Electrophysiological characterization of the prokinetic agents cisapride and mosapride in vivo and in vitro: implications for proarrhythmic potential?

In the present study the electrophysiological characteristics and the proarrhythmic potential of cisapride and a structurally related drug, mosapride, were compared. In the anesthetized guinea pig, cisapride and d-sotalol (0.01-10 micromol/kg i.v., n = 6) dose-dependently prolonged the duration of the monophasic action potential recorded from the left ventricle. The maximal lengthening was 18 +/- 3.2% at 1.0 micromol/kg (mean +/- S.E.M., P < .01 vs. base line) and 19 +/- 2.5% at 10 micromol/kg (P < .001) for cisapride and d-sotalol, respectively. In contrast, mosapride did not increase this variable. In a rabbit model of the acquired long QT syndrome, infusion of cisapride (0.3 micromol/kg/min for 10 min maximum, n = 6), but not mosapride or vehicle, was associated with a significant lengthening of the QTU interval (43 +/- 3.8 ms, P < .01). Furthermore, torsades de pointes appeared in two of the six rabbits given cisapride. In isolated rabbit Purkinje fibers (PF), cisapride increased the action potential duration (48 +/- 5.6% at 0.1 micromol/l, P < .01 vs. control, n = 4). Mosapride did not significantly influence the action potential duration (3 +/- 2.0% increase at 1.0 micromol/l, n = 6). However, after mosapride was washed out, the addition of cisapride (0.1 micromol/l) caused a 46 +/- 3.2% lengthening of the action potential duration (P < .01 vs. 1.0 micromol/l mosapride). Early afterdepolarizations and triggered activity appeared in four of eight cisapride-superfused PF stimulated at a very low frequency (0.1 Hz). In isolated rabbit cardiomyocytes, cisapride concentration-dependently blocked (IC50 = 9 nmol/l) the rapid component of the delayed rectifying K+ current (I(Kr)). Mosapride was approximately 1000-fold less potent in blocking I(Kr) (IC50 = 4 micromol/l). It is concluded that the electrophysiological characteristics of cisapride may explain the recently reported propensity to prolong the QT interval and to induce torsades de pointes in susceptible patients, although a structurally related benzamide, mosapride, did not appear to have electrophysiological features of relevance for induction of torsades de pointes in common with cisapride.

Rhythm anomalies related to delayed repolarization in vivo: influence of sarcolemmal Ca++ entry and intracellular Ca++ overload.

The present study examined how Ca++ entry and intracellular Ca++ overload may contribute to the appearance of torsades de pointes in the setting of delayed repolarization. In anesthetized rabbits, the infusion of methoxamine and the selective I kappa s blocker almokalant (8.8 micrograms/kg.min) was associated with a lengthening of the QTU interval (37 +/- 2.6 ms, P < .001) and the appearance of torsades de pointes in 9/10 rabbits. In rabbits pretreated with nisoldipine (7.7 or 37 micrograms/kg i.v.), the incidence of almokalant-induced torsades de pointes was reduced to 7/10 (P = .5820 vs. vehicle) and 1/10 (P = .0006) rabbits, respectively. This occurred without attenuating the QTU-prolonging effect of almokalant (47 +/- 7.0 ms and 56 +/- 8.6 ms, respectively). Likewise, pretreatment with flunarizine (0.5 or 3.0 mg/kg i.v.) reduced the incidence to 1/6 (P = .0076) and 0/6 animals (P = .0009), respectively. In 10 of the rabbits that were given nisoldipine or flunarizine and did not experience torsades de pointes with almokalant, BAY K 8644 (0.11 mg/kg) was injected. In six of these rabbits, BAY K 8644 promptly induced torsades de pointes. In four vehicle-pretreated rabbits that experienced torsades de pointes with almokalant, acute injection of nisoldipine (37 micrograms/kg) abruptly suppressed the proarrhythmia. In separate experiments, rabbits were treated with ryanodine or BAPTA-AM and were subsequently administered almokalant. Compared with the vehicle-pretreated rabbits, these interventions did not significantly reduce the incidence of torsades de pointes (from 6/5 rabbits to 3/8 and 3/8 rabbits, respectively, P = .1776). The results demonstrate that Ca++ entry through the L-type Ca++ channel may be of crucial importance for the induction of torsades de pointes in the acquired long QT syndrome.

