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Biomedical subjects

M A Wood

Publications and source records attributed to M A Wood.

At least 19 recordsLinked to original sources
PubMed1996

Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators.

BACKGROUND: Currently available antiarrhythmic drugs have limited efficacy for acute termination of atrial fibrillation and flutter, especially if the arrhythmia is not of recent onset. The purpose of this multicenter study was to determine the efficacy and safety of repeated doses of intravenous ibutilide, a class III antiarrhythmic drug, in terminating atrial fibrillation or flutter. METHODS AND RESULTS: Two hundred sixty-six patients with sustained atrial fibrillation (n = 133) or flutter (n = 133), with an arrhythmia duration of 3 hours to 45 days, were randomized to receive up to two 10-minute infusions, separated by 10 minutes, of ibutilide (1.0 and 0.5 mg or 1.0 and 1.0 mg) or placebo. The conversion rate was 47% after ibutilide and 2% after placebo (P < .0001). The two ibutilide dosing regimens did not differ in conversion efficacy (44% versus 49%). Efficacy was higher in atrial flutter than fibrillation (63% versus 31%, P < .0001). In atrial fibrillation but not flutter, conversion rates were higher in patients with a shorter arrhythmia duration or a normal left atrial size. Arrhythmia termination occurred a mean of 27 minutes after start of the infusion. Of 180 ibutilide-treated patients, 15 (8.3%) developed polymorphic ventricular tachycardia during or soon after the infusion. The arrhythmia required cardioversion in 3 patients (1.7%) and was nonsustained in 12 patients (6.7%). CONCLUSIONS: Intravenous ibutilide given in repeated doses is effective in rapidly terminating atrial fibrillation and flutter and under monitored conditions is an alternative to current cardioversion options.

Aged↗
PubMed1996

Sensing lead-related complications in patients with transvenous implantable cardioverter-defibrillators.

The widespread use of the redesigned Endotak lead (CPI, St. Paul, Minnesota), which combines transvenous pacing, sensing, and defibrillation on a single transvenous lead in patients receiving transvenous implantable cardioverter-defibrillators (ICDs), has reduced morbidity and shortened length of hospital stay after ICD implantation. We describe the incidence and management of Endotak sensing lead-related failures in a series of 348 consecutive patients from 4 institutions who underwent implantation between 1990 and 1995. We retrospectively reviewed the databases for patients receiving an ICD with an Endotak lead for the incidence of lead-related sensing abnormalities. Ten patients (2.8%) with lead-related sensing abnormalities were detected at a mean of 15 +/- 11 months after ICD implantation. Sensing abnormalities were detected in 6 patients after they received inappropriate shocks. Noise or oversensing was noted in 7 patients from interrogation of the devices' data logs. Eight patients had a new transvenous sensing lead placed, 1 patient had a new Endotak lead placed, and 1 had a chronic pacemaker sensing lead converted to function as a sensing lead. No further sensing problems were noted in 8 of 10 patients during a mean follow-up of 14 +/- 8 months. The site of the sensing lead failure was localized to the subrectus pocket in 5 patients and to the clavicle-first rib area in 3 patients; it was undetermined and presumed to be in the clavicle-first rib area in the other 2 patients. One patient had late failure of the defibrillation lead. We conclude that Endotak sensing lead failure does not require insertion of a new Endotak lead, but can be managed with close follow-up and insertion of a new transvenous sensing lead. Endotak lead fractures are frequently localized to the ICD pocket.

Aged↗
PubMed1996

Modulation of atrial repolarization by site of pacing in the isolated rabbit heart.

BACKGROUND: Single-site or multisite atrial pacing may reduce the incidence of atrial fibrillation in humans. The therapeutic mechanisms may include synchronization of atrial repolarization (repolarization "memory") and/or decreased dispersion of atrial repolarization. These responses have not been well documented in intact atria. METHODS AND RESULTS: Monophasic action potential recordings were made from six atrial epicardial sites in 39 isolated perfused rabbit heart preparations during 3 hours of continuous right atrial, left atrial, or biatrial pacing. Action potential recordings obtained at times 0, 45, 90, 135, and 180 minutes were computer analyzed for activation time (AT) and 90% action potential duration (APD) at each site. No consistent relationship could be demonstrated between APD and AT at any time during atrial pacing (all P > .05). On average, left atrial APDs were longer than right atrial APDs by up to 6.3 ms at all times, regardless of the site of pacing (P < or = .05). At all times, dispersion of atrial repolarization was minimized by left atrial pacing compared with right atrial pacing (21.6 +/- 9.1 versus 32.4 +/- 15.1 ms, respectively, at time 0; P < .05). Biatrial pacing provided no further reduction in dispersion of repolarization compared with left atrial pacing (all P > .05). CONCLUSIONS: No relationship can be demonstrated between atrial AT and APD in the isolated rabbit heart preparation. This differs from ventricular repolarization "memory," which is demonstrable under the same conditions. Left atrial APD is, on average, longer than right atrial APD, suggesting spatial heterogeneity in repolarization. Dispersion of atrial repolarization is minimized by left atrial pacing in this preparation with no further advantage to biatrial pacing.

