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Biomedical subjects

K Witte

Publications and source records attributed to K Witte.

At least 91 records · Page 5Linked to original sources
PubMed1995

Efficiency of beta-adrenoceptor subtype coupling to cardiac adenylyl cyclase in cardiomyopathic and control hamsters.

Densities of beta-adrenoceptor subtypes and their contributions to stimulation of adenylyl cyclase were studied in heart ventricles from cardiomyopathic (BIO 8262) and control Syrian hamsters (CLAC) at 4 different ages: 30, 100, 200, and 300 days. In BIO ventricles neither total beta-adrenoceptor density nor that of the beta 1-adrenoceptor subtype differed from the controls, whereas the density of beta 2-adrenoceptors was significantly higher in myocardium from 200- and 300-day-old BIO compared to that from age-matched CLAC hamsters. Stimulation of adenylyl cyclase by the non-selective beta-adrenoceptor agonist isoprenaline did not differ between strains, but the beta 1-adrenoceptor mediated component was significantly reduced in cardiomyopathic hamsters of all age groups. In 300-day-old animals beta 1-adrenoceptors accounted for 83% (CLAC) and 68% (BIO) of total beta-adrenoceptor binding sites, whereas only 26% (CLAC) and 6% (BIO) of the isoprenaline effect on cAMP formation were mediated via beta 1-adrenoceptors. Thus, the present study shows a lower coupling efficiency of beta 1-adrenoceptors compared to the beta 2-adrenoceptor subtype in ventricles from healthy Syrian hamsters and a progressive, further reduction in beta 1-adrenergic function in cardiomyopathic animals.

Adenylyl Cyclases↗
PubMed1995

Mechanisms of the circadian regulation of beta-adrenoceptor density and adenylyl cyclase activity in cardiac tissue from normotensive and spontaneously hypertensive rats.

Circadian variation in beta-adrenoceptor density and adenylyl cyclase activity was studied in myocardium from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In SHR cardiac beta-adrenoceptor density was significantly lower than in WKY. This reduction in total beta-adrenoceptors was exclusively due to a loss in the beta 1-subtype. Total and beta 1-adrenoceptor density in ventricles from both strains exhibited significant circadian variation with peaks occurring in the middle of the light and dark periods, whereas the beta 2-subtype did not show rhythmicity. Similarly, stimulation of adenylyl cyclase via total beta-adrenoceptors and via the beta 1-subtype was circadian time dependent, but circadian peaks occurring at the beginning of the light and dark periods were 6 h apart from those in beta-adrenoceptor density. Rhythmicity in the formation of cAMP was observed under basal conditions and after stimulation by isoprenaline or a forskolin derivative, whereas addition of manganese-ions abolished the circadian variation. In conclusion, the present study demonstrates that in ventricular tissue from WKY and SHR circadian rhythms observed in total beta-adrenoceptor density are due exclusively to variations in the beta 1-subtype. Since peaks in cAMP formation coincided with troughs in beta-adrenoceptor number, cAMP mediated phosphorylation of beta-adrenoceptors enhancing their down-regulation, could be involved in the circadian regulation of myocardial beta-adrenoceptor density. Rhythmicity in cAMP formation itself seems to involve coupling of G-proteins, because manganese ions abolished the circadian variation.

Adenylyl Cyclases↗
PubMed1995

Effects of the angiotensin II receptor antagonist losartan on 24-hour blood pressure profiles of primary and secondary hypertensive rats.

Primary and secondary hypertension differ with regard to circadian blood pressure (BP) profiles. To evaluate the contribution of the renin-angiotensin system (RAS) to circadian BP regulation, we studied cardiovascular effects of the angiotensin II (AII) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril in animal models of primary and secondary hypertension after morning and evening dosing. Systolic/diastolic BP (SBP/DBP) and heart rate (HR) were measured telemetrically in spontaneously hypertensive rats (SHR) and transgenic hypertensive rats (TGR[mRen-2]27). Losartan (0.3 to 30 mg/kg) or enalapril maleate (10 mg/kg) were injected intraperitoneally (i.p.) either at 0700 or 1900 h. Baseline SBP/DBP and HR showed significant circadian rhythmicity in both strains. The 24-h means in SBP/DBP were 190/127 mm Hg in SHR and 200/139 mm Hg in TGR. TGR showed a reversed circadian profile in BP, with peaks occurring during the daily resting period, whereas HR peaked at night. Losartan reduced BP dose dependently; reductions in TGR were significantly greater and obtained at 30-fold lower doses than in SHR. Maximum decreases induced by losartan were similar to those induced with enalapril 10 mg/kg. Both drugs reduced BP in TGR more effectively when applied at 0700 than at 1900 h, resulting in a normalized circadian BP profile. Our results demonstrate that the RAS is involved in both the pathomechanism of hypertension and in the inverse circadian BP pressure pattern in TGR.

Angiotensin II↗
PubMed1995

Contribution of the nitric oxide-guanylyl cyclase system to circadian regulation of blood pressure in normotensive Wistar-Kyoto rats.