Attenuation of proarrhythmias related to delayed repolarization by low-dose lidocaine in the anesthetized rabbit.

Polymorphous ventricular tachyarrhythmias (torsades de pointes) were induced in seven of eight (88%) anesthetized rabbits receiving the class III antiarrhythmic agent almokalant (25 nmol/kg/min i.v.). The tachyarrhythmia was preceded by a significant lengthening of the QT interval from 118 +/- 7.2 to 148 +/- 9.0 msec, P < .01. Two separate groups of eight rabbits in each were given lidocaine (4.3 mumol/kg + 12.8 mumol/kg/hr or 12.8 mumol/kg + 38.4 mumol/kg/hr), before almokalant was administered. In comparison with the vehicle-pretreated rabbits, lidocaine treatment caused a dose-dependent attenuation in the incidence of torsades de pointes. Hence, the incidence was reduced to four of eight (50%, P = .1538 vs. the vehicle-treated group) rabbits and to none of eight (0%; P = .0007) rabbits in the groups treated with the "low" and the "high" dose of lidocaine, respectively. This attenuation was observed despite a significant prolongation of the QT interval by almokalant (from 128 +/- 7.6 to 175 +/- 15.9 msec, P < .01, and from 116 +/- 8.4 to 159 +/- 10.3 msec, P < .001, respectively). Acute injection of lidocaine (12.8 mumol/kg, n = 4) during recurrent episodes of torsades de pointes in vehicle-treated rabbits caused an abrupt restoration of sinus rhythm without influencing the almokalant-induced prolongation of the QT interval. It is concluded that lidocaine may inhibit the initiation of and suppress rhythm abnormalities related to delayed repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiarrhythmic effects of potassium channel openers in rhythm abnormalities related to delayed repolarization.