Action Potentials↗
PubMed1996

Comparative efficacy of intravenous ibutilide versus procainamide for enhancing termination of atrial flutter by atrial overdrive pacing.

This study compares the influence of intravenous ibutilide, a class III antiarrhythmic agent, with procainamide, a class IA antiarrhythmic agent, and with placebo on its ability to terminate atrial flutter using rapid atrial pacing. Fifty-nine episodes of atrial flutter in 54 patients who failed to terminate with an intravenous infusion of ibutilide, procainamide, or placebo alone underwent attempts at pacing termination using a standard protocol of burst atrial overdrive pacing. Atrial flutter cycle length and atrial monophasic action potential duration recorded from the right atrium during atrial flutter were measured at baseline and following infusion of ibutilide, procainamide, or placebo. Both ibutilide and procainamide significantly enhanced (p <0.001) pacing-induced termination of atrial flutter compared with placebo. Pacing converted 2 of 11 patients (18%) who received placebo, 13 of 15 patients (87%) who received ibutilide, and 29 of 33 patients (88%) who received procainamide to sinus rhythm. Ibutilide and procainamide compared with placebo markedly reduced (p <0.001) the incidence of pacing-induced atrial fibrillation. The atrial flutter cycle length was prolonged significantly less (p <0.001), and the atrial monophasic action potential duration was increased significantly more (p <0.001) by ibutilide than by procainamide. Although the electrophysiologic changes induced by these antiarrhythmic agents contributed to facilitating pacing-induced termination, neither tachycardia cycle length nor action potential duration were useful predictors of the ability of pacing to terminate atrial flutter. In conclusion, despite differing electrophysiologic effects, the use of intravenous ibutilide or procainamide enhances the termination of atrial flutter by atrial overdrive pacing.

Aged↗
PubMed1996

Pharmacologic alterations in human type I atrial flutter cycle length and monophasic action potential duration. Evidence of a fully excitable gap in the reentrant circuit.

OBJECTIVES: This study compared the effect of changes in action potential duration versus conduction velocity on atrial flutter cycle length to determine whether there is a fully or partially excitable gap in atrial flutter. BACKGROUND: In an excitable gap reentrant circuit, cycle length is proportional to conduction velocity. Action potential duration is not a direct determinant of cycle length when the gap is fully excitable. METHODS: Right atrial monophasic action potentials were recorded from 41 patients during type I atrial flutter before and during pharmacologic interventions. RESULTS: Adenosine (17 +/- 3 mg [mean +/- SD]) shortened (p < 0.001) action potential duration but did not change cycle length. Edrophonium (10 mg) had no significant effect on action potential duration or cycle length. Isoproterenol (0.03 microgram/kg body weight per min) shortened (p < 0.05) and procainamide (15 mg/kg, then 2 mg/min) prolonged (p < 0.001) action potential duration and cycle length. Alterations in cycle length were not correlated with changes in action potential duration. Procainamide's prolongation of action potential duration was reversed by adenosine without affecting cycle length. Procainamide's prolongation of action potential duration and cycle length was partially reversed by isoproterenol. Adenosine's and isoproterenol's shortening of action potential duration and isoproterenol's shortening of cycle length were enhanced by procainamide. CONCLUSIONS: Atrial flutter cycle length is determined primarily by conduction velocity and does not depend directly on action potential duration. Atrial flutter has a fully excitable gap, and procainamide does not convert the gap from full to partial excitability. Adenosine and isoproterenol interact with procainamide such that their effects are enhanced and procainamide's effects are diminished.

Action Potentials↗
PubMed1996

Conversion of atrial flutter by ibutilide is associated with increased atrial cycle length variability.

