Showing papers in "Acta physiologica et pharmacologica Bulgarica in 1999"

Studies on paraquat-induced oxidative stress in rat liver.

Abstract: Oxidative injury of liver was studied 20 hr after a single oral administration of 150 mg/kg paraquat (PQ) to rats. PQ exerted no effect on cytosolic superoxide dismutase (SOD) activity but increased mitochondrial SOD activity by 14%. The level of GSH was decreased by 30%, and GSH/GSSG ratio was diminished almost twice. The correlation between the enhancement of mitochondrial SOD activity and the diminution of GSH level by PQ implicates O2- in the liver toxicity of the drug. Mitochondrial aconitase activity was slightly decreased (by 9%) while cytosolic aconitase activity was not affected. The results cast additional light on the responses of both aconitases to oxidative stress.

Circadian rhythms of arterial pressure: basic regulatory mechanisms and clinical value.

Abstract: The circadian rhythm of arterial pressure (AP) is not a passive consequence of the impact of exogenous factors. Endogenous mechanisms play an important role in the generation and maintenance of AP rhythm. The adaptation of the exogenous components of AP rhythm to the demands of the environment is modulated by the circadian-time-dependent responsiveness of the biologic oscillator. A neuronal network in the rostral hypothalamus including the suprachiasmatic nucleus is implicated in the generation of AP rhythm, in the modification of the rhythm amplitude (possibly due to homeostatic constraints), and in the regulation of its phase. The central sympathoexcitatory pathway to the upper thoracic cord plays a crucial role in the maintenance of normal circadian AP rhythm. The circadian pattern of AP is influenced also by hormonal factors such as the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-thyroid axes, the renin-angiotensin-aldosterone system, opioids, and various vasoactive peptides. The circadian variations of AP depend on physiological state--sleep and wakefulness, pregnancy, work, and senescence (primary aging). In some essential hypertensive patients and in patients with secondary hypertension the nocturnal fall in AP is reduced or absent (nondippers). Target-organ damage is more advanced in nondippers than in dippers. The occurrence of cardiovascular events exhibits a prominent circadian pattern, with events more frequent in the morning (06:00-12:00 h).

Chronopharmacology and its impact on antihypertensive treatment.

Abstract: Circadian rhythms have been documented throughout the plant and animal kingdom at every level of eukariotic organization. Circadian rhythms are endogenous in nature, driven by oscillators or clocks, and persist under free-running (e.g. constant darkness) conditions. The genes expressing the biological clock have been identified in various species. The important feature of endogeneous biological rhythms is their anticipatory character. Rhythmicity inherent to all living systems, allows them to adapt more easily and to better survive under changing environmental conditions during the 24 hours of a day as well as during changing seasons. Having this in mind it is easy to conceive that not only must the right amount of the right substance be at the right place, but also this must occur at the right time. Also in man nearly all functions of the body including those influencing pharmacokinetic parameters such as drug absorption and distribution, drug metabolism and renal elimination display significant daily variations. Also the onset and symptoms of diseases such as coronary infarction, angina pectoris, stroke, ventricular tachycardia are circadian phase dependent. Myocardial infarction and angina attacks as well as silent ischemias (ST-segment depression) in stable angina pectoris have an early morning peak between 8-12 h. In contrast, ECG abnormalities and angina attacks in variant angina mainly occur at night. Blood pressure and heart rate in normotensives and essential (primary) hypertensive patients display highest values during daytime followed by a nightly drop and an early morning rise. In about 70% of forms of secondary hypertension (e.g. renal disease, hyperthyroidisms, hormonal diseases, gestational hypertension), however, this rhythmic pattern is abolished or even reversed exhibiting nightly peaks in blood pressure. This form of hypertension is accompanied by increased end organ damages. Thus, different subtypes of a disease (angina pectoris, hypertension) can display different circadian patterns in symptoms. These observations are a challenge for basic and clinical research to get a better understanding on the underlying mechanisms of regulation. Moreover, they call for a circadian time-specified drug treatment. From above it is evident that pharmacokinetics may also not be constant within a day. Chronopharmacokinetics have been shown for several cardiovascular active drugs (propranolol, nifedipine, verapamil, enalapril, isosorbide-5-mononitrate, digoxin, etc.). Far more drugs were shown to display significant daily variations in their effects (chronopharmacodynamics, chronotoxicology) even after chronic application or constant infusion. In conclusion, there is clear evidence that the dose/concentration-response relationship of drugs can be significantly dependent on the time of day. Thus, circadian time has to be taken into account as an important variable influencing a drug's pharmacokinetics and/or its effects or side effects.

Circadian clocks and hypertension: genetics and interactions.

Abstract: Recent advances in molecular genetics of circadian rhythms and hypertension led to the discovery of separate groups of genes implicated in their regulation. Importantly, the identification in both mammals and flies of 6 homologous circadian clock genes strongly indicates that the circadian period is controlled by an evolutionary conserved set of genes. Studies in familial and experimental hypertension reveal that elevated blood pressure is due to mutations in genes implicated in the function of the renin-angiotensin-aldosterone system. A chronobiologic approach to experimental hypertension indicates that hypertension can be associated with selectively inverted circadian rhythm of arterial pressure. Several lines of evidence suggest that the rostral hypothalamus is an area of central integration of the endogenous rhythmic and other regulatory influences that modulate the phase and amplitude of circadian arterial pressure rhythmicity. The combination of advanced molecular genetics and continuous blood pressure monitoring with chronobiologic assessment emerges as a fruitful approach in better understanding the pathogenesis of hypertension.

