QT interval measurement and correction in patients with atrial flutter: a pilot study.

BACKGROUND AND PURPOSE: Measurement of QT intervals during atrial flutter (AFL) is relevant to monitor the safety of drug delivery. Our aim is to compare QT and QTc intervals in AFL patients before and after catheter ablation in order to validate QT measurement during AFL. METHODS: 25 patients suffering from AFL underwent catheter ablation; 9 were in sinus rhythm and 16 were in AFL at the time of the procedure. Holter ECGs were continuously recorded before, during and after the procedure. In AFL signals, flutter waves were subtracted using a previously-validated deconvolution-based method. Fridericia's QTc was computed before and after ablation after hysteresis reduction. RESULTS: Comparing QTc values obtained before and after ablation showed that (1) the intervention did not significantly affect QTc, and (2) the QTc during AFL was concordant with the QTc value in sinus rhythm. CONCLUSION: QTc can be reliably measured in patients with AFL using flutter wave subtraction and hysteresis reduction.

Purification and characterization of transcription factors.

Transcription factors (TFs) are essential for the expression of all proteins, including those involved in human health and disease. However, TFs are resistant to proteomic characterization because they are frequently masked by more abundant proteins due to the limited dynamic range of capillary liquid chromatography-tandem mass spectrometry and protein database searching. Purification methods, particularly strategies that exploit the high affinity of TFs for DNA response elements (REs) on gene promoters, can enrich TFs prior to proteomic analysis to improve dynamic range and penetrance of the TF proteome. For example, trapping of TF complexes specific for particular REs has been achieved by recovering the element DNA-protein complex on solid supports. Additional methods for improving dynamic range include two- and three-dimensional gel electrophoresis incorporating electrophoretic mobility shift assays and Southwestern blotting for detection. Here we review methods for TF purification and characterization. We fully expect that future investigations will apply these and other methods to illuminate this important but challenging proteome.

Postseismic relaxation along the San Andreas fault at Parkfield from continuous seismological observations.

Seismic velocity changes and nonvolcanic tremor activity in the Parkfield area in California reveal that large earthquakes induce long-term perturbations of crustal properties in the San Andreas fault zone. The 2003 San Simeon and 2004 Parkfield earthquakes both reduced seismic velocities that were measured from correlations of the ambient seismic noise and induced an increased nonvolcanic tremor activity along the San Andreas fault. After the Parkfield earthquake, velocity reduction and nonvolcanic tremor activity remained elevated for more than 3 years and decayed over time, similarly to afterslip derived from GPS (Global Positioning System) measurements. These observations suggest that the seismic velocity changes are related to co-seismic damage in the shallow layers and to deep co-seismic stress change and postseismic stress relaxation within the San Andreas fault zone.

Sprouty genes are expressed in osteoblasts and inhibit fibroblast growth factor-mediated osteoblast responses.

Fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) are major regulators of skeletal growth and development. Signal transduction via FGFRs is complex and mediates proliferation, differentiation, or migration depending upon the cellular context. Members of the Spry gene family antagonize the FGFR signal transduction pathway and inhibit lung morphogenesis, angiogenesis, and chondrogenesis. We examined the expression of Spry2 in the osteoblastic MC3T3-E1 cell line. MC3T3-E1 cells express Spry2 in response to FGF1 stimulation. Treatment of MC3T3-E1 cells with FGF1 results in the expression of Spry2 in a manner consistent with an early response gene. Pharmacological inhibitors of mitogen-activated protein kinase activation inhibit FGF1-induced expression of Spry2 mRNA. Transient overexpression of Spry2 in MC3T3-E1 resulted in decreased FGF1-mediated extracellular signal-regulated kinase phosphorylation and FGF1-stimulated osteopontin promoter activity. Furthermore, we show that Spry2 interacts with Raf-1 in a glutathione-S-transferase pulldown assay and that this interaction may involve multiple sites. Finally, Spry2 expression precedes the onset of the expression of osteoblast differentiation markers in an in vitro assay of primary osteoblast differentiation. Taken together, these results indicate that Spry2 expression is an early response to stimulation by FGF1 in MC3T3-E1 cells and acts as a feedback inhibitor of FGF1-induced osteoblast responses, possibly through interaction with Raf1.

Implications for prediction and hazard assessment from the 2004 Parkfield earthquake.