OBJECTIVES: This study was designed to test the hypothesis that conversion of atrial flutter in humans by ibutilide, a new class III antiarrhythmic agent, is characterized by an increase in atrial cycle length variability. BACKGROUND: Conversion of tachyarrhythmias has been associated with increased oscillations of cycle length. METHODS: Electrograms and monophasic action potentials from the right atrium in 35 patients with spontaneous, sustained atrial flutter were recorded before, during and after intravenous ibutilide (0.005 to 0.025 mg/kg body weight, n = 25) or placebo (n = 10). Atrial cycle length, cycle length variability (coefficient of variation), diastolic interval and diastolic interval variability were measured from 10 consecutive cycles at baseline and 3 min before, 1 min before, 30 s before and immediately before conversion. Similar measurements were made in patients who received ibutilide or placebo but did not convert. RESULTS: Ibutilide converted atrial flutter in 14 of 25 patients 25 +/- 16 min (mean +/- SD) after initiation of the infusion, whereas placebo converted no patients. Atrial cycle length was prolonged to the same extent in ibutilide converters and nonconverters (36 +/- 19 vs. 38 +/- 21 ms, p = NS) and was not affected by placebo. Beat-to-beat variability in atrial cycle length (baseline 1.2 +/- 0.7 vs. preconversion 7.3 +/- 4.9, p < 0.01) and diastolic interval (baseline 11 +/- 8 vs. preconversion 33 +/- 23, p < 0.05) increased significantly just before atrial flutter conversion and remained unchanged in ibutilide nonconverters and placebo group patients. CONCLUSIONS: Ibutilide prolongs atrial cycle length, but conversion of atrial flutter by ibutilide is characterized by increased variability in atrial cycle length and diastolic interval.

Aged↗
PubMed1996

Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study.

OBJECTIVES: Currently available antiarrhythmic drugs have limited efficacy for short-term, rapid termination of atrial fibrillation and atrial flutter. BACKGROUND: Ibutilide fumarate is an investigational class III antiarrhythmic agent that prolongs repolarization by increasing the slow inward sodium current and by blocking the delayed rectifier current. It can be administered intravenously and has a rapid onset of electrophysiologic effects. METHODS: The efficacy and safety of ibutilide were studied in 200 patients with atrial flutter > 3 h in duration or atrial fibrillation 3 h to 90 days in duration. Patients were randomized to receive a single intravenous dose of placebo or an infusion of ibutilide fumarate at 0.005, 0.010, 0.015 or 0.025 mg/kg body weight over 10 min. Conversion was defined as termination of the atrial arrhythmia during or within 60 min after infusion. Forty-one patients received placebo and 159 received ibutilide (0.005 mg/kg [n = 41], 0.010 mg/kg [n = 40], 0.015 mg/kg [n = 38] or 0.025 mg/kg [n = 40]). RESULTS: The arrhythmia terminated in 34% of drug-treated patients. The rates of successful arrhythmia termination were 3% for placebo and 12%, 33%, 45% and 46%, respectively, for 0.005-, 0.010-, 0.015- and 0.025-mg/kg ibutilide. The placebo and 0.005-mg/kg ibutilide groups had lower success rates than all other dose groups (p < 0.05). The mean time to termination of the arrhythmia was 19 min (range 3 to 70) from the start of infusion. Successful arrhythmia termination was not affected by enlarged left atrial diameter, decreased ejection fraction, presence of valvular heart disease or the use of concomitant medications (beta-adrenergic blocking agents, calcium channel blocking agents or digoxin). Arrhythmia termination was not predicted by the magnitude of corrected QT interval prolongation but was associated with a shorter duration of atrial arrhythmia. The most frequent adverse events in ibutilide-treated patients were sustained and nonsustained polymorphic ventricular tachycardia (3.6%). All patients with sustained polymorphic ventricular tachycardia were successfully treated with direct current cardioversion and had no recurrence. The occurrence of proarrhythmia did not correlate with ibutilide plasma concentration. CONCLUSIONS: These data demonstrate that ibutilide is able to rapidly terminate atrial fibrillation and atrial flutter.

Aged↗
PubMed1996

Comparison of bipolar atrial electrogram amplitude in sinus rhythm, atrial fibrillation, and atrial flutter.