Diagnostic thresholds for the clinical use of ambulatory blood pressure monitoring.

Abstract: The technique of noninvasive ambulatory blood pressure monitoring is now well established as an instrument in clinical research and as a diagnostic tool in clinical practice. Diagnostic thresholds for ambulatory monitoring were derived by averaging the 95th percentiles of the ambulatory blood pressure measurements in the normotensive subjects enrolled in various large-scale studies. Subjects normotensive on conventional sphygmomanometry, in the absence of other risk factors, have a low cardiovascular risk profile in comparison with their hypertensive counterparts. The evidence from prospective outcome studies also supports the proposed thresholds. More outcome studies are still ongoing. However, their results are unlikely to change the proposed thresholds, which are in line with the recommendations of the JNC VI (the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) and those of many other national expert committees.

Spectral sensitivity of the visual system as revealed by evoked potentials in normal and anomalous trichomats.

Abstract: The spectral sensitivity of the visual system upon adaptation by white light at intensity of 10,500 td was studied in Maxwellian view. The monochromatic stimuli had a size of 8 degrees and duration of 700 ms. They were superimposed on an adaptation field of 14 degrees. The spectral sensitivity was determined by the off-VEP amplitude measured from the negative peak with a latency of 75-80 ms to the positive peak with a latency of 100-110 ms. The EEG was led off monopolarly from the occipital scalp area. Eight normal trichomats, 2 protanomalous and 2 deuteranomalous subjects were investigated. Some specificity of the spectral sensitivity curve, determined by the VEP amplitude, were studied. Special attention was placed on the sensitivity decrease between lambda = 550 nm and lambda = 590 nm, which was much pronounced in the normal trichomats. Maximum sensitivity was observed at lambda = 527 nm. The sensitivity at lambda = 578 nm was lower than the maximum one by 0.8 logarithmic units or more. It is assumed that this sensitivity decrease is a manifestation of opponency between the middle wavelength and long wavelength mechanisms. In the anomalous trichomats the sensitivity decrease between lambda = 550 nm and lambda = 590 nm was much less pronounced. Maximum sensitivity was obtained at lambda = 551 nm. In the long wavelength range of the spectrum the deuteranomalous subjects showed a higher sensitivity as compared to the protanomalous ones. The obtained results suggest disturbances of color opponency in the anomalous trichomats.

Effect of stimulus contrast uncertainty on simple reaction time.

Abstract: Both reaction time (RT) and the latency of the visually evoked potentials (VEP) to grating onset increase with increasing stimulus spatial frequency (SF). At SF higher than 5 c/deg RT increases faster than VEP latency, the difference resulting in a "central delay" (Mihaylova et al., 1999). Due to the equipment limitations, RT and VEP experiments of Mihaylova et al. (1999) differed in constancy of stimulus contrast within a sequence of trials. The present experiments were aimed at testing the assumption that the central delay is a result of contrast uncertainty effect on RT. To this end, RT were measured in condition of both constant and variable grating contrast. The stimuli were sinusoidal gratings ranging in SF from 0.5 to 16 c/deg and in contrast from 2.5 to 50%. In addition, VEP were recorded to the same stimuli in blocks of fixed contrast and the latencies of the early VEP wave were subtracted from RT. Contrast uncertainty did not affect RT at low SF, 0.5 and 2 c/deg, while increasing RT at SF higher than 5 c/deg both at low and high stimulus contrast. The results showed that the central component of RT increase at high SF is reduced but not eliminated under constant contrast condition. The uncertainty effect at high SF might be due to contrast sensitivity reduction, reduced subjective stimulus probability and differences in response strategy adopted by the subjects when contrast was constant or variable. An alternative explanation is a larger ability of low SF stimuli compared to high SF stimuli to attract visual attention.

Effect of CPAP on breathlessness perception in healthy subjects during methacholine induced bronchoconstriction.

Abstract: Application of continuous positive airway pressure (CPAP) in asthmatic patients decreases breathlessness (B). The effect of CPAP on induced bronchoconstriction was studied in healthy subjects. The changes in B were related to changes in lung function indices. In nine healthy volunteers, males aged 20-27 years, acute bronchoconstriction was induced by inhalation of 1 to 128 mg/ml methacholine (M). CPAP (0.5 kPa) was then applied for 1 min. It was followed by inhalation of albuterol. Forced expiratory volume in 1 s (FEV1) and vital capacity (VC) were measured by spirometry and end expiratory lung level (EELL), to derive inspiratory capacity (IC), by inductive plethysmography. B was assessed by Borg scale. After the maximal concentration of M, FEV1 decreased by 14% (p < 0.01) as compared to the control values and Borg score (BS) increased to 2.4 (p < 0.01). In 7 out of 9 subjects we found a significant (p < 0.05) correlation between the changes in FEV1 and BS. BS decreased during CPAP (p < 0.01) and it further decreased significantly after albuterol. There was no correlation between the changes in IC and FEV1 during bronchoconstriction, or between IC and BS during CPAP. In conclusion, in healthy subjects with induced bronchoconstriction CPAP decreased significantly BS, which was further improved by inhalation of albuterol. B was related to changes in FEV1 but not in IC.