The Role of Circadian Rhythms in the Hypertension of Diabetes Mellitus and the Metabolic Syndrome.

PURPOSE OF THE REVIEW: Cellular circadian clocks regulate physiological functions during day and night. It has been convincingly demonstrated that hypertension in patients suffering from diabetes mellitus or metabolic syndrome is characterized in most cases by a disturbed 24-h profile resulting in a nondipper pattern. We consider possible correlation between biological clocks and symptoms of the metabolic syndrome. RECENT FINDINGS: Changes in circadian clock function have been linked to metabolic disorders in genome-wide association studies. Epidemiological studies have shown that a loss of nocturnal decline in blood pressure increases the risk of cardiovascular morbidity and mortality and end-organ damage. Looking at clock genes, however, there is no obvious association between symptoms of diabetes or metabolic syndrome and clock gene expression. Emerging data suggest that circadian rhythm disruption is a risk factor for metabolic and cardiovascular disorders, while disease feedback on clock function is limited.

Signal Transduction and Chronopharmacology of Regulation of Circadian Cardiovascular Rhythms in Animal Models of Human Hypertension.

Inbred strains of rats can be used as models of human hypertension to evaluate mechanisms of regulation of the circadian rhythms underlying hypertension. Blood pressure and heart rate rhythms in rodents are endogenous (circadian). Studies have been performed in rats on the turnover of norepinephrine, on processes of signal transduction in the beta-adrenoceptor-adenylate cyclase-cyclic AMP-phosphodiesterase system and in the renin-angiotensin-aldosterone system, and on circadian rhythms in blood pressure and heart rate using radiotelemetry. The findings allowed a better understanding of the circadian phase-dependent kinetics and effects of cardiovascular active drugs (chronopharmacology) used in humans.

Safety pharmacology--current and emerging concepts.

Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds.

Insufficient reply by Hermida et al. to the critical comments to the MAPEC and HYGIA studies.

The reply of Hermida et al. (2020) to our critical comments on the MAPEC and HYGIA Lemmer and Middeke (2020) studies in this Journal is insufficient and incomplete. Hermida does not address our first and main point on the baseline blood pressure values of 131/77 mmHg over 48 hours comprising 57.4% of the treated hypertensives (according to Table 1 in HYGIA) and consequently 42.6% of the untretated hypertensives! We criticized that in the HYGIA study; both normal and treated patients were included in one group not separated by statistics and without information on the baseline blood pressure values in each subgroup. This basic failure is our key issue of criticism and the basis of unreliability concerning the whole publication. This issue was not picked up in the recent comment of Hermida et al. (2020). They just concentrated on minor points in order to reject our severe criticism.

A commentary on the Spanish hypertension studies MAPEC and HYGIA.

The recently published chronotherapeutic Spanish papers MAPEC and HYGIA proposing that antihypertensive drug treatment should be given at bedtime suffers from obvious deficiencies in study design and are not a valid basis for drug treatment of hypertension.

[Chronopharmacology--importance of the biological clock in drug treatment]. / Chronopharmakologie. Bedeutung der inneren Uhr für die Arzneitherapie.

Nearly all functions of living creatures including man exhibit significant daily variations. Today, internal biological clocks are traced down to the molecular level. In man pathophysiological events such as coronary infarction, angina pectoris, asthma attacks and gastro-intestinal ulcers do not occur at random but exhibit a clear-cut daily rhythmic pattern. It is, therefore, not surprising that the pharmacokinetics as well the effects and side-effects of drugs can vary significantly with the time of day as has been documented in many clinical studies. Thus, "time-of-day" has to be regarded as an important factor to evaluate drug efficacy and its therapeutic window.

No correlation between lunar and menstrual cycle - an early report by the french physician J. A. Murat in 1806.

Jean Arnaud Murat was a physician at the Medical School of Montpellier in France. In 1806 he published his outstanding book "De L'Influence de la Nuit sur les Maladies ou Traité des Maladies Nocturne". In his book he concentrated on the following questions: - Does the night has an influence on a disease? - Are there diseases in which this is more or less obvious? - What is the physical background of this influence? Murat described in detail certain diseases which dominate at night and he concluded that the most evident motivation for his observations is the constant and periodic movement of the earth around its axis, resulting in a period of about 24 h, and the elliptic rotation around the sun. Most important Murat presented for the first time data that the menstrual cycle is not governed by the lunar cycle.

