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Biomedical subjects

B Lemmer

Publications and source records attributed to B Lemmer.

At least 91 records · Page 5Linked to original sources
PubMed1994

Effects of age on circadian blood pressure and heart rate rhythms in patients with primary hypertension.

To evaluate whether circadian rhythms in blood pressure and heart rate are influenced by age, we analyzed 24-h ambulatory blood pressure and heart rate recordings from 31 patients with primary hypertension. Data were collected during hospitalization, after a drug-free run-in period. Set times were administered for lights-on, meals, and lights-off. Daytime napping was prohibited. The patients were divided into sex-matched groups of young (group I: 25-45 years, n = 9), middle-aged (group II: 47-57 years, n = 11), and old (group III: 57-74 years, n = 11) subjects. Hourly data were analysed by fitting a two-component cosine function (24- and 12-h periods). Amplitudes of the circadian rhythms in systolic blood pressure and heart rate were significantly reduced with age. This finding could be partly attributed to the recording of higher nocturnal values in older patients. Elderly hypertensives also evidenced a significantly greater ultradian component (12-h period) in the systolic blood pressure rhythm than did young patients, with the secondary afternoon decline in blood pressure being more pronounced in groups II and III. The 24-h acrophase of heart rate was found to occur approximately 1.6 h earlier than that of systolic blood pressure in the young group (p < 0.01). This phase advance of heart rate compared with systolic blood pressure was reduced to 1 h in group II (p < 0.05) and was not evident in group III (p > 0.1). These results indicate that circadian blood pressure and heart rate profiles of primary hypertensives change with age. Since measures were obtained in a typical clinical setting, these findings have implications for the diagnosis and treatment of hypertension in the elderly. The marked afternoon decline in blood pressure for the elderly patients may also render conventional cosinor analysis inappropriate for accurate description of the circadian rhythms of geriatric hypertensives.

Adult↗
PubMed1994

Effects of enalaprilat on circadian profiles in blood pressure and heart rate of spontaneously and transgenic hypertensive rats.

We investigated the dose-dependent cardiovascular effects of enalaprilat at different dosing times in two animal models of hypertension. Blood pressure (BP) and heart rate (HR) were measured telemetrically in 5 spontaneously hypertensive rats (SHR) and in 5 transgenic hypertensive rats (TGR) after intraperitoneal (i.p.) injection of enalaprilat either at 700 h or at 1900 h. In SHR, dosing of enalaprilat at the beginning of the resting period, i.e., at 700 h, significantly reduced BP but did not influence HR. After dosing at 1900 h, BP was unchanged, whereas HR increased, which might have resulted from reflexly increased sympathetic tone. In TGR, enalaprilat at either dosing time decreased BP dose dependently and to a higher extent than in SHR, but the effects were more pronounced after morning than after evening dosing. These findings demonstrate that in two animal models of hypertension the antihypertensive effects of enalaprilat depended on the time of drug dosing.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Correlative circadian rhythms of cholecystokinin and dopamine content in nucleus accumbens and striatum of rat brain.

Due to contrary results concerning the interaction of cholecystokinin and dopamine (CCK/DA) circadian variations in CCK/DA concentration were investigated in forebrain nuclei of rats (Nc. accumbens, striatum) in order to assess the influence of time of day on neurotransmission. CCK was determined by a radioimmunoassay, DA was measured by electrochemical detection after HPLC separation. A distinct circadian rhythm, superimposed by harmonics (12 h, 6 h) was found in the content of both DA and CCK. A trough was shown for CCK during the light phase and a crest during the late afternoon and the dark phase, respectively. For DA the opposite was found. Caused by a phase-shift of about 3-4 h, the CCK/DA rhythms are negatively correlated. The differences are significant at 11.00 h, 13.00 h, 21.00 h, and 03.00 h. The results indicate that circadian processes are involved in neuronal transmission of CCK and DA.

Animals↗
PubMed1993

Uncoupling of beta 1-adrenoceptors from cardiac adenylyl cyclase in cardiomyopathic and control hamsters.