Obtaining high-quality measurements close to a large earthquake is not easy: one has to be in the right place at the right time with the right instruments. Such a convergence happened, for the first time, when the 28 September 2004 Parkfield, California, earthquake occurred on the San Andreas fault in the middle of a dense network of instruments designed to record it. The resulting data reveal aspects of the earthquake process never before seen. Here we show what these data, when combined with data from earlier Parkfield earthquakes, tell us about earthquake physics and earthquake prediction. The 2004 Parkfield earthquake, with its lack of obvious precursors, demonstrates that reliable short-term earthquake prediction still is not achievable. To reduce the societal impact of earthquakes now, we should focus on developing the next generation of models that can provide better predictions of the strength and location of damaging ground shaking.

Deglycosylated ceruloplasmin maintains its enzymatic, antioxidant, cardioprotective, and neuronoprotective properties.

Ceruloplasmin (CP), an important serum antioxidant, is a blue copper glycoprotein with ferroxidase and oxidase activities. Among other physiological actions, plasma CP was shown to protect isolated rat hearts and cultured P19 neurons exposed to oxidative stress conditions, raising the possibility of using this protein in the treatment of cardiac and neuronal diseases related to oxidative damage. However, since therapeutic applications of CP must be compatible with restrictions in the administration of blood derivatives to humans, there is a need to produce the protein by genetic engineering. To help in the choice of adequate expression systems, we undertook this study to determine if the carbohydrate moiety on the protein is essential for its functions. CP was completely deglycosylated using N-glycosidase F under nondenaturing conditions. Deglycosylated CP was found to retain most of the conformational, antioxidant, and enzymatic properties of the native protein in vitro. Moreover, both forms of the protein had similar cardioprotective and neuronoprotective effects against oxidative stress as evaluated with isolated rat hearts undergoing ischemia-reperfusion and with cultured P19 neurons exposed to xanthine-xanthine oxidase. The data thus indicate that the carbohydrate moiety of CP is not essential for its enzymatic and protective actions. Accordingly, even the use of expression systems that do not glycosylate mammalian proteins could provide a recombinant CP that retains its therapeutic potential.

The role of a new noninvasive imaging technology in the diagnosis of anemia.

Traditionally, numerical data regarding the status of a patient are a combination of measurements made at the point of care (POC) and those made in the laboratory on specimens withdrawn from the patient. We report here on our experiences with a new method for a noninvasive determination of anemia, as defined by blood hemoglobin (Hb) concentration. This method is based on a novel technology, orthogonal polarization spectral imaging, which provides high quality digitized images of the microcirculation using reflected light. Measurements of Hb, based on the analysis of these images at the POC, were found to compare favorably with results obtained with traditional laboratory methods. Additional advantages of these new POC technologies are that they will make possible completely new measurements that may have no direct analog with existing methods. For example, orthogonal polarization spectral imaging can give feedback regarding microvascular density, which also may be reduced in anemic subjects. This information may give earlier and different insights regarding the patient status in nutritional deficiency anemia than an Hb concentration only. However, additional research will be required to confirm the accuracy and utility of this measurement, especially in adult and pediatric populations, where anemia is more commonly encountered. The ultimate success of POC testing will require collaboration between the attending health care professional, the laboratory and institutional management to rapidly assimilate improved methodologies and new information to provide benefits to the patient.

Telehealth and communication technologies in health: summary and action plan.

INTRODUCTION: Rapid innovations and improvements in communication technologies have opened many new channels for health education and delivery, as well as disaster management. Theme 2 examined the role and applicability of these technologies to Disaster Medicine and Management and the various issues involved in their use. METHODS: Details of the methods used are provided in the introductory paper. The chairs moderated all presentations and produced a summary that was presented to an assembly of all of the delegates. The chairs then presided over a workshop that resulted in the generation of a set Action Plans that then were reported to the collective group of all delegates. RESULTS: Main points developed during the presentations and discussion included harnessing convergence, seeking interoperability, building partnerships and making it appropriate. This group identified four Principles of Action underlying its plan: (1) investigate possibilities, (2) identify stakeholders, (3) invite participation, and (4) involve discussants in activities. DISCUSSION: Action plans were categorized into three areas that included "thinking globally, acting regionally", forming a telehealth advisory group, and increasing corporate partnerships. CONCLUSIONS: Technology is opening many opportunities that have applications in disaster management. To optimize benefits, goals and standards must be agreed upon and implemented.

Spontaneous changes in ventricular tachycardia cycle length and their relation to earliest sites of epicardial activation in a canine model.

BACKGROUND: The purpose of this study was to examine the spontaneous changes in cycle length during episodes of sustained monomorphic (MVT) and polymorphic (PVT) ventricular tachycardias and to relate these changes with the earliest epicardial activation site of the beat. METHODS: Isochronal activation maps were obtained from 127 unipolar electrograms recorded from the surface of both ventricles with a sock electrode array in 24 open chest anesthetized dogs. After atrioventricular block, the left anterior descending coronary artery was occluded for 60 min under ventricular pacing (140/min), followed by reperfusion. In 7 dogs the left stellate ganglion was stimulated 5 min after reperfusion. RESULTS: In 7 MVTs (reperfusion) and 4 PVTs (sympathetic stimulation), cycle length changes showed an initial acceleration, reaching a minimum cycle length and then decelerating before termination. Isochronal maps showed radial spread from earliest activation, without conduction block. Cycle length (481 +/- 80 msec) in MVT had beat to beat variations of 15 +/- 17 msec corresponding to small shifts in sites of the earliest activation, clustered along the border of the ischemic myocardium. In PVTs the cycle length (352 +/- 90 msec, p < 0.01) had a variability of 62 +/- 23 msec, corresponding to wide changes in the sites of earliest activation in right and left ventricles. Linear regression analysis showed a strong and significant correlation between cycle length variability and the number of electrodes with the earliest activation (r = 0.77, p < 0.0001). CONCLUSION: In these models of monomorphic and polymorphic ventricular tachycardias, cycle length variability showed a significant correlation with the number of electrodes with the earliest activation. MVTs showed concentrated origins with regular cycle length, whereas PVTs showed dispersed origins with irregular cycle length. These results suggest that the earliest epicardial activation site of the beat could be a factor in determining the dynamics in the cycle length.

Body surface mapping of retrograde P waves in the intact dog by simulation of accessory pathway re-entry.

OBJECTIVES: To investigate a noninvasive technique to localize the atrial insertion site of concealed accessory pathways based on the analysis of body surface potential maps (BSPMs) of retrograde P waves in dogs with simulated retrograde pathways. ANIMALS AND METHODS: Orthodromic tachycardias were simulated by atrial stimulations at eight different sites around the atrioventricular ring with long (250 ms and 300 ms) and short (100 ms and 130 ms) coupling times in 14 anesthetized dogs to have P waves well separated from the T wave or occurring during the T wave, respectively. The distance between pacing sites was 15 to 40 mm in group 1 (eight dogs) and 2 mm (in the right atrial free wall region) in group 2 (six dogs). Beats were signal-averaged during 30 s and BSPMs were constructed from 63 unipolar leads. RESULTS: The P wave BSPM pattern for any specific stimulation site was stable and reproducible (correlation coefficient greater than 0.98), and similar in different dogs at long coupling interval stimulations. The thoracic distribution of negative potentials and position of the potential minimum clearly identified the stimulation site when long coupling time stimulations were used. The spatial resolution of the technique as determined by comparison of correlation coefficients in group 2 was 6 mm (P<0.05). When short coupling time stimulations were used (fast tachycardia simulation), the T wave masked the P wave potential distribution in four of eight dogs, but the retrograde P wave map could still be accurately extracted by subtracting a straight line joining the onset and offset of the P wave in 24 of 28 (86%) of the tachycardia simulation sites in these four dogs. CONCLUSIONS: The BSPM patterns of simulated retrograde P waves are specifically related to the site of atrial stimulation. Although the T wave altered these BSPM patterns, a subtraction technique recovered the pattern of the retrograde P wave in 93% of all simulated orthodromic tachycardias. The spatial resolution of the retrograde P wave BSPM method was 6 mm.

New body surface isopotential map evaluation method to detect minor potential losses in non-Q-wave myocardial infarction.