Caelius Aurelianus' textbook on medicine of the fifth century: rhythm in asthma, pain, and drug effects.

Caelius Aurelianus was a Greek-Roman physician in the fifth century. He translated the work of Soranus from Ephesus into Latin and extended the medical knowledge of his time in several textbooks. His book "De Morbis acutis et chronicis" was reprinted many times up to the 19th century and served as the handbook for physicians. Aurelianus aready described in detail the rhythmic pattern - daily and seasonally - of asthma. Tooth pain was also first described by Caelius Aurelianus to peak at night and that drugs were not able to fully suppress the pain, a first indication of chronopharmacology.

The physiologist Johann Autenrieth (1772-1835) at Tübingen University: early reports on biological rhythms and their use for medical lectures.

Johann, Heinrich, Ferdinand von Autenrieth [1772-1835], was a teacher of anatomy, physiology and pharmacology at the University of Tübingen, Germany. He was the author of a famous textbook on Physiology and one of the earliest pharmacologists [Öffentlicher Lehrer der Arzneykunst]. In his textbooks, he presented a lot of information that and how biological rhythms influenced physiological functions in the human body, the book was used for his medical lectures for students. He can be regarded as on of the earliest chronophysiologists. Most important, he assumed a chemical stimulation responsible for generating the periodicities in the human body.

Chronobiology, drug-delivery, and chronotherapeutics.

All functions in man are highly organized in time as biological rhythms of diverse periods, both in health and in disease. This represents a challenge for those involved in the development of drug-delivery systems to make possible the treatment of illness according to these physiological biological rhythms as a means of improving therapeutic outcomes. Though constant-release drug-delivery systems seem to improve patient compliance to many diverse treatments (e.g., for hypertension), rhythmicity in biological functions and in the mechanisms of disease should be mirrored by respective drug-release programs.

Chronobiology and chronotherapy of ischemic heart disease.

The occurrence of the clinical manifestations of ischemic heart disease (IHD)--myocardial ischemia and angina pectoris, acute myocardial infarction, and sudden cardiac death--is unevenly distributed during the 24 h with greater than expected events during the initial hours of the daily activity span and in the late afternoon or early evening. Such temporal patterns result from circadian rhythms in pathophysiological mechanisms plus cyclic environmental stressors that trigger ischemic events. Both the pharmacokinetics (PK) and pharmacodynamics (PD) of many, though not all, anti-ischemic oral nitrate, calcium channel blocker, and beta-adrenoceptor antagonist medications have been shown to be influenced by the circadian time of their administration. The requirement for preventive and therapeutic interventions varies predictably during the 24 h, and thus therapeutic strategies should also be tailored accordingly to optimize outcomes. During the past decade, two first generation calcium channel blocker chronotherapies have been developed, trialed, and marketed in North America for the improved treatment of IHD. Nonetheless, there has been relatively little investigation of the administration-time (circadian rhythm) dependencies of the PK and PD of conventional anti-ischemic medications, and there has been little progress in the development of new generation IHD chronotherapies. Available epidemiologic, pharmacologic, and clinico-therapeutic evidence demonstrates how the chronobiologic approach to IHD can contribute new insight and opportunities to improve drug design and drug delivery to enhance therapeutic outcomes.

The importance of circadian rhythms on drug response in hypertension and coronary heart disease--from mice and man.