The beta-adrenoceptor-adenylyl cyclase system was studied in heart ventricles from Wistar rats, cardiomyopathic (BIO 8262) and nonfailing control hamsters (CLAC) using the beta 1-adrenoceptor antagonist CGP 20712A. In radioligand binding studies, the majority of beta-adrenoceptors in ventricles from rats as well as from CLAC hamsters was of the beta 1-subtype (72.2% and 76.6%, respectively). In BIO ventricles a significant (CLAC vs. BIO, P < 0.05) reduction in the beta 1-subtype (62.9%) was found. In Wistar rats the subtype-mediated stimulation of adenylyl cyclase reflected the beta 1:beta 2 ratio as determined by binding studies. In hamster ventricles the effect of isoprenaline was mediated predominantly (CLAC) or exclusively (BIO) via the beta 2-subtype, indicating that cardiac beta 1-adrenoceptors were partly (CLAC) or completely (BIO) uncoupled from the adenylyl cyclase.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Beta-adrenoceptor density and subtype distribution in cerebellum and hippocampus from patients with Alzheimer's disease.

beta-Adrenoceptor density and beta 1- and beta 2-subtype distribution were examined in hippocampi and cerebella from patients with Alzheimer's disease (AD/SDAT). Tissues from age-, sex and post-mortem delay matched non-demented patients served as controls. The total beta-adrenoceptor density as evaluated in saturation experiments with the hydrophilic radioligand [3H]CGP 12177 was higher in hippocampal (36-39 fmol/mg protein) than cerebellar tissues (20-21 fmol/mg), however, no differences were found in either brain region between AD/SDAT patients and controls. Subtype distribution using the highly selective beta 1-adrenoceptor antagonist CGP 20712A revealed a slightly higher proportion of beta 1-adrenoceptors in hippocampus (26%-27%) than in cerebellum (20%-21%) with, again, no difference between AD/SDAT and controls. We recently described a 40% reduction in basal and stimulated adenylyl cyclase activity in post-mortem hippocampus of AD/SDAT patients, a brain region greatly affected by the disease, the present data now demonstrate that this disease-related effect is not mirrored by a similar change in beta-adrenoceptor density nor in subtype distribution.

Adrenergic beta-Antagonists↗
PubMed1993

Recent advances in chronopharmacokinetics: methodological problems.

Chronopharmacokinetics deals with the study of the temporal changes in absorption, distribution, metabolism and elimination and thus takes into account the influence of time of administration on these different steps. In the last decade, numerous studies have been devoted to chronokinetics: recent advances will be reviewed in the first part. As representative examples, the main chronokinetic changes of anaesthetics, cardiovascular active drugs and antiinflammatory drugs in men are listed. Temporal changes can be involved at each step of the sequence of pharmacokinetic processes: temporal variations in drug absorption from the gastro-intestinal tract, in plasma protein binding and drug distribution, in drug metabolism (temporal variations in enzyme activity, hepatic blood flow) and in renal drug excretion may play a role. Thus, the time of administration of a drug is an important source of variation which must be taken into account in kinetic studies and particular methodological aspects of chronokinetics are needed. In a chronopharmacokinetic study many factors of variation must be controlled: factors related to the drug itself (influence of food, galenic formulation, drug interactions), subject related-factors (age, gender, pathology, posture, exercise, synchronization) and factors related to the conditions of the administration (single or repeated dosing, constant rate delivery, route of administration). In conclusion, there are some instances in which a chronokinetic study is needed: 1) when possible daily variations in pharmacokinetics may be responsible for time dependent variations in drug effects, 2) when drugs have a narrow therapeutic range, 3) when symptoms of a disease are clearly circadian phase-dependent (e.g. nocturnal asthma, angina pectoris, myocardial infarction, ulcer disease) 4) when drug plasma concentrations are well correlated to the therapeutic effect in case the latter is circadian phase-dependent. Variables influencing pharmacokinetics such as fasting, meals and meal times, galenic formulation, posture, activity-rest, have to be controlled according to the aim of the investigation. The main aim of chronokinetic studies is to control the time of administration which among others, can be responsible for variations of drug kinetics but also may explain chronopharmacological effects observed with certain drugs.