OBJECTIVES: The study was performed in order to elucidate whether or not the nitric oxide-guanylyl cyclase system is involved in the circadian regulation of blood pressure. METHODS: Basal and sodium nitroprusside-stimulated guanylyl cyclase activity was studied in vitro in aortic tissue from normotensive Wistar-Kyoto rats sacrificed at 7 circadian times. Effects of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) on blood pressure and heart rate of rats were measured telemetrically after acute injection of L-NAME either in the morning or in the evening as well as after chronic application in drinking water. RESULTS: Guanylyl cyclase activity exhibited significant circadian rhythmicity under basal conditions and after stimulation by sodium nitroprusside 10 microM. Peaks in cGMP formation were observed in the daily resting period, i.e. the period of low blood pressure in rats. Acute application of L-NAME dose-dependently increased blood pressure; effects were more pronounced after injection in the morning than in the evening, leading to an inverse blood pressure profile after the highest dose (30 mg/kg i.p.). Chronic treatment with L-NAME resulted in a dose-dependent upward shift of the control blood pressure profile. Only at the highest dose applied in drinking water (100 mg/kg per day) was the circadian pattern in blood pressure altered, showing a reduced fall in the morning. CONCLUSIONS: Circadian rhythmicity in basal and stimulated soluble guanylyl cyclase activity and the reversed blood pressure profile after acute injections of L-NAME indicate an involvement of the nitric oxide-guanylyl cyclase system in circadian blood pressure regulation. After chronic inhibition of nitric oxide synthase additional and counterregulatory mechanisms have to be considered.

Animals↗
PubMed1994

Adenylyl cyclase activity in Alzheimer's disease brain: stimulatory and inhibitory signal transduction pathways are differently affected.

Adenylyl cyclase (AC) activity was studied in post mortem hippocampus and cerebellum from eight patients with Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) and seven non-demented control patients. AC was stimulated via stimulatory guanine nucleotide binding proteins (Gs) using guanosine triphosphate (GTP) and GppNHp (both 10(-4) M) or directly with either forskolin (10(-4) M) or Mn2+ (10(-2) M). Inhibition of AC via A1-receptors was performed with N6-cyclohexyladenosine (CHA) under basal conditions and in the presence of forskolin (10(-5) M). In both brain regions AC activity was significantly reduced in AD/SDAT when compared to controls. Under basal conditions and after stimulation via Gs mean reduction in hippocampus and cerebellum was 47.7% and 58.2%, respectively. The reduction was less pronounced after direct activation of the AC, amounting to 21.8% in hippocampus and 28.1% in cerebellum. CHA inhibited basal and forskolin-stimulated AC concentration-dependently by about 20% (basal) and 30% (forskolin). Inhibition by CHA was similar in hippocampus and cerebellum and tended to be more pronounced in AD/SDAT than in controls. Since the reduction of AC activity in AD/SDAT is greater after stimulation via Gs than after direct activation of the catalytic subunit, we suggest that both Gs and the catalytic subunit seem to be impaired. The fact that CHA-mediated inhibition of AC is not significantly different in AD/SDAT and controls, indicates that in contrast to Gs-, inhibitory G-proteins (Gi) coupling to AC remains intact in Alzheimer's disease.

Adenosine↗
PubMed1994

Effects of bright light on circadian patterns of cyclic adenosine monophosphate, melatonin and cortisol in healthy subjects.

Bright light is known as a strong zeitgeber on human circadian rhythms and influences several endocrine and neuroendocrine functions. In the present study we examined the influence of a 3-h bright light stimulus, given at different times during the day (morning or evening), on circadian patterns of cyclic adenosine monophosphate (cAMP), melatonin and cortisol. Two groups of synchronized healthy volunteers (lights on: 05.00-23.00 h) were exposed to bright light (2500 lux) for 3 h over 6 days either in the morning (05.00-08.00 h) or in the evening (18.00-21.00 h). The results showed a significant phase advance in the circadian rhythms of melatonin and cortisol when bright light was given in the morning but not when given in the evening. Rhythm in plasma cAMP basically was not affected by either light treatment.

Adult↗
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

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

Managerial style and health promotion programs.

Organizational correlates of worksite health promotion programs were isolated and interpreted within a diffusion of innovation framework. A sample of managers from California (U.S.A.) 500 organizations were interviewed via telephone on their corporate management styles and health care strategies. Organizational management style was found to be related to prevalence of health promotion programs and future plans for health promotion programs. Specifically, this study found that organizations with democratic management styles are more likely to plan, adopt, and/or implement worksite health promotion programs when compared to organizations with authoritarian management styles. An additional contribution of this study was the development and validation of the Organizational Management Style (OMS) scale. These results have important theoretical and practical implications. For example, these findings explain why some organizations are more or less likely to adopt health promotion programs. Both diffusion of innovation and social control explanations are used to interpret the results.

California↗
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

A comparison of amlodipine with enalapril in the treatment of moderate/severe hypertension.