The cardiovascular system is highly organised in time; blood pressure (BP), heart rate (HR), peripheral resistance, pressure and the release/activity of vasodilating hormones all display pronounced circadian variations. Pathophysiological events within the cardiovascular system are also not random, as shown for instance by sudden cardiac death (SCD), stroke, ventricular arrhythmias (VA), arterial embolism, and symptoms of coronary heart disease (CHD) such as myocardial infarction (MI) and ischemia, angina attacks (AA) in stable angina (stA) or variant angina (varA) or silent ischemia. In hypertensive patients various anti-hypertensive drugs were investigated in crossover studies (morning vs. evening dosing); however consistent data were only obtained for angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. Whereas in dippers ACE inhibitors had a super-dipping effect when dosed at night, no consistent difference in BP lowering effect on the 24-hr BP profile was found with calcium channel blockers after morning and evening dosing. In non-dippers the calcium channel blockers isradipine and amlodipine consistently transformed non-dippers into dippers, after evening dosing. Diuretics are also able to normalize a non-dipping behaviour. Moreover, a circadian phase-dependency in pharmacokinetics has been demonstrated for various cardiovascular active drugs such as beta-blockers, calcium channel blockers, oral nitrates and ACE inhibitors, modified by the pharmaceutical formulation. There is evidence that in hypertensive dippers anti-hypertensive drugs should be given in the early morning, whereas in non-dippers it may be necessary to add an evening dose or even to use a single evening dose in order to not only reduce high BP but also to normalize a disturbed non-dipping 24 hr BP profile. In CHD, calcium channel blockers-mainly short acting and non-retarded preparations-seem to be less effective than beta-adrenoceptor antagonists in reducing ischemic events during the night and early morning. However, the role of formulation and/or subclasses of the calcium channel blockers remains to be elucidated. In order to get more insight into the circadian regulation of the cardiovascular system animal models of primary and secondary hypertension have been studied in various strains of normotensive and hypertensive rats and mice. At least in rodents there is ample evidence that the 24-hr rhythms in BP and HR are under the control of biological clock(s) as they persist under constant darkness (i.e. in free-run conditions) with a period deviating from 24 hr; these rhythms are abolished by lesioning of the "master clock" located in the suprachiasmatic nuclei (SCN). In conclusion, chronobiological and chronopharmacological studies are important experimental and clinical approaches to get a better insight into the physiological and pathophysiological regulation of the cardiovascular system including their rhythmic organisation. Circadian time-dependent clinical studies also have implications for drug therapy in hypertension and CHD.

Evidence for an estradiol-agonistic action of nebivolol in spontaneously hypertensive rats.

OBJECTIVES: Unlike classical beta1-selective blockers, nebivolol (NEB) has vasodilatory properties due to the release of nitric oxide (NO) by a mechanism that is, so far, unknown. We hypothesized that NEB stimulates NO release by binding to estrogen receptors (ER) and subsequent activation of endothelial NO synthase (eNOS). The aim of this study was to elucidate the underlying mechanism of NEB action by investigating estradiol-dependent effects of NEB on the NO system in spontaneously hypertensive rats (SHR). METHODS: The effects of NEB on the NO system were determined by measuring urinary nitrate/nitrite (NOx) as well as eNOS and caveolin-1 protein expression in aortae. RESULTS: NEB did not influence NOx excretion in sham-operated (SO) female rats during proestrus. In male and ovariectomized female (OVX) rats, NEB increased NOx excretion significantly, whereas N(G)-nitro-L-arginine methyl ester (L-NAME) inhibited the NEB-induced increase in NOx. ER blockade with ICI182,780 prevented NEB-induced NOx excretion in OVX rats. In the aortae of SO females, NEB treatment did not alter eNOS expression. In OVX rats eNOS expression was increased two-fold after NEB application and this could be prevented by pretreatment with ICI182,780. In contrast to eNOS, NEB did not influence caveolin-1 expression in either group. CONCLUSION: The ability of NEB to up-regulate NOx excretion in male and OVX SHR and the inhibitory effect of ICI182,780 on NEB-induced NOx excretion suggests that NEB has an estradiol-agonistic action in vivo. NEB provokes NO generation by up-regulation of eNOS protein expression, whereas the expression of the negative eNOS regulator caveolin-1 remains unaffected.

The sleep-wake cycle and sleeping pills.

