous myocardial infarction.


Asunto(s)
Antiarrítmicos/farmacología , Piperidonas/farmacología , Compuestos de Espiro/farmacología , Animales , Función Atrial , Células Cultivadas , Perros , Electrofisiología , Hurones , Cobayas , Atrios Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Técnicas In Vitro , Masculino , Infarto del Miocardio/fisiopatología , Isquemia Miocárdica/fisiopatología , Función Ventricular
19.
Circulation ; 96(3): 949-58, 1997 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-9264506

RESUMEN

BACKGROUND: A conscious dog model of left circumflex coronary artery electrolytic injury was used to assess the oral antithrombotic efficacy of L-738,167, a potent nonpeptide antagonist of platelet GP IIb/IIIa. L-738,167 was administered either as a single oral pretreatment dose 2 hours before initiation of vessel injury or as two oral doses administered 24 hours apart, 12 hours before and after initiation of vessel injury. METHODS AND RESULTS: In untreated controls, electrolytic coronary injury (50 microA, 3 hours) resulted in thrombotic occlusion and myocardial ischemia in 15 of 16 dogs, with 4 developing lethal arrhythmias. Significant reductions in thrombus mass and complete prevention of myocardial ischemia and infarction were achieved with a single 100- to 300-microg/kg dose of L-738,167 pretreatment and with two 100-microg/kg doses administered 12 hours before and after initiation of vessel injury. Delays and/or reductions in incidence of ischemia, thrombus mass, and infarct sizes also were achieved with 10- to 30-microg/kg pretreatment and with two 30-microg/kg doses administered 12 hours before and after initiation of vessel injury. None of the L-738,167-treated animals developed lethal arrhythmias. A single oral 100-microg/kg dose of L-738,167 achieved >90% inhibitions of ADP (extent)- and collagen (rate)-induced ex vivo platelet aggregation and fivefold to sixfold or greater elevations in bleeding time; a single oral 30-microg/kg dose of L-738,167 achieved sustained 40% to 70% inhibitions of ADP- and collagen-induced ex vivo platelet aggregation and modest twofold to threefold elevations in bleeding time. At 12 to 24 hours after single oral 30- and 100-microg/kg doses of L-738,167, a substantially greater L-738,167 concentration was associated with platelets than free in plasma. CONCLUSIONS: These findings are indicative of potent and sustained oral antithrombotic efficacy and suggest that L-738,167 possesses potential for the oral management of chronic thrombotic occlusive disorders.


Asunto(s)
Azepinas/farmacología , Enfermedad Coronaria/sangre , Fibrinolíticos/farmacología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Sulfonamidas/farmacología , Administración Oral , Animales , Azepinas/administración & dosificación , Tiempo de Sangría , Plaquetas/efectos de los fármacos , Trombosis Coronaria/prevención & control , Perros , Esquema de Medicación , Femenino , Fibrinolíticos/administración & dosificación , Masculino , Pruebas de Función Plaquetaria , Sulfonamidas/administración & dosificación
20.
J Pharmacol Exp Ther ; 289(1): 503-10, 1999 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10087043

RESUMEN

The small molecule direct thrombin inhibitor L-374,087 was characterized across species in an in vitro activated partial thromboplastin clotting time (aPTT) assay and in vivo in rhesus monkey and dog thrombosis models. In vitro in rhesus, dog, and human plasma, L-374,087 concentrations eliciting 2-fold increases in aPTT were 0.25, 1.9, and 0.28 microM, respectively. In anesthetized rhesus monkeys, 300 microgram/kg bolus plus 12 microgram/kg/min and 300 microgram/kg bolus plus 30 microgram/kg/min L-374,087 i.v. infusions significantly reduced jugular vein thrombus extension, with both regimens limiting venous thrombus extension to 2-fold that of baseline thrombus mass compared with a 5-fold extension observed in the vehicle control group. Antithrombotic efficacy in the rhesus with the lower-dose regimen was achieved with 2.3- to 2.4-fold increases in aPTT and prothrombin time. In a conscious instrumented dog model of electrolytic vessel injury, the oral administration of two 10 mg/kg L-374,087 doses 12 h apart significantly reduced jugular vein thrombus mass, reduced the incidence of and delayed time to occlusive coronary artery thrombosis, and significantly reduced coronary artery thrombus mass and ensuing posterolateral myocardial infarct size. Antithrombotic efficacy in the dog was achieved with 1.6- to 2.0-fold increases in aPTT at 1 to 6 h after oral dosing with L-374,087. These results indicate significant antithrombotic efficacy against both venous and coronary arterial thrombosis with L-374,087 with only moderate elevations in aPTT or prothrombin time. The oral efficacy of L-374,087 characterizes this compound as a prototype for the further development of orally active direct thrombin inhibitors.


Asunto(s)
Trombosis Coronaria/tratamiento farmacológico , Fibrinolíticos/farmacología , Venas Yugulares/patología , Piridonas/farmacología , Sulfonamidas/farmacología , Trombina/antagonistas & inhibidores , Trombosis de la Vena/tratamiento farmacológico , Administración Oral , Anestesia , Animales , Tiempo de Sangría , Coagulación Sanguínea/efectos de los fármacos , Trombosis Coronaria/sangre , Perros , Femenino , Fibrinolíticos/administración & dosificación , Fibrinolíticos/farmacocinética , Hematócrito , Hemoglobinas/metabolismo , Humanos , Técnicas In Vitro , Inyecciones Intravenosas , Macaca mulatta , Masculino , Tiempo de Tromboplastina Parcial , Recuento de Plaquetas/efectos de los fármacos , Piridonas/administración & dosificación , Piridonas/farmacocinética , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Trombosis de la Vena/sangre
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA