Acute effect of propranolol on resting energy expenditure in hyperthyroid patients.

Objective: Hyperthyroidism is a common endocrine disorder which leads to higher resting energy expenditure (REE). Increased activity of brown adipose tissue (BAT) contributes to elevated REE in hyperthyroid patients. For rapid control of hyperthyroid symptoms, the non-selective ß-blocker propranolol is widely used. While, long-term treatment with propranolol reduces REE it is currently unclear whether it can also acutely diminish REE. Design: In the present prospective interventional trial we investigated the effect of propranolol on REE in hyperthyroid patients. Methods: Nineteen patients with overt primary hyperthyroidism were recruited from the endocrine outpatient clinic. REE was measured by indirect calorimetry before and after an acute dose of 80mg propranolol and during a control period, respectively. Additionally, skin temperature was recorded at eleven predefined locations during each study visit, vital signes and heart rate (HR) were measured before and after administration of propranolol. Results: Mean REE decreased slightly after acute administration of 80mg propranolol (p= 0.03) from 1639 ± 307 kcal/24h to 1594 ± 283 kcal/24h. During the control visit REE did not change significantly. HR correlated significantly with the level of free T3 (R2 = 0.38, p=0.029) free T4 (R2 = 0.39, p=0.026). HR decreased 81 ± 12 bpm to 67 ± 7.6 bpm 90 minutes after oral administration of propranolol (p<0.0001). Skin temperature did not change after propranolol intake. Conclusions: In hyperthyroid patients a single dose of propranolol reduced heart rate substantially but REE diminished only marginally probably due to reduced myocardial energy consumption. Our data speak against a relevant contribution of BAT to the higher REE in hyperthyroidism. Clinical trial registration: ClinicalTrials.gov, identifier (NCT03379181).

Solid-phase microextraction for assessment of plasma protein binding, a complement to rapid equilibrium dialysis.

Aim: Determination of plasma protein binding (PPB) is considered vital for better understanding of pharmacokinetic and pharmacodynamic activities of drugs due to the role of free concentration in pharmacological response. Methodology & results: Solid-phase microextraction (SPME) was investigated for measurement of PPB from biological matrices and compared with a gold standard approach (rapid equilibrium dialysis [RED]). Discussion & conclusion: SPME-derived values of PPB correlated well with literature values, and those determined by RED. Respectively, average protein binding across three concentrations by RED and SPME was 33.1 and 31.7% for metoprolol, 89.0 and 86.6% for propranolol and 99.2 and 99.0% for diclofenac. This study generates some evidence for SPME as an alternative platform for the determination of PPB.

Voluntary Corn Oil Ingestion Increases Energy Expenditure and Interscapular UCP1 Expression Through the Sympathetic Nerve in C57BL/6 Mice.

SCOPE: Previously, it has been found that corn oil ingestion activates both the gustatory system and brain reward system, stimulating motivation for eating. In the present study, the effect of voluntary corn oil ingestion on body weight gain and energy metabolism in mice is investigated. METHODS AND RESULTS: Voluntary corn oil ingestion with normal chow feeding does not lead to higher body weight than that of only the chow-fed control group. Mice that ingested corn oil have a higher total caloric intake and energy expenditure than did mice in the control group. Further, voluntary corn oil ingestion significantly upregulates Ucp1 mRNA and protein in interscapular brown adipose tissue (IBAT). Finally, the sympathetic nerve connected to IBAT was surgically transacted, then the body weight is measured for 8 weeks. IBAT sympathetic nerve transection surgery does not affect the body weight gain and food intake; however, when mice ingested corn oil, it induces significant body weight gain without changing the total caloric intake. IBAT sympathetic nerve transection surgery significantly suppresses UCP1 upregulation by corn oil ingestion. CONCLUSION: The present data suggest that corn oil ingestion activates IBAT through the sympathetic nerve, upregulating UCP1 expression and increasing energy expenditure.

A new analysis of heart rate variability in the assessment of fetal parasympathetic activity: An experimental study in a fetal sheep model.

Analysis of heart rate variability (HRV) is a recognized tool in the assessment of autonomic nervous system (ANS) activity. Indeed, both time and spectral analysis techniques enable us to obtain indexes that are related to the way the ANS regulates the heart rate. However, these techniques are limited in terms of the lack of thresholds of the numerical indexes, which is primarily due to high inter-subject variability. We proposed a new fetal HRV analysis method related to the parasympathetic activity of the ANS. The aim of this study was to evaluate the performance of our method compared to commonly used HRV analysis, with regard to i) the ability to detect changes in ANS activity and ii) inter-subject variability. This study was performed in seven sheep fetuses. In order to evaluate the sensitivity and specificity of our index in evaluating parasympathetic activity, we directly administered 2.5 mg intravenous atropine, to inhibit parasympathetic tone, and 5 mg propranolol to block sympathetic activity. Our index, as well as time analysis (root mean square of the successive differences; RMSSD) and spectral analysis (high frequency (HF) and low frequency (LF) spectral components obtained via fast Fourier transform), were measured before and after injection. Inter-subject variability was estimated by the coefficient of variance (%CV). In order to evaluate the ability of HRV parameters to detect fetal parasympathetic decrease, we also estimated the effect size for each HRV parameter before and after injections. As expected, our index, the HF spectral component, and the RMSSD were reduced after the atropine injection. Moreover, our index presented a higher effect size. The %CV was far lower for our index than for RMSSD, HF, and LF. Although LF decreased after propranolol administration, fetal stress index, RMSSD, and HF were not significantly different, confirming the fact that those indexes are specific to the parasympathetic nervous system. In conclusion, our method appeared to be effective in detecting parasympathetic inhibition. Moreover, inter-subject variability was much lower, and effect size higher, with our method compared to other HRV analysis methods.

Oral propranolol for infantile hemangiomas: a prospective study on the role of 48-hour Holter monitoring in additional safety assessment.

PURPOSE: Oral propranolol has been recently approved for infantile hemangiomas (IHs), but potential side effects stay a challenge. We sought to make an additional assessment on oral propranolol safety for this indication. MATERIALS AND METHODS: Prospective study included 108 infants consecutively treated for IHs at the University Children's Hospital Tirsova, Belgrade from January 2010 to December 2013. Propranolol was administered orally at a daily dose of 0.5 mg/kg and doubled every 48 hours in the absence of side effects until reaching the maximum dose of 2 mg/kg daily. Systolic and diastolic blood pressure and heart rate were measured every 48 hours with clinical observation. Heart rate was monitored by standard electrocardiogram (ECG) and 48-hour Holter ECG. RESULTS: Statistically significant, but asymptomatic decreases in systolic blood pressure and heart rate recorded by Holter ECG were observed during the first doubling of dose and then remained stable. Arrhythmias were not detected. Despite mild sleep disturbance observed in 31% of infants in the hospital milieu, Holter monitoring indicated circadian rhythm maintenance. CONCLUSIONS: Oral propranolol for IHs does not remarkably affect heart rhythm including circadian variations throughout hospital initiation. Therefore, there is no necessity for Holter monitoring in additional safety assessment.

Functional and histological assessment of an experimental model of Takotsubo's cardiomyopathy.

BACKGROUND: Our objectives were to characterize functional and structural features of an experimental model of Takotsubo cardiomyopathy, and its response to beta-blockers. METHODS AND RESULTS: In protocol 1, a dose-finding study: 69 rats received various doses of isoproterenol (ISO) and echocardiographic and histologic parameters were measured on days 2 to 3 or day 8. There were no dose-dependent effects and, out of 69 ISO-treated rats, 40 (58.0%) survived and 29 (42.0%) died within 24 hours. Of survivors, 30 had apical akinesis averaging 12.1 ± 1.6% of the long axis LV circumference. Out of the 40 survivors, 32.5% showed apical akinesis ≥ 10%, 42.5% showed akinesis<10% and 25% showed no apical akinesis. The basal portion of the LV was always preserved. At 24 hours, histology and ultrastructure showed necrosis, vacuolization, lipid droplets, mononuclear cell infiltration, damaged mitochondria, and edema. On day 8, apical akinesis fully resolved but histologic abnormalities were still present. In protocol 2, rats were randomized to Control; ISO100 mg/kg; propranolol+ISO; and metoprolol+ISO groups. Pretreatment with propranolol and metoprolol improved survival to 90% and 100% respectively, compared with 60% in the ISO group, but did not reduce the incidence and extent of akinesis or the structural damage. CONCLUSION: TC can be mimicked in a rat model of ISO exposure that demonstrates apical akinesis on days 2 to 3 with full recovery of systolic regional wall motion abnormality despite the presence of persistent foci of necrosis and fibrosis on day 8. Pretreatment with beta-blockers improved survival but did not affect structural and functional alterations.

Assessment of trabecular bone microarchitecture by two different x-ray microcomputed tomographs: a comparative study of the rat distal tibia using Skyscan and Scanco devices.

Important aspects of modern skeletal research depend on the phenotypical characterization of trabecular bone microarchitecture as assessed by microcomputed tomography (micro-CT). Until now, however, there have been no studies which compare the two most commonly utilized micro-CT devices, namely, Skyscan and Scanco. The purpose of the current study was to examine the reproducibility and accuracy of these two micro-CT devices in comparison to traditional histomorphometry in ovariectomized rats treated with either propranolol, salbutamol, or vehicle. 6 month old female Wistar rats were ovariectomized (n = 48) or sham operated (n = 12). OVX rats were divided into four groups and then subcutaneously injected with propranolol 0.1 mg/kg/day, propranolol 20 mg/kg/day, salbutamol 3 mg/kg/day, or vehicle for 10 weeks. At sacrifice, the left tibial trabecular bone microarchitecture was analyzed using both the micro-CT Skyscan 1072 (ex vivo) and Scanco vivaCT40 (in vivo). Histomorphometric analysis was performed on the right proximal tibia. Comparisons between the different methods were performed using regression analysis, Bland-Altman, Passing-Bablock, and Mountain plots. Correlations were highly significant for all parameters measured between the two micro-CT instruments and were less significant between histomorphometry and micro-CT measurements taken from either the Skyscan or Scanco apparatus. Micro-CT overestimated bone volume compared to histomorphometry. In the ovariectomized rat model, the two micro-CT instruments revealed the same difference between groups whereas histomorphometry revealed only the difference which displayed the largest disparity between groups. In regards to the comparison between the two micro-CT devices, Mountain plot methods indicated that BV/TV, BS/BV, and TbSp were equivalent, whereas a systematic bias was observed for TbN and TbTh. The authors were also able to describe the routine method used to determine the threshold between the two micro-CT devices, which may help explain these differences. While some minor differences in the absolute values of the morphometry parameters exist between the micro-CT measurements from the Skyscan and Scanco instruments, both of these devices display a high degree of accuracy and reproducibility.

Central and peripheral administration of amylin induces energy expenditure in anesthetized rats.

Amylin is a peptide hormone that is co-released with insulin from pancreatic beta-cells following a meal. Intracerebroventricular (icv) administration of amylin (1-100 pmol), or an amylin agonist, salmon calcitonin, elicited dose-dependent thermogenic, tachycardic, and hyperthermic responses in urethane-anesthetized rats. Intravenous (iv) administration of higher doses of amylin (100 pmol-20 nmol) also induced similar responses, although the amplitudes of these responses were significantly smaller than those elicited by icv administration, suggesting the primary action of amylin to be in the brain. However, the iv administration of amylin induced the responses slightly faster than the icv injection, the former responses occurring<4 min and the latter, at 8-10 min, after the administration. The iv but not the icv injection of amylin increased the respiratory exchange ratio transiently (<20 min), though the thermogenic response lasted for a longer period after both injections, indicating a shift from mixed fuel to predominantly carbohydrate utilization in the initial phase of thermogenesis induced by the iv injection of amylin. The differences in substrate utilization and latency of the responses suggest that the actions of amylin include partly different targets when administered centrally and peripherally. Moreover, pretreatment with a beta-adrenergic blocker, propranolol (5 mg kg(-1), iv), blocked all responses elicited by either icv or iv administration of amylin, whereas ablation of the area postrema in the hindbrain did not influence the effects of icv-administered amylin. These results suggest the involvement of amylin in postprandial energy expenditure, mediated by peripheral beta-adrenoceptors.

Assessment of drug-induced QT interval prolongation in conscious rabbits.

INTRODUCTION: Most preclinical trials are designed to identify potential torsadogenicity test only for surrogates of torsade de pointes, most commonly prolongation of the heart rate corrected QT interval (QTc). This study was conducted to determine which correction method best accounts for the effects of changes in the RR interval on the QT interval of conscious rabbits. This study was also conducted to validate the use of conscious, sling-trained rabbits to assess the QTc interval, and to evaluate the reliability and accuracy of this preparation in predicting drug-induced QTc prolongation in humans. METHODS: ECGs were recorded via bipolar transthoracic ECG leads in 7 conscious rabbits previously trained to rest quietly in slings. The heart rate was slowed with 2.0 mg/kg zatebradine to assess the effects of heart rate on the QT interval. The same ECG and sling preparation was used to evaluate the effects in of three drugs known to be torsadogenic in humans (cisapride, dofetilide and haloperidol), two drugs known to be non-torsadogenic in humans (propranolol and enalaprilat) and a control article (vehicle). All of the test articles were administered intravenously to 4 rabbits, and both RR and QT intervals were measured and the corrected QT values were calculated by an investigator blinded to the test article, utilizing our own algorithm (QTc=QT/(RR)(0.72)) which permitted the least dependency of QTc on RR interval. RESULTS: The following regression equations were obtained relating QT to RR: QT=2.4RR(0.72), r(2)=0.79, with RR intervals varying between 210 and 350 ms. QTc lengthened significantly in all conscious rabbits given intravenous cisapride, dofetilide and haloperidol (p<0.05), and QTc did not change with DMSO (vehicle control), propranolol or enalaprilat. DISCUSSION: Results indicate that a bipolar transthoracic ECG recorded in conscious, sling-trained rabbits may provide an easy and economical methodology useful in predicting QTc lengthening of novel pharmacological entities.

Energy expenditure by intravenous administration of glucagon-like peptide-1 mediated by the lower brainstem and sympathoadrenal system.

Glucagon-like peptide-1 (GLP-1) is released from the gut in response to nutrient ingestion. Intravenous (iv) administration of GLP-1 (50 pmol-20 nmol) elicited dose-dependent increases in the rate of whole-body O2 consumption (VO2), an index of energy expenditure, and heart rate of urethane-anesthetized rats. The body core (colonic) temperature increased up to 0.3 degrees C without accompanying alteration of tail skin temperature. Intracerebroventricular (icv) administration of GLP-1 induced a slower and smaller increase in VO2 than the intravenous administration. The injection of glucagon-like peptide-2 (iv or icv) had no effect on VO2, body temperatures, or heart rate. Decerebration had no effect on the thermogenic responses induced by the iv administration of GLP-1, suggesting that the forebrain is not essential for these responses. However, cervical spinal transection greatly attenuated the responses, suggesting the critical involvement of the lower brainstem. Adrenalectomy or pretreatment with an autonomic ganglion blocker, hexamethonium, or a beta-adrenergic blocker, propranolol, also significantly attenuated the thermogenic response. However, subdiaphragmatic vagotomy or celiac-superior mesenteric ganglionectomy had no effect. Rats made insulin-deficient by pretreatment with streptozotocin also exhibited the normal thermogenic response to GLP-1. These results suggest the involvement of the GLP-1 in postprandial energy expenditure, mediated by the lower brainstem and sympathoadrenal system.

QT PRODACT: usability of miniature pigs in safety pharmacology studies: assessment for drug-induced QT interval prolongation.

To investigate whether miniature pigs are useful for evaluating the potential of drugs for drug-induced prolongation of the QT interval, we performed an in vivo QT assay using conscious and unrestricted miniature pigs. Compared with the vehicle average baseline values, haloperidol at 3 and 10 mg/kg, p.o. prolonged the QTcF interval (Fridericia's formula) by 8%-16%. The plasma concentration of haloperidol at which QT interval was prolonged (Cmax=42.9 ng/mL) was almost equal to that in humans. dl-Propranolol at 3, 10, and 30 mg/kg, p.o. caused no alterations in QT interval. dl-Propranolol at 3, 10, and 30 mg/kg, at which plasma concentrations were lower than in humans treated with dl-propranolol at the therapeutic dose level, shortened QTcF interval by 7%-12%. dl-Sotalol at 10 mg/kg, p.o. prolonged QTcF interval by 7%. From the above results, we considered that the miniature pig can be used for prediction of drug-induced prolongation of QT interval in humans, and thus, it is one of the useful animal species for assessing electrocardiograms in safety pharmacology studies.

[Effect of propranolol on renal hemodynamics in patients with cirrhosis: assessment with Doppler US]. / Siroz hastalarinda propranololün renal hemodinamik etkileri: Doppler US ile degerlendirme.

PURPOSE: To determine the renal resistive index profile in cirrhotic patients before and after propranolol treatment and assess the effects of propranolol on renal hemodynamics. MATERIALS AND METHODS: Thirty-six patients with cirrhosis and ascites (decompensated group), 39 patients with cirrhosis but no ascites (compensated group) and 25 patients with normal renal and hepatic functions (control group) were studied. All had normal blood urea nitrogen and serum creatinine levels. The renal resistive index was calculated in all patients before and after oral propranolol treatment. RESULTS: Resistive index was significantly higher in the decompensated group (p<0.05) than in other groups. After propranolol treatment, resistive indices decreased in the compensated patients (p<0.05) but increased in the decompensated group (p<0.05). There was a slight but statistically insignificant increase in the control group. CONCLUSION: In patients with cirrhosis renal failure is a significant risk factor for liver transplantation. In these patients, Doppler sonography provides early detection of renal dysfunction even before renal function tests are abnormal. Doppler sonography is a useful noninvasive method to evaluate the effects of drugs on renal hemodynamics.

Idiopathic left ventricular tachycardia: assessment and treatment.

Idiopathic left ventricular tachycardia (VT) has been classified into three subgroups according to mechanism: verapamil-sensitive, adenosine-sensitive, and propranolol-sensitive types. VT can be categorized also into left fascicular VT and left outflow tract VT. Although the mechanism of fascicular VT is verapamil-sensitive reentry, the mechanism of left outflow tract VT is not homogeneous. Fascicular VT can be classified into three subtypes: (1) left posterior fascicular VT with a right bundle branch block (RBBB) and superior axis configuration (common form); (2) left anterior fascicular VT with RBBB and right-axis deviation configuration (uncommon form); and (3) upper septal fascicular VT with a narrow QRS and normal axis configuration (rare form). Posterior and anterior fascicular VT can be successfully ablated at the mid-septum guided by a diastolic Purkinje potential or at the VT exit site guided by a fused presystolic Purkinje potential. Upper septal fascicular VT also can be ablated at the site indicated by a diastolic Purkinje potential. The mechanism of left ventricular outflow tract VT is most likely adenosine-sensitive triggered activity. This VT can be classified into three subtypes according to the location where catheter ablation is successful, i.e., (1) endocardial origin; (2) coronary cusp origin; and (3) epicardial origin. The R-wave duration and R/S-wave amplitude in V1/V2 can be used to differentiate coronary cusp VT from other types of outflow tract VT. Recognition of the characteristics of the various forms of this group of arrhythmias should facilitate appropriate diagnosis and therapy.

Assessment of spinal cord pathology following trauma using early changes in the spinal cord evoked potentials: a pharmacological and morphological study in the rat.

The possibility that spinal cord pathology following trauma can be assessed with early changes in the spinal cord evoked potentials (SCEPs) was examined in a rat model. Spinal cord injury (SCI) was produced in Equithesin-anesthetized (3 ml/kg, i.p.) rats through a longitudinal incision into the right dorsal horn at the T10-11 segments. The SCEPs were recorded with epidural electrodes placed over the T9 (rostral) segment of the cord. The SCEPs consisted of a small positive amplitude and a broad and high negative amplitude (NA). SCI resulted in an instant depression of the rostral NA that lasted for 1 h. However, the latency of NA continued to increase over time. At 5 h, spinal cord blood flow declined by 30% in the T9 segment, whereas the spinal cord water content and the permeability of the blood-spinal cord barrier (BSCB) were markedly increased. Damage to the nerve cells, glial cells, and myelin was quite common in the spinal cord, as seen by light and electron microscopy. Pretreatment with p-chlorophenylalanine, indomethacin, ibuprofen, and nimodipine attenuated the SCEP changes immediately after trauma and resulted in a marked reduction in edema formation, BSCB permeability, and blood flow changes at 5 h. However, pretreatment with cyproheptadine, dexamethasone, phentolamine, and propranolol failed to attenuate the SCEP changes after SCI and did not reduce the cord pathology. These observations suggest that early changes in SCEP reflect secondary injury-induced alterations in the cord microenvironment. Obviously, these changes are crucial in determining the ultimate magnitude and severity of cord pathology.

Power spectral analysis of heart rate variability for assessment of diurnal variation of autonomic nervous activity in guinea pigs.

We established characteristics of power spectral analysis of heart rate variability, and assessed the diurnal variations of autonomic nervous function in guinea pigs. For this purpose, an electrocardiogram (ECG) was recorded for 24 hr from conscious and unrestrained guinea pigs using a telemetry system. There were two major spectral components, at low frequency (LF) and high frequency (HF) bands, in the power spectrum of HR variability. On the basis of these data, we defined two frequency bands of interest: LF (0.07-0.7 Hz) and HF (0.7-3.0 Hz). The power of LF was higher than that of HF in the normal guinea pigs. Atropine significantly reduced power at HF. Propranolol also significantly reduced power at LF. Furthermore, the decrease in the parasympathetic mechanism produced by atropine was reflected in a slight increase in the LF/HF ratio. The LF/HF ratio appeared to follow the reductions of sympathetic activity produced by propranolol. Autonomic blockade studies indicated that the HF component reflected parasympathetic activity and the LF/HF ratio seemed to be a convenient index of autonomic balance. Nocturnal patterns, in which the values of heart rate in the dark phase (20:00-06:00) were higher than those in the light phase (06:00-20:00), were observed. However, the HF, LF and the LF/HF ratio showed no daily pattern. These results suggest that the autonomic nervous function in guinea pigs has no clear circadian rhythmicity. Therefore, this information may be useful for future studies concerning the autonomic nervous function in this species.

Impact of high-intensity exercise on energy expenditure, lipid oxidation and body fatness.

OBJECTIVE: Two studies were conducted to assess the potential of an increase in exercise intensity to alter energy and lipid metabolism and body fatness under conditions mimicking real life. METHODS: Study 1 was based on the comparison of adiposity markers obtained in 352 male healthy adults who participated in the Québec Family Study who either regularly participated in high-intensity physical activities or did not. Study 2 was designed to determine the effects of high-intensity exercise on post-exercise post-prandial energy and lipid metabolism as well as the contribution of beta-adrenergic stimulation to such differences under a real-life setting. RESULTS: Results from Study 1 showed that men who regularly take part in intense physical activities display lower fat percentage and subcutaneous adiposity than men who never perform such activities, and this was true even if the latter group reported a lower energy intake (917 kJ/day, P<0.05). In Study 2, the high-intensity exercise stimulus produced a greater post-exercise post-prandial oxygen consumption as well as fat oxidation than the resting session, an effect which disappeared with the addition of propranolol. In addition, the increase in post-prandial oxygen consumption observed after the high-intensity exercise session was also significantly greater than that promoted by the low-intensity exercise session. CONCLUSION: These results suggest that high-intensity exercise favors a lesser body fat deposition which might be related to an increase in post-exercise energy metabolism that is mediated by beta-adrenergic stimulation.

Functional assessment of beta adrenoceptor subtypes in human colonic circular and longitudinal (taenia coli) smooth muscle.

BACKGROUND AND AIMS: The subtype and species related heterogeneity of beta adrenoceptors prompted a functional reappraisal of these molecular targets of motility inhibition in the human colon. METHODS: Relaxation of muscle strips was measured in vitro. RESULTS: The following agonists had decreasing relaxing potency (effective concentration range 10(-8)-10(-4) mol/l): (-)isoprenaline (non-selective), terbutaline (beta(2) selective), CGP 12177 (beta(3) selective, also beta(1), beta(2) antagonist), and SR 58611A (beta(3) selective). Isoprenaline and terbutaline were more potent on circular than taenia strips; CGP 12177 and SR 58611A weakly and partially relaxed taenia but had little effect on circular strips. The potency of isoprenaline on circular strips was greatly reduced by the beta(1) selective antagonist CGP 20712 (10(-7) mol/l), and less so by ICI 118551 (10(-7) mol/l, beta(2) selective). CGP 20712 and ICI 118551 together (both 3 x 10(-6) mol/l) had no effect on taenia relaxation by SR 58611A and rendered isoprenaline and terbutaline virtually inactive on circular strips, although not on taenia, which was relaxed at higher than control concentrations and maximally by isoprenaline. Propranolol, a beta(1), beta(2) non-selective antagonist, at high concentrations (10(-5) mol/l) prevented taenia relaxation by CGP 12177 and SR 58611A; its quantitative antagonism of isoprenaline (in common with that of CGP 12177 used as an antagonist) was competitive in circular strips but not on taenia. CONCLUSIONS: beta(1), beta(2), and beta(3) adrenoceptors are functionally detectable in the human colon; agonist stimulation of any one type relaxed taenia but only isoprenaline was fully effective at the beta(3) subtype.

Lack of interaction between lansoprazole and propranolol, a pharmacokinetic and safety assessment.

Due to the prevalence of both gastrointestinal and cardiovascular diseases, it is likely that patients may be coprescribed gastric parietal cell proton pump inhibitors and beta-adrenergic antagonists. Therefore, the objectives of this phase I study were to assess the potential effects of the coadministration of lansoprazole on the pharmacokinetics of propranolol and to evaluate the safety of propranolol with concomitant lansoprazole dosing. In a double-blind fashion, 18 healthy male nonsmokers were initially randomized to receive either 60 mg oral lansoprazole, each morning for 7 days, or an identical placebo (period 1). On day 7, all subjects were concomitantly administered oral propranolol, 80 mg. After a minimum of 1 week following the last dose of either lansoprazole or placebo, subjects were crossed over to the opposite treatment for another 7 days (period 2). Subjects were again administered oral propranolol on day 7. During both treatment periods, blood samples for the determination of plasma propranolol and 4-hydroxy-propranolol were obtained just before the dose and at 0.5, 1, 2, 3, 4, 6, 8 12, 16, 20, and 24 hours postdose. Plasma propranolol and 4-hydroxy-propranolol concentrations were determined by using HPLC with fluorescence detection. The Cmax, tmax, AUC0-infinity, and t1/2 values for propranolol, as well as the AUC0-infinity for 4-hydroxy-propranolol, were calculated and compared between the lansoprazole and placebo regimens. The mean age of the 15 subjects who successfully completed the study was 31 years (range: 24-38 years), and their average weight was 174.8 pounds (range: 145-203 pounds). There were no statistically significant differences between the lansoprazole and placebo regimens for the propranolol Cmax, tmax, AUC0-infinity, and t1/2 values. Also, there were no statistically significant differences between regimens for the 4-OH-propranolol AUC0-infinity. Safety evaluations, which included adverse events, vital signs, clinical laboratory determinations, ECG, and physical examinations, revealed no unexpected clinically significant findings and did not suggest a drug-drug interaction. In conclusion, lansoprazole does not significantly alter the pharmacokinetics of propranolol, suggesting that it does not interact with the CYP2D6- or CYP2C19-mediated metabolism of propranolol. Modification of a propranolol dosage regimen in the presence of lansoprazole is not indicated, based on the pharmacokinetic analysis and the lack of a clinically significant alteration in the pharmacodynamic response.

Power spectral analysis of heart rate variability for assessment of diurnal variation of autonomic nervous activity in miniature swine.

BACKGROUND AND PURPOSES: The purpose of the study was to document diurnal variation of autonomic nervous functions by use of power spectral analysis of heart rate (HR) variability. METHODS: To clarify characteristics of power spectral analysis of HR variability, electrocardiogram (ECG), blood pressure (BP), and respiratory (Resp) waveform simultaneously were recorded. RESULTS: Two major spectral components were examined at low (LF)- and high (HF)-frequency bands for HR variability. Coherence between HR and Resp variabilities and HR and BP variabilities was maximal at approximately 0.14 and 0.03 Hz, respectively. On the basis of these data, two frequency bands of interest--LF (0.01 to 0.07 Hz) and HF (0.07 to 1.0 Hz)--were defined. Autonomic blockade studies indicated that the parasympathetic system mediated the HF and LF components, whereas the sympathetic system mediated only the LF component; HR had a diurnal pattern. The LF and HF bands in the dark phase tended to be higher than those in the light phase. The LF-to-HF ratio had a diurnal pattern similar to that of the HR. CONCLUSION: Parasympathetic nervous activity in miniature swine may be predominant in the dark phase. The characteristics of power spectra and diurnal variations of autonomic nervous functions are almost the same as those of humans. Therefore, miniature swine may be a useful animal model for future biobehavioral and pharmacotoxicologic studies.

Assessment of cardiac sympathetic regulation by respiratory-related arterial pressure variability in the rat.

1. Mechanical ventilation evokes a corresponding arterial pressure variability (APV) which is decreased by beta-adrenoceptor antagonism. Therefore, in this study we set out to determine whether the respiratory-related APV can be used to assess cardiac sympathetic tone. 2. Computer-generated broad-band mechanical ventilation (0-3 Hz) was applied to Sprague-Dawley rats that had been anaesthetized with ketamine and paralysed with pancuronium. APV and its relationship to lung volume variability (LVV-APV) was systematically quantified with auto- or cross-spectral frequency domain analysis. 3. APV and LVV-APV transfer magnitudes between 0.5 and 1.5 Hz showed dose-dependent suppression by propranolol from 0.01 to 1 mg kg-1, while the static value of arterial pressure remained unchanged. Stroke volume variability, assessed by the use of a pulse contour method, exhibited a similar pattern of suppression by propranolol. In contrast, heart rate variability was not lowered with propranolol. 4. The effect of propranolol on respiratory-related APV persisted even in the presence of combined alpha-adrenoceptor and muscarinic receptor blockade by phentolamine and atropine. 5. The frequency range of 0.5-1.0 Hz was optimal for LVV-APV transfer magnitude to correlate with cardiac sympathetic tone. 6. We conclude that respiratory-related APV may provide a valid assessment of cardiac sympathetic regulation which is independent of parasympathetic and vascular sympathetic influences in ketamine-anaesthetized and positive pressure-ventilated rats.