Sleeping pills are drugs which are used world-wide to combat sleep disturbances, and to prevent symptoms due to maladjustment to shiftwork or jet-lag. Today, benzodiazepines and the so-called "non-benzodiazepines", such as zolpidem, which both act on benzodiazepine receptors, are drugs of first choice and they are substitutes for barbiturates. Their use as sleeping pills in insomniacs is established after appropriate medical diagnosis. Symptoms from shiftwork or jet-lag are due to an internal desynchronisation of biological rhythms, and there is ample evidence that benzodiazepines are not effective in preventing these symptoms. Cabin crews in particular should never take sleeping pills, in order not to impair cognitive functions or to reduce the reactivity needed to fly an aircraft safely. The biological clock(s) cannot be reset instantaneously by any drug.

Disturbance of circadian rhythms in analgosedated intensive care unit patients with and without craniocerebral injury.

Melatonin, cortisol, heart rate, blood pressure, spontaneous motor activity, and body temperature follow stable circadian rhythms in healthy individuals. These circadian rhythms may be influenced or impaired by the loss of external zeitgebers during analgosedation, critical illness, continuous therapeutic intervention in the intensive care unit (ICU), and cerebral injury. This prospective, observational, clinical study examined 24 critically ill analgo-sedated patients, 13 patients following surgery, trauma, or acute respiratory distress (ICU), and 11 patients with acute severe brain injury following trauma or cerebral hemorrhage (CCI). Blood samples for the determination of melatonin and cortisol were obtained from each patient at 2 h intervals for 24 h beginning at 18:00 h on day 1 and ending 16:00 h on day 2. Blood pressure, heart rate, body temperature, and spontaneous motor activity were monitored continuously. Level of sedation was assessed using the Ramsey Sedation Scale. The severity of illness was assessed using the APACHE-II-score. The time series data were analyzed by rhythm analysis with the Chronos-Fit program, using partial Fourier series with up to six harmonics. The 24 h profiles of all parameters from both groups of patients were greatly disturbed/abolished compared to the well-known rhythmic 24 h patterns in healthy controls. These rhythm disturbances were more pronounced in patients with brain injury. The results of this study provide evidence for a pronounced disturbance of the physiological temporal organization in ICU patients. The relative contribution of analgosedation and/or brain injury, however, is a point of future investigation.

The use of heat-induced hydrolysis in immunohistochemistry on angiotensin II (AT1) receptors enhances the immunoreactivity in paraformaldehyde-fixed brain tissue of normotensive Sprague-Dawley rats.

The research on components of the renin-angiotensin system delivered a broad image of angiotensin II-binding sites. Especially, immunohistochemistry (IHC) provided an exact anatomical localization of the AT(1) receptor in the rat brain. Yet, controversial results between in vitro receptor autoradiography and IHC as well as between immunohistochemical studies using various antisera started a vehement discussion concerning specificity and cross-reactivity of these antisera. In particular the magnocellular subdivision of the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) provided controversial results on the localization of AT(1) receptors. Both areas are known for angiotensin II-induced release of vasopressin (VP) and oxytocin (OXT). To evaluate the significance of the appropriate method of antigen retrieval and its relevance for the detection of AT(1) receptors we performed IHC on AT(1) receptors in paraformaldehyde-fixed and paraffin-embedded brain tissue of Sprague-Dawley rats using either the detergent Triton X-100 or microwave oven heating. This study demonstrates that heat-induced hydrolysis enhances the quality and quantity of immunoreactivity (IR) in IHC on AT(1) receptors. In the organum vasculosum lamina terminalis and in the parvocellular subdivisions of the PVN we report a distribution of AT(1)-like-IR similar to that observed with other methods. However, in addition, we provide evidence that distinct AT(1)-like-IR is also localized in few magnocellular neurons of the PVN and in few parvocellular neurons of the dorsal SON but not in magnocellular neurons of the SON. Moreover, parallel IHC indicates that few magnocellular OXT- or VP-releasing neurons of the PVN as well as parvocellular OXT-releasing neurons of the SON do also contain AT(1) receptors.

Gender dependency of circadian blood pressure and heart rate profiles in spontaneously hypertensive rats: effects of beta-blockers.