Automatic mode switching pacemakers revert to non-atrial tracking modes in response to sensed atrial tachyarrhythmias. It is unclear how atrial electrogram amplitudes in sinus rhythm compare to those during atrial tachyarrhythmias. In this study, peak-to-peak bipolar atrial electrogram amplitudes were measured during sinus rhythm and either atrial fibrillation or atrial flutter in 69 patients. The mean atrial electrogram amplitudes were 1.59 +/- 1.36 mV during sinus rhythm and 0.77 +/- 0.58 mV during atrial fibrillation (P < 0.0001) for 25 patients with atrial fibrillation and 1.81 +/- 2.07 mV during sinus and 1.5 +/- 1.81 mV (P < 0.0001) for 44 patients with atrial flutter. The mean electrogram amplitudes during both atrial fibrillation and flutter correlated significantly with amplitudes during sinus rhythm (R = 0.79, R = 0.94, respectively, both P < 0.0001). The coefficient of variance of individual electrogram amplitudes was greater in atrial fibrillation than sinus (P < 0.0001). By comparing 20th percentile electrogram amplitudes in atrial fibrillation and flutter to mean sinus amplitudes, intermittent very low electrogram amplitudes (< 0.3 mV) were more likely during atrial fibrillation and flutter if the mean sinus electrogram amplitudes were < 1.5 mV and < 0.5 mV, respectively (P < 0.01). Eightieth percentile electrogram amplitude values in atrial fibrillation and flutter were equally likely to exceed mean sinus amplitude values in respective patients. In conclusion, mean atrial electrogram amplitudes during atrial fibrillation and flutter are less than but correlated to sinus rhythm electrogram amplitudes. Very low amplitude individual electrograms during these atrial arrhythmias are associated with low mean sinus rhythm electrogram amplitudes. These findings may have implications for the programming of permanent dual chamber pacemakers in patients with paroxysmal atrial fibrillation and flutter.

Adolescent↗
PubMed1996

Acute effects of radiofrequency ablation of atrial arrhythmias on implanted permanent pacing systems.

We studied the safety of performing RF catheter ablation in patients with implanted permanent pacemakers by monitoring the function of implanted pacing systems before, during, and immediately after exposure to RF energy. Patients with implanted pacing systems may require RF ablation for treatment of a variety of tachyarrhythmias. High frequency electromagnetic fields, such as RF energy, may affect implanted pacing systems, causing temporary or permanent loss of output, undersensing, oversensing, asynchronous pacing, or reversion to "reset" (Recommended Replacement Time or Power On Reset) parameters. Thirty-five patients with implanted pacing systems (23 DDDR, 6 VVIR, 5 DDD, 1 VVI, 31 bipolar and 4 unipolar) underwent RF catheter ablation. Prior to ablation, each pacing system underwent measurements of pacing and sensing thresholds, telemetry of intracardiac electrograms and measurement of battery voltage and lead impedance(s). During ablation, pacemaker function was monitored by real-time telemetry, intracardiac electrograms, and surface ECG. Immediately after ablation, each pacing system was reevaluated. Telemetry during RF ablation revealed normal pacing and sensing in 14 (40%) of 35 patients. Refractory period extension with asynchronous pacing and noise mode reversion were seen in 16 (46%) of 35 patients. Rare under- and/or oversensing, reversion to reset parameters, and telemetry "lock up" with inhibition of pacing output was seen in a few patients. After ablation, there were no significant changes in atrial or ventricular pacing or sensing thresholds or measurements of atrial and ventricular lead impedances. We conclude that most permanent pacemakers are not adversely affected by exposure to RF energy during catheter ablation. A variety of pacemaker behaviors may be seen during RF ablation, and a thorough understanding of each pulse generator's potential response(s) to electromagnetic interference is important before undertaking catheter ablation in patients with permanent pacemakers. Careful reevaluation of the patient's pacing system following the procedure is mandatory.

Adult↗
PubMed1996

Reduction of antiarrhythmic drug use in patients receiving implantable cardioverter defibrillators.

Widespread use of implantable cardioverter defibrillators (ICDs) for the treatment of ventricular tachycardia (VT) and ventricular fibrillation (VF) occurred in the late 1980s and early 1990s. Additionally, there has been increasing appreciation during this time for both the lack of efficacy and proarrhythmic activity of antiarrhythmic drugs to treat these cardiac arrhythmias. We evaluated the use of antiarrhythmic drugs from 1987 to 1991 (5-year period) at the time of ICD implantation in 25,450 patients. The use of all classes of antiarrhythmic agents decreased from 61% to 24% during this time period (P < 0.05). In addition, there was a significant reduction in antiarrhythmic agent use for each drug class (P < 0.05) with the exception of Class II agents (beta blockers). These changes in drug use occurred independent of any changes in age, sex, ejection fraction, prevalence of coronary artery disease, or type of ventricular arrhythmia (VT vs VF).