BACKGROUND: Potential losses caused by stable non-Q-wave myocardial infarction (MI) are too small to diagnose with the use of standard ECG. The aim of the present study was to obtain accurate diagnostic criteria for this prognostically important disease with the help of body surface mapping. METHODS AND RESULTS: Body surface potentials were recorded with the use of 63 unipolar leads in 45 patients with a non-Q-wave MI (41 to 75 years old); 24 healthy adults, 42 patients with unstable angina, and 70 patients with Q-wave MI served as reference groups. Qualitative pathological features of the isopotential maps, such as onset time and site and magnitude of the first right-anterior/anterior minimum, as well as pathological negativities at that time, were defined in non-Q-wave MI cases. These features, which account for the activation sequence and the body surface projections of specific cardiac regions (Selvester classification), showed a 91% sensitivity and an 88% specificity for the detection of non-Q-wave MI. In comparison, the different departure maps (first third QRS, QRS, and QRST isoarea) resulted in less favorable specificities (50% to 58%). Concordance between the isopotential maps and the acute-phase ECG (90%), hypokinesis (64%), fixed perfusion defects (59%), and significant stenosis of the infarct-related coronary artery (87%) supported the concept that these isopotential map changes correspond to the supposed sites of MI. There were pathological features in 69% of patients with unstable angina, with similar concordances as in non-Q-wave MI. CONCLUSIONS: Isopotential maps revealed characteristic features that were suitable for the detection and localization of non-Q-wave MI in the clinical setting of unstable coronary artery disease.

Influence of extracellular potassium on the antiarrhythmic effect of global preconditioning in isolated perfused rat hearts.

The objective of this study was to investigate if a variation in extracellular-K+ concentrations alters the effects of global pre-conditioning on ischemia-induced arrhythmias. Rat hearts were Langendorff-perfused with Krebs-Henseleit solution and randomised in 8 groups (n = 12/group): four control groups (K+: 2, 4, 6, or 8 mmol/L) which underwent 30-min coronary artery occlusion and four preconditioned groups (K+: 2, 4, 6, or 8 mmol/L) in which the 30-min regional ischemia was preceded by 2 cycles of 3 min global ischemia. In the presence of low K+ (2 mmol/L), there were no differences between control and preconditioning groups in the number of ventricular premature beats (VPBs): 194 +/- 64 vs. 217 +/- 81, the incidence of ventricular tachycardia (VT): 100% vs. 100% and of ventricular fibrillation (VF): 100% vs. 100%. In the presence of normal K+ concentration (4 mmol/L), ischemic preconditioning reduced the number of VPBs from 88 +/- 26 to 25 +/- 10, (p < 0.05), the incidence of VT from 100 to 50% (p < 0.05), and of VF from 67 to 16% (p < 0.05). In the condition of higher K+ concentration (6 mmol/ L), VPBs (34 +/- 8 vs. 11 +/- 4), the incidence of VT (100% vs. 25%; p < 0.05 ) and VF (25% vs. 8%) were further reduced in preconditioned hearts. In the condition of K+ concentration (8 mmol/L), there were no differences in VPBs (11 +/- 3 vs. 7 +/- 2), the incidence of VT (8% vs. 0%) and VF (8% vs. 0%) between control and preconditioned hearts. Our data show that ischemic preconditioning affords protection against arrhythmias during coronary artery occlusion in the isolated rat heart and that hypokalemia abolishes the antiarrhythmic effects of global preconditioning.

Novel cardiac protective effects of urea: from shark to rat.

1. This study was carried out to investigate novel cardioprotective effects of urea and the underlying mechanisms. The cardiac functions under oxidative stress were evaluated using Langendorff perfused isolated heart. 2. Isolated dogfish shark hearts tolerated the oxidative stress generated by electrolysis (10 mA, 1 min) of the perfusion solution (n=4), and also showed normal cardiac functions during post-ischaemia reperfusion (n=4). The high concentration of urea (350 mM) in the heart perfusate was indispensable for maintaining the normal cardiac functions of the shark heart. 3. Urea at 3 - 300 mM (n=4 for each group) protected the isolated rat heart against both electrolysis-induced heart damage and post-ischaemia reperfusion-induced cardiac injury. 4. A concentration-dependent scavenging effect of urea (3 - 300 mM, n=4 for each group) against electrolysis-induced reactive oxygen species was also demonstrated in vitro. 5. Urea derivatives as hydroxyurea, dimethylurea, and thiourea had antioxidant cardioprotective effect against the electrolysis-induced cardiac dysfunction of rat heart, but were not as effective as urea in suppressing the post-ischaemia reperfusion injury. 6. Our results suggest that urea and its derivatives are potential antioxidant cardioprotective agents against oxidative stress-induced myocardium damage including the post-ischaemia reperfusion-induced injury.

Characterization of ventricular tachycardias based on time and frequency domain analyses of cycle length variability in patients with implantable cardioverter defibrillator.

OBJECTIVE: To discriminate between monomorphic (MVT) and polymorphic (PVT) ventricular tachycardias in humans using cycle length variability (CLV), and to characterize the onset of MVT and PVT using power spectral analysis of the CLV during sinus rhythm and the number of ventricular extrasystoles before onset of arrhythmia. PATIENTS AND METHODS: Medtronic, Inc's Spontaneous Ventricular Tachy- arrhythmia Database was analyzed. This data base contains sets of 1000 RR intervals (n=135) that preceded spontaneous onset of ventricular tachycardia or fibrillation and sets of controls (n=135) without spontaneous ventricular tachycardia or fibrillation from 78 patients with the Medtronic Model 7218 implantable cardioverter defibrillator. CLV was measured as the standard deviation of RR intervals normalized by the mean RR value. Power spectral analysis based on the fast Fourier transform analysis was performed on 128 RR samples, and the normalized power spectrum of the low frequency band (0.04 to 0.15 Hz) and of the high (NHF) frequency band (0.15 to 0.4 Hz) were estimated. RESULTS: During PVT the CLV was much greater (0. 133+/-0.095) than during MVT (0.04+/-0.035) (P<0.0001). Also, 64% of patients who developed PVT had more than 27 extrasystoles compared with 40% of patients during control conditions (P=0.03). This parameter was not significantly different in patients with MVT. Due to the high incidence of extrasystoles in this population, only 36% of PVT and 43% of MVT recordings could be analyzed for CLV during sinus rhythm. NHF characterizing parasympathetic activity decreased from 50.6% (PVT control) to 34.4% (PVT onset) (P=0.06) and from 47. 4% (MVT control) to 43.7% (MVT onset) (P=0.18). CONCLUSIONS: Discrimination between MVT and PVT episodes was possible based on CLV analysis. The onset of PVT was characterized by a greater number of preceding extrasystoles compared with the control. During sinus rhythm, the NHF spectral power activity decreased at the onset of both types of arrhythmic episodes compared with control, although statistical significance was marginal.

Down-regulation of the pharmacokinetic-pharmacodynamic response to interleukin-12 during long-term administration to patients with renal cell carcinoma and evaluation of the mechanism of this "adaptive response" in mice.

BACKGROUND: Interleukin-12 (IL-12) is a cytokine that promotes type-1 helper T-cell responses and may have therapeutic utility in the treatment of cancer, asthma, and a variety of infectious diseases. METHODS: In a phase I trial, recombinant human IL-12 (rHuIL-12) was administered subcutaneously once a week at a fixed dose of 0.1 to 1.0 microg/kg to 24 patients with renal cell carcinoma. A similar study was later performed in mice to evaluate the mechanism of down-regulation of pharmacokinetic-pharmacodynamic response observed in patients with cancer. RESULTS: Adverse events, serum IL-12 levels, and serum levels of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) produced in response to IL- 12 were all maximum in the week after the first dose of rHuIL-12 and decreased after long-term administration. Similar to these results, repetitive subcutaneous administration of recombinant mouse IL-12 (rMoIL-12) to normal mice led to down-regulation of serum levels of IL-12 and IFN-gamma measured 5 hours after rMoIL-12 injection. Down-regulation of IL-12 serum levels was inversely correlated with the up-regulation of IL-12 receptor expression and may be the result of increased clearance of rMoIL-12 from serum by binding to lymphoid cells expressing increased amounts of IL-12 receptor. The down-regulation of serum IFN-gamma levels correlated with decreased IFN-gamma messenger ribonucleic acid expression and may result from feedback inhibition of IL-12 signaling or from a more specific inhibition of IFN-gamma synthesis. CONCLUSION: Administration of rHuIL-12 in fixed weekly doses resulted in decreased serum levels of IL-12 and of IFN-gamma, a secondary cytokine believed to be critical to response of IL-12. A better understanding of the complex regulation of the pharmacokinetic-pharmacodynamic response to IL-12 should facilitate the development of more effective dosing regimens for its use in the clinic.

Effects of antihypertensive therapies on the sympathetic nervous system.

The sympathetic nervous system is a major modulator of cardiovascular function. Over the past three decades, numerous studies, using various methodologies, have reported the existence of a variety of pre- and postsynaptic sympathetic dysfunctions in essential hypertension. Most of these abnormalities facilitate sympathetic neurotransmission, resulting in a chronic increase in the sympathetic tone and reactivity in a significant proportion of hypertensive patients. Chronic sympathetic activation is also associated with major alterations in the balance among postsynaptic adrenergic receptors in cardiovascular tissues. Indeed, an attenuation of beta-adrenergic function and a potentiation of alpha1-adrenergic function has been demonstrated in cardiovascular tissues in hypertensive patients, suggesting the development of a sympathetic postsynaptic alpha1 dominance during the development and evolution of hypertension. Chronic activation of the sympathetic system is deleterious and could contribute to the development of most cardiovascular complications associated with hypertension. One of the major aims of antihypertensive therapy should thus be to attenuate pre- or postsynaptic sympathetic tone. Most antihypertensive drugs have been found to improve either pre- or postsynaptic sympathetic function in hypertensive patients. At the presynaptic level, diuretics were found to increase the liberation of noradrenalin, presumably through baroreflex sympathetic activation. In contrast, beta-blockers were shown to attenuate noradrenalin release from sympathetic nerves by blocking presynaptic facilitatory beta-receptors, thus reducing the sympathetic tone on postsynaptic receptors. Similarly, angiotensin-converting enzyme inhibitors or angiotensin II type 1 (AT1) receptor antagonists have been found to reduce sympathetic reactivity by acting on the central nervous system, but also by blocking AT1-mediated facilitatory mechanisms located on sympathetic fibres and in the adrenal medulla. Short acting dihydropyridine calcium channel blockers (CCBs) were found to enhance noradrenalin release from sympathetic nerves, but longer acting CCBs seems to have variable effects. Indeed, while the chronic slow release formulation of nifedipine gastrointestinal therapeutic system (GITS) did not raise circulating noradrenalin levels, treatment with amlodipine increased circulating noradrenalin levels, suggesting that nifedipine GITS is neutral on the sympathetic tone but that amlodipine chronically activates the sympathetic system. At the postsynaptic level, however, dihydropyridine CCBs were shown to attenuate the sympathetic tone on alpha1-adrenoceptors. In conclusion, it appears that most antihypertensive drugs interfere with pre- or postsynaptic sympathetic mechanisms and that these mechanisms could contribute to their hypotensive effects.

Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.

OBJECTIVE: To compare the acute and chronic effects of nifedipine retard (NPA), nifedipine gastrointestinal therapeutic system (NGITS) and amlodipine at trough and peak plasma concentrations of drug on blood pressure and heart rate, and on plasma norepinephrine and epinephrine levels in patients with mild-to-moderate hypertension (diastolic blood pressure 95-115 mmHg). DESIGN AND METHODS: After 3-4 weeks' placebo treatment, patients of both sexes were randomly allocated to be administered 10 or 20 mg NPA twice a day, 30 or 60 mg NGITS once a day, and 5 or 10 mg amlodipine once a day for 6 weeks. Initially, for the first 2 weeks, the lowest dose of each drug was used, but higher doses were administered after 2 weeks if sitting diastolic blood pressure was > 90 mmHg. Patients were evaluated after administration of the first dose and after 6 weeks' therapy in a hospital setting. Blood samples were taken for high-performance liquid chromatography measurement of catecholamine and drug levels at various intervals for a period covering trough to peak drug level ranges. RESULTS: Administration of all three drugs reduced clinic blood pressure to the same level after 6 weeks' therapy, but heart rate was increased slightly only with amlodipine (P < 0.05). Administration of NPA reduced blood pressure more abruptly whereas administrations of NGITS and amlodipine induced smoother falls after acute and chronic treatments: a significant increase in heart rate was observed with amlodipine after chronic treatment. Both acute and chronic treatments with NPA (n = 19) increased norepinephrine levels (P < 0.01) transiently (2-4 h). In contrast, administration of NGITS (n = 22) did not increase norepinephrine levels and even induced a slight but significant decrease in norepinephrine levels 5-6 h after chronic treatments. Although administration of amlodipine (n = 22) did not increase norepinephrine levels transiently either after acute or after chronic administration, it did induce a sustained rise in basal norepinephrine levels by more than 50% after chronic therapy (P < 0.01). Plasma epinephrine levels were not increased by any of the treatments and even a slight decrease was observed 4 h after administration of a dose following chronic treatments with NGITS and amlodipine (P < 0.05). CONCLUSIONS: The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.