1. The safety and efficacy of amlodipine vs enalapril as monotherapy was evaluated in patients with moderate/severe hypertension (supine DBP 105-125 mm Hg, SBP 140-220 mm Hg). 2. After 2 weeks placebo treatment 31 patients were randomised by the technique of minimisation in an observer-blind study to receive once daily treatment with either amlodipine (15 patients) 5-10 mg, or enalapril (16 patients) 5-20 mg for 8 weeks. The study design concluded with 2 weeks placebo treatment. In addition to clinic measurements, home blood pressure monitoring (Copal UA-251) was performed during the study. 3. Clinic supine systolic blood pressure was reduced from 177 to 152 mm Hg (amlodipine) and 183 to 169 mm Hg (enalapril) (95% CI for the intergroup difference -22.1, 0.3, P = 0.06) after 8 weeks treatment. 4. Clinic supine diastolic blood pressure was reduced from 110 to 93 mm Hg (amlodipine) and 109-102 mm Hg (enalapril) (95% CI for the intergroup difference -17.7, -2.7, P < 0.01) after 8 weeks treatment. 5. Home blood pressure recordings confirmed these reductions in blood pressure. Although the reduction in blood pressure was greater for the amlodipine treated group, the differences between treatments were not statistically significant. 6. Both drugs were reasonably well tolerated. The adverse events occurring most frequently in the amlodipine group were headache (5), peripheral oedema (3), upper respiratory infection (3) and anxiety (2). The adverse events occurring most frequently in the enalapril treated patients were headache (6), dizziness (3) and upper respiratory infection (2).

Adult↗
PubMed1993

A comparison of amlodipine with enalapril in the treatment of isolated systolic hypertension.

1. The safety and efficacy of amlodipine and enalapril were compared in patients with isolated systolic hypertension (supine DBP < 95 mm Hg and supine SBP 160-200 mm Hg). 2. After 2 weeks treatment with placebo 31 patients were randomised by the technique of minimisation in an observer-blind study to receive once daily treatment with either amlodipine (16 patients) or enalapril (15 patients) for 8 weeks. The study design concluded with 2 weeks placebo treatment. In addition to clinic measurements, home blood pressure monitoring (Copal UA-251) was performed during the study. 3. Mean supine systolic blood pressure was reduced from 185 to 164 mm Hg (amlodipine) and 183 to 159 mm Hg (enalapril) (95% CI for the difference between the drugs -10.5, 15.3) after 8 weeks treatment. 4. Mean supine diastolic blood pressure was reduced from 86 to 80 mm Hg (amlodipine) and 88 to 80 mm Hg (enalapril) (95% CI for the difference between the drugs -4.9, 7.6) after 8 weeks treatment. 5. Home blood pressure recordings confirmed these reductions in blood pressure, although there was no significant difference between treatments for the reductions in blood pressure. 6. Both drugs were reasonably well tolerated. The adverse events occurring most frequently in the amlodipine group were headache (2), peripheral oedema (5) and palpitations (2). The adverse events occurring most frequently in the enalapril group were headache (2), peripheral oedema (2), palpitations (2) and dizziness (3).

Aged↗
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

Platelet Na(+)-H+ exchanger activity in normotensive and hypertensive subjects: effect of enalapril therapy upon antiport activity.

OBJECTIVE: Primary hypertension has been reported to be associated with an enhancement of Na(+)-H+ exchange. However, details of the kinetic properties of the Na(+)-H+ exchanger in hypertensives and its dependence upon age and gender in normotensives are unknown. PARTICIPANTS: We determined the activity of the platelet Na(+)-H+ exchanger in 20 normotensives and 26 untreated primary hypertensives. INTERVENTIONS: In eight hypertensive individuals antihypertensive treatment was interrupted for 1 week. Treatment for 6 weeks with a daily single dose of 10 mg enalapril decreased mean arterial pressure to 105.7 +/- 11.6 mmHg. METHODS: Platelets were loaded with the intracellular pH (pHi) indicator 2'-7'-bis-carboxyethyl-5(6)-carboxyfluorescein (BCECF) and acidified by propionic acid. Initial velocities of pH recovery were determined and used for calculation of maximum velocity (Vmax), baseline pHi and the pHi value for half maximal activation (pH0.5) of the Na(+)-H+ exchanger in each individual. RESULTS: In normotensives, Vmax averaged 0.05 +/- 0.01 dpHi/min independently of age, gender and actual diastolic blood pressure. In hypertensives, two different subgroups were defined bearing either low or high Na(+)-H+ exchange activity. Values of pHi and pH0.5 were identical in all subgroups irrespective of Vmax. The twofold enhancement of Na(+)-H+ exchange in the second group was preserved in thrombin-stimulated platelets. Vmax values remained unaffected by enalapril treatment. CONCLUSIONS: Enhanced Na(+)-H+ exchange activity in hypertensives is primarily characterized by an increase in Vmax. This enhancement is refractory to antihypertensive treatment and therefore appears to be a relatively fixed parameter.

Age Factors↗
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↗