Anti-Arrhythmia Agents↗
PubMed1995

Examination of mechano-electrical feedback in the transplanted human heart.

Several investigators have demonstrated that changes in atrial or ventricular pressure and size may modulate changes in electrophysiologic properties. The coupling of mechanical and electrical changes in the heart has been termed mechano-electrical feedback and is believed to play a role in arrhythmias observed with mitral valve disease, congestive heart failure, and left ventricular hypertrophy. To avoid confounding influences of the autonomic nervous system on electrophysiologic measurements, we measured right atrial and ventricular pacing thresholds with temporary epicardial pacing wires, right ventricular monophasic action potential duration at 90% repolarization during right ventricular pacing at 600 and 400 ms, donor heart rate, systolic, diastolic, and mean arterial and central venous pressures in 22 patients after orthotopic heart transplantation. Each variable was measured at baseline, in the resting supine state, and during graded lower body negative pressure of -10, -20, and -30 mm Hg. All levels of lower body negative pressure resulted in a significant decrease in mean right atrial pressure up to 5 +/- 6 mm Hg at maximal lower body negative pressure, and a significant decrease in mean arterial pressure occurred only at -20 and -30 mm Hg. Lower body negative pressure did not result in a significant change in any electrophysiologic variable despite significant changes in right atrial pressure. Thus, in the denervated transplanted human heart, unloading of the right heart results in no or small changes in atrial or ventricular pacing thresholds and ventricular monophasic action potential duration.

Action Potentials↗
PubMed1995

Long-term temporal patterns of ventricular tachyarrhythmias.

BACKGROUND: Technological limitations have precluded investigation of long-term temporal patterns of ventricular tachyarrhythmia recurrences. Newer implantable cardioverter-defibrillators permit such analyses by accurately recording the time and date of tachycardia detections during long-term follow-up. This study tests the hypothesis that ventricular tachycardia occurrences are randomly distributed over time in individual patients. METHODS AND RESULTS: The time and date of 727 episodes of ventricular tachyarrhythmias were recorded from the data logs of 31 patients with implantable cardioverter-defibrillators followed for a median of 177 days (range, 7 to 782 days). All patients had three or more ventricular tachycardia detections and no detections from causes other than ventricular arrhythmias. In 28 of 31 patients, the distribution of the interdetection time intervals during follow-up differed significantly (all P < .01) from an exponential model distribution of interdetection intervals that assumed that detections were equally likely to occur at any time during follow-up (random). The Kolmogorov-Smirnov goodness-of-fit test was used to compare sample and model distributions. In each patient, the nonrandom distributions resulted from a preponderance of interdetection time intervals that were shorter than predicted by the random model, resulting in a temporal clustering of arrhythmic events. The interdetection interval was < or = 1 hour and < or = 91 hours for 55% and 78% of all intervals, respectively. When only those episodes receiving shock or antitachycardia pacing therapy were analyzed, 25 of 29 patients still manifested nonrandom distributions (all P < .01). When only episodes with tachycardia rates > 240 beats per minute were analyzed, 11 of 13 patients manifested non-random distributions (all P < .01). CONCLUSIONS: Ventricular tachycardia detections and delivered antitachycardia therapies by implantable cardioverter-defibrillators are nonrandomly distributed throughout long-term follow-up in the majority of patients. The temporal clustering of these arrhythmic events may allow preemptive antiarrhythmic therapy and should be considered in the design of therapy based on suppression of spontaneous ventricular arrhythmias to statistically derived end points.

Aged↗
PubMed1995

Circadian pattern of ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillators.