Chronobiology Phenomena↗
PubMed1993

Cardiovascular effects, pharmacokinetics, and converting enzyme inhibition of enalapril after morning versus evening administration.

The cardiovascular effects and pharmacokinetics of once-daily enalapril were studied after single-dose and subchronic treatment in eight patients with hypertension by use of ambulatory blood pressure monitoring. Enalapril, 10 mg, was given at either 7 AM or 7 PM in a randomized crossover design. In addition, inhibition of serum converting enzyme was studied. Subchronic treatment at 7 AM significantly reduced blood pressure during the day but was less effective at night. Subchronic dosing at 7 PM significantly further decreased nighttime blood pressure followed by a slow increase during the day, with no effect on elevated afternoon values. Peak concentrations of enalaprilat were found 3.5 hours (morning) and 5.6 hours (evening) after drug intake (p < 0.05), whereas peak effects occurred 7.4 hours (morning) and 12 hours (evening) after drug administration. In conclusion, 24-hour blood pressure profiles in patients with hypertension were significantly influenced by the time of enalapril dosing. Differences in effect profiles could not be attributed to similar changes in pharmacokinetics or to different time courses of angiotensin converting enzyme inhibition.

Adult↗
PubMed1993

Circadian blood pressure variation in transgenic hypertensive rats.

Automatic, around-the-clock blood pressure measurements have increased our understanding of hypertension in humans. Patients with essential hypertension display patterns similar to those observed in normotensive subjects, whereas those with secondary hypertension frequently show abnormal circadian rhythms characterized by a failure to reduce blood pressure at night. We have modeled this situation in rats. Normotensive Wistar-Kyoto and Sprague-Dawley rats, spontaneously hypertensive rats, and rats made hypertensive by transgenic implantation of the mouse salivary gland renin gene (TGR[mRen-2]27) underwent chronic implantation of a device that telemetrically monitored their blood pressures, heart rates, and motor activities. In either normotensive or hypertensive rats, motor activity peaked during the dark phase, indicating that animals from all strains were nocturnal. In both normotensive and spontaneously hypertensive rats, the 24-hour blood pressure and heart rate profiles showed peak values during the rats' active phase at night, ie, between midnight and 3 AM. In the transgenic rats, on the other hand, blood pressure values were at maximum during the day around noon, when the rats were in their resting phase. The heart rate of the transgenic rats nevertheless still peaked around midnight. These data suggest that normotensive rats and those with primary and secondary hypertension display circadian rhythms of blood pressure and heart rate analogous to those observed in normotensive and primary or secondary hypertensive humans, respectively. The TGR(mRen-2)27 strain may be a useful model with which to investigate the mechanisms responsible for alterations in circadian rhythms of blood pressure and heart rate in forms of secondary hypertension.

Analysis of Variance↗
PubMed1993

Chronobiologic evaluation of angiotensin-converting enzyme activity in serum and lung tissue from normotensive and spontaneously hypertensive rats.

Angiotensin-converting enzyme (ACE) activity in serum and lung tissue from both normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) was determined at six different circadian times. In WKY rats serum ACE varied significantly within 24 h, mainly due to reduced enzyme activity at 12:00 h. In SHR the 24-h profile of serum ACE did not exhibit time-dependent differences. Mean serum ACE activity over 24 h was significantly higher in WKY than in SHR. In lung tissue ACE activity did not depend on the circadian time in either strain. Mean enzyme activity in lung tissue was not different between WKY and SHR. We conclude that circadian changes in the activity of serum and tissue ACE are unlikely to play an important role in the regulation of the circadian blood pressure profile in both normotensive and spontaneously hypertensive rats.

Analysis of Variance↗
PubMed1992

[Rhythm analysis of individual 24-hour blood pressure profiles of patients with essential hypertension].

Circadian rhythms in ambulatory blood pressure profiles of eight primary hypertensive patients were analyzed by nonlinear fit of a combined cosine function. Significant circadian variation in systolic blood pressure was found in each patient, and in diastolic blood pressure in seven out of eight patients. The eight primary hypertensive subjects revealed typical circadian blood-pressure profiles with two daytime maxima and a single nighttime minimum. Whereas daytime maxima differed between the subjects, all nighttime minima occurred within a narrow range of 1:54 a.m. to 4:42 a.m. The PHARMFIT-program allows to analyze in more detail the circadian blood pressure profiles obtained by ABPM in single patients as well as in a group of hypertensives.

Adult↗
PubMed1992

[PHARMFIT--a program for the evaluation of digitally collected cardiovascular parameters].

The PHARMFIT program allows the non-linear fit of simple and combined cosine functions to data from long-term monitoring of cardiovascular parameters and the statistical evaluation of the quality of fit. With the SYNOPS utility a statistical comparison of different fit models can be achieved. As an example, the systolic blood-pressure data obtained in a hypertensive subject by ambulatory blood-pressure monitoring (ABPM) over a period of 36 h is used. The program demonstrates that the fit of a combined cosine function including a 24-h and a 12-h period describes the data better than a simple 24-h cosine function. The quality of fit is significantly improved by inclusion of the first harmonics. The PHARMFIT program can help to get a better analysis of ABPM data.

Blood Pressure↗
PubMed1991

Dose-dependent stimulation of adenylate cyclase in rat hippocampal tissue by isoprenaline, Gpp(NH)p and forskolin: lack of circadian phase-dependency.

In rat hippocampal tissue the basal as well as drug-stimulated adenylate cyclase (AC) activity was studied after sacrificing the animals at 9 different circadian times (01.00, 04.00, 07.00, 10.00, 13.00, 16.00, 19.00, 22.00, 01.00 h). The AC was stimulated in vitro either via the beta-adrenoceptor by isoprenaline (IPN, 0.01-100 mumol/l plus GTP 0.005-50 mumol/l, via the GTP-binding protein by Gpp(NH)p (0.03-100 mumol/l) or via the catalytic unit of the AC by forskolin (0.1-600 mumol/l). For each drug dose-response curves could be constituted in single hippocampal tissues at each of the time points of sacrifice. Whereas maximal stimulation by forskolin was not achieved with the highest dose used (600 mumol/l, EC50-, Emax-values and Hill-coefficients could be calculated for both IPN and Gpp(NH)p, respectively. Thus, the rank order of drug stimulated AC activity was forskolin > Gpp(NH)p > IPN. However, no circadian phase-dependency in basal as well as drug-stimulated AC activity was found.

Adenylyl Cyclases↗
PubMed1991

Reduced basal and stimulated (isoprenaline, Gpp(NH)p, forskolin) adenylate cyclase activity in Alzheimer's disease correlated with histopathological changes.

Cyclic adenosine monophosphate (cAMP) is an adenylate cyclase borne second messenger involved in basic metabolic events. The beta-adrenoceptor sensitive adenylate cyclase was studied in post-mortem hippocampi of controls and Alzheimer patients. Virtually identical subsets of each hippocampus homogenate were stimulated by 100 mumol isoprenaline, Gpp(NH)p and forskolin, respectively, in presence of an ATP-regenerating system. The determination of cAMP formed was carried out by means of a radioassay. The observed significant 50% reduction in basal as well as in stimulated adenylate cyclase activity in Alzheimer's disease is negatively correlated with semiquantitative evaluations of amyloid plaques (P less than 0.05) but not with neuritic plaques, neurofibrillary tangles or neuropil threads. This reduction in enzyme activity is obviously not due to simple cell loss alone. It is likely that the crucial point of the observed functional disturbance is at the level of the catalytic unit of the adenylate cyclase, since the same degree of reduction is maintained at all steps of the signal cascade.

Adenylyl Cyclases↗