This study investigated (i) blood pressure (BP), heart rate (HR), and their relation to urinary NOx and eNOS protein expression in male and female spontaneously hypertensive rats (SHR), as well as (ii) gender-dependent cardiovascular effects of nebivolol (NEB) in comparison to metoprolol (MET) in SHR. BP and HR were measured telemetrically after a single intraperitoneal application of NEB or MET at 07.00 and 19.00 h in male rats and at 19.00 h in proestrus female rats. The two beta-blockers varied in time of decreasing BP and HR and also in duration. In males, MET decreased BP and HR for few hours exclusively when applied at the onset of the activity phase (i.e., at 19.00 h), while after its application at 07.00 h, BP and HR were unchanged. In females, MET also caused a short-lasting BP and HR reduction, with the effect being more pronounced than in males. In males, NEB at either dosing time decreased HR and BP to a greater extent than did MET. This effect was evident both during the activity and rest periods and persisted for at least five days. In females, NEB provoked a similar, but more pronounced, effect on BP and HR in comparison to males. These findings demonstrate that significant gender-dependent differences in the circadian profile of BP and HR exist. BP and urinary NOx as well as eNOS expression are inversely correlated, and the cardiovascular effects of NEB and MET vary, depending on the time of application as well as gender.

Clinical chronopharmacology of the cardiovascular system: hypertension and coronary heart disease.

There is sound evidence that the cardiovascular and the renal systems are well organized in time. Mechanisms of regulation and pathophysiological events are not evenly distributed over the 24-h scale. Moreover, certain diseases may even alter the physiological circadian pattern both in the cardiovascular system and in the kidneys. This observation bares implications for drug treatment, e.g., regarding drug formulations and dosing time intervals. Pitfalls may arise from neglecting circadian phase-dependency in pharmacokinetics and in the concentration-effect relationship. Moreover, different types of drugs may be superior to others when circadian time-related symptoms are concerned. No doubt, "time-of-day" has to be included in our diagnostic and therapeutic strategies.

[Light and Medicine]. / Licht und Medizin.

There would be no life without light. The rotation of the earth around its axis has introduced the development of biological clocks in all living subjects regulating all functions of the body. The rhythms best described are the 24-hour/circadian and the seasonal rhythms. The rhythmic composition around the body clock has great impact on health and disease, both in diagnostics and treatment. Nowadays, bright light, e.g. in seasonal affective disorder, can be regarded as a drug, being even more effective than selective serotonin reuptake inhibitors.

Circadian rhythms in blood pressure, heart rate, hormones, and on polysomnographic parameters in severe obstructive sleep apnea syndrome patients: effect of continuous positive airway pressure.

INTRODUCTION: Seventeen male patients with severe obstructive sleep apnea syndrome (OSAS; apnea-hypopnea index>30/h) were monitored by polysomnography in the sleep lab before and after about 8 weeks of continuous positive airway pressure (CPAP). Twelve of the patients were hypertensive, but treated by antihypertensive drugs. The circadian rhythms in blood pressure (BP) and heart rate were determined by ambulatory BP monitoring and motor activity was monitored by a motion logger. As the sympathetic tone is reported to be increased in sleep apnea, the circadian rhythm in plasma norepinephrine was studied in parallel and as a marker rhythm of the biological clock plasma melatonin was determined around the clock by radioimmunoassay. RESULTS: Level and rhythm in BP and heart rate were not significantly affected by CPAP in this group of patients, but the number of dippers increased after CPAP intervention. The high 24 h plasma values of norepinephrine were lowered by CPAP therapy. In contrast, melatonin values were disturbed in OSAS patients with a loss in nocturnal increase; this pattern was not corrected by CPAP. Sleep functions (deep sleep, slow wave sleep, rapid eye movement sleep, arousal index, apnea-hypopnea index, desaturation index) were disturbed in OSAS patients as monitored by polysomnography and were significantly improved by CPAP therapy. CONCLUSION: The study indicates that BP-controlled hypertensive patients with OSAS can additionally benefit from CPAP therapy by increasing the number of dippers. This treatment significantly improved sleep functions and OSAS symptoms. In addition, arousal movements at night were also reduced and the high sympathetic tone during early morning hours was also decreased. However, there is still an indication of a disturbed function of the biological clock as the loss in the rhythm in plasma melatonin was not corrected by CPAP.