OBJECTIVES: This study examined the temporal patterns of ventricular tachycardia detections by implantable cardioverter-defibrillators for circadian variability. BACKGROUND: Previous studies of circadian arrhythmia patterns have been methodologically limited by very brief observational periods. Late-generation implantable cardioverter-defibrillators accurately record the times of arrhythmia detections during unlimited follow-up. METHODS: Forty-three patients with late-generation implantable cardioverter-defibrillators were followed up for 226 +/- 179 days (mean +/- SD). The times of all recorded episodes of ventricular tachyarrhythmias were retrieved from the data log of each device during follow-up. RESULTS: The weighted distribution of 830 ventricular tachyarrhythmia episodes from the 43 patients fit a single harmonic sine curve model with a peak between 2 and 3 P.M. (95% confidence interval 1:13 to 4:13 P.M., R = 0.75, p < 0.05). The distributions of spontaneously terminating episodes, episodes receiving device therapy, episodes receiving shocks and episodes in the absence of antiarrhythmic therapy also fit the sine curve model (all R = 0.53 and 0.73, all p < 0.05), all with peak frequencies between 2:08 and 3:09 P.M. and 95% confidence intervals for peak frequencies between 11:38 A.M. and 5:07 P.M. Episodes recorded during continuous antiarrhythmic drug therapy did not fit the model (p > 0.05). CONCLUSIONS: The distribution of ventricular tachyarrhythmias detected by late-generation implantable cardioverter-defibrillators follows a circadian pattern, with a peak tachycardia frequency between noon and 5 P.M. This pattern was not observed in patients receiving antiarrhythmic drug therapy. Knowledge of circadian periodicity for these events has implications for patient management.

Aged↗
PubMed1995

Safety and efficacy of intravenous diltiazem in atrial fibrillation or atrial flutter.

This study examines the efficacy of various doses of intravenous diltiazem to control the ventricular response during atrial fibrillation or atrial flutter. Control of the ventricular response of patients with atrial fibrillation and a rapid ventricular response can provide patients with relief of symptoms and improve hemodynamics. Eighty-four consecutive patients with atrial fibrillation or atrial flutter, or both, received an intravenous bolus dose of diltiazem followed by a continuous infusion of diltiazem at 5, 10, and 15 mg/hour. The mean ventricular response and blood pressure were monitored. Overall, 94% of patients (79 of 84) responded to the bolus dose with a > 20% reduction in heart rate from baseline, a conversion to sinus rhythm, or a heart rate < 100 beats/min. Seventy-eight patients received the continuous infusion. After 10 hours of infusion, 47% of patients (confidence interval [CI]: 36%, 59%) had maintained response with the 5 mg/hour infusion, 68% (CI: 57%, 79%) maintained response after the infusion was titrated to 10 mg/hour, and 76% (CI: 66%, 85%) after titration from the 5 and 10 mg/hour infusion to the 15 mg/hour dose. For the 3 diltiazem infusions studied, mean (+/- SD) heart rate was reduced from a baseline value of 144 +/- 14 beats/min to 98 +/- 19, 107 +/- 25, 107 +/- 22, 101 +/- 22, 91 +/- 17, and 88 +/- 18 beats/min at infusion times 0, 1, 2, 4, 8, and 10 hours, respectively. By the end of the infusion, 18% of patients (14 of 78) had conversion to sinus rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1995

FK506 binding protein 12 mediates sensitivity to both FK506 and rapamycin in murine mast cells.

The immunosuppressive drugs FK506 and rapamycin bind to a family of intracellular proteins termed FK506-binding proteins (FKBP). FK506 and rapamycin inhibit lymphocyte-activation pathways by forming complexes with an FKBP; subsequently, the drug/FKBP complexes interact with target molecules involved in signal transduction. A key target of FK506/FKBP12 complexes is calcineurin, a calcium- and calmodulin-dependent serine/threonine phosphatase. In mammalian cells, rapamycin treatment is associated with inhibition of the activity of several cellular serine/threonine kinases, including p70 S6 kinase. These kinases may function in signaling pathways involving TOR gene producs, which have been shown to interact with rapamycin/FKBP12 complexes in vitro. To determine if FKBP12 mediates the effects of both FK506 and rapamycin in mammalian cells, we overexpressed FKBP12 in a murine mast cell line. Increased expression of FKBP12 resulted in increased sensitivity to FK506 and rapamycin, as measured by inhibition of calcineurin activity and p70 S6 kinase activity, respectively. In contrast, overexpression of FKBP25 had no effect on sensitivity to either drug. Two distinct point mutations in FKBP12, one altering a hydrophobic residue within the drug-binding pocket and the other changing a charged surface residue of FKBP12, abrogated its ability to mediate sensitivity to FK506 and rapamycin. These results establish that FKBP12 can mediate sensitivity to both FK506 and rapamycin in mammalian cells.

Animals↗