BACKGROUND: Earlier observations have indicated that repolarization-delaying agents may, under certain circumstances, have the propensity to induce polymorphous ventricular tachyarrhythmias (PVTs) (i.e., torsade de pointes). We have studied whether the potassium channel opener pinacidil and two of its pyridylcyanoguanidine analogues (P1075 and P1188) have any antiarrhythmic effects on clofilium-induced PVTs and triggered responses in rabbits in vivo and in vitro. METHODS AND RESULTS: Anesthetized rabbits were pretreated with propranolol (2 mumol/kg i.v.) and subsequently given a concomitant intravenous infusion of clofilium (63 nmol/kg/min for maximally 15 minutes) and the alpha 1-agonist methoxamine (70 nmol/kg/min). In vehicle-pretreated rabbits (n = 19), clofilium invariably induced PVTs, which closely resembled torsade de pointes and were preceded by a marked prolongation of the QTU interval (27 +/- 2.4%, p less than 0.001). In a separate group of seven rabbits in which monophasic action potentials were recorded from the left ventricular endocardium, the tachyarrhythmia was preceded by deflections consistent with early afterdepolarizations (EADs) of the plateau repolarization phase of the monophasic action potentials. Intravenous administration of the pyridylcyanoguanidines in doses reducing mean arterial blood pressure by 25 or 50 mm Hg, respectively, was associated with a dose-dependent attenuation in the occurrence of clofilium-induced PVTs. In the pinacidil-pretreated rabbits (0.41 mumol/kg or 1.86 mumol/kg i.v.), the occurrence of PVTs was reduced from seven of seven rabbits to five of six and to three of seven rabbits (p = 0.035 versus vehicle-pretreated controls), respectively. In rabbits pretreated with the low dose of P1075 (0.01 mumol/kg i.v.), PVT occurrence was reduced from six of six rabbits to two of six rabbits (p = 0.030), whereas in six rabbits given the high dose of P1075 (0.13 mumol/kg), no PVTs appeared (p = 0.001). When the sulfonylurea glibenclamide (10 mumol/kg i.v.) was administered to rabbits before P1075 (0.13 mumol/kg) was infused, clofilium induced PVTs in five of six rabbits (not significantly different from the incidence in the vehicle-pretreated rabbits). Pretreatment with P1188 (4.36 mumol/kg or 11.88 mumol/kg i.v.) caused a reduction in the occurrence of PVT from six of six rabbits to five of six and to none of six rabbits (p = 0.001), respectively. In the six animals pretreated with the high dose of P1188 in which no clofilium-induced arrhythmias were elicited, glibenclamide (20 mumol/kg i.v.) was injected after the entire dose of clofilium had been administered. In these rabbits, premature ventricular systoles and PVTs appeared within a few minutes in five and four of the animals, respectively. In contrast to the pyridylcyanoguanidines, diltiazem pretreatment (0.9 mumol/kg i.v., decreasing arterial pressure by 50 mm Hg) did not attenuate PVT occurrence (five of six rabbits). Acute administration of P1075 (0.13 mumol/kg) during recurrent attacks of PVTs abruptly regularized the rhythm in 12 of 13 animals and diminished EADs observed in monophasic action potentials recorded from the left ventricular endocardium. In in vitro experiments, action potentials were simultaneously recorded from rabbit Purkinje fibers and ventricular muscle cells. Clofilium markedly prolonged action potential duration in Purkinje fibers but not in ventricular muscle cells, and eventually, bradycardia-dependent EADs and triggered activity were elicited. P1075 completely abolished EADs and triggered activity in all (six of six) experiments. Glibenclamide antagonized the suppressive effect of P1075; hence, EADs and triggered responses reappeared and resembled those present before P1075. CONCLUSIONS: These results suggest that ATP-sensitive potassium channel activat BACKGROUND: Earlier observations have indicated that repolarization-delaying agents may, under certain circumstances, have the propensity to induce polymorp

Effect of dietary fiber on copper, zinc, and magnesium utilization by adolescent boys.

The effect of three dietary fibers on zinc, copper, and magnesium utilization by adolescent boys was studied. The 21-day study was divided into a 2-day introductory nitrogen depletion period, a 3-day adjustment period, and a four 4-day randomly arranged experimental period. During the four experimental periods, the eight adolescent male subjects received a basal diet plus 14.2 g supplements of cellulose, hemicellulose, or pectin. All subjects received all experimental diets. Zinc, copper, and magnesium contents of food, urine and blood serum were measured by atomic absorption spectrophotometry. Relatively small changes in urinary excretion or in blood serum contents of these minerals were found that could be attributed to dietary fiber supplementation. Statistically significant changes in fecal mineral loss were demonstrated. While receiving the basal diet alone or plus hemicellulose, cellulose, or pectin, mean fecal zinc contents (milligrams per subject per day) were 9.64, 13.32, 10.26, and 9.63, respectively; mean fecal copper contents (milligrams per subject per day) were 3.78, 5.04, 4.07, and 3.91, respectively; and mean fecal magnesium contents (milligrams per subject per day) were 303.71, 379.20, 325.69, and 278.48, respectively.

Anti-hypertensive effect of metoprolol in spontaneously hypertensive rats.

1. Oral and intravenous administration of metoprolol to adult spontaneously hypertensive rats (SHR) with established hypertension lowered arterial blood pressure within 4 days of treatment. 2. Steady state plasma concentrations of metoprolol were similar to those of patients during anti-hypertensive treatment with this drug. 3. The neuroeffector function of portal veins of SHR treated orally for 14 days or intravenously for 4 days was not impaired when studied in vitro. This is in contrast to previous findings after long-term treatment. 4. It is concluded that the anti-hypertensive effect of metoprolol in SHR in many respects resembles that observed in patients. It is suggested that impairment of vasomotor nerve control may contribute to the anti-hypertensive effect of beta-adrenoreceptor antagonists.