A promising pharmacological approach in cardiovascular disease prevention (9.7. 2019)

Epoxyeicosatrienoic acids (EETs), cytochrome P450 epoxygenase metabolites of arachidonic acid, represent a promising pharmacological approach in cardiovascular disease prevention. In our study, cardioprotective effects of a novel, stable and orally active agonistic 14,15-EET analog EET-B on the progression of post-ischemic heart failure  was examined in spontaneously hypertensive rats (SHR), a pre-clinical rodent model of human essential hypertension. SHR were subjected to myocardial infarction and the effects of continuous EET-B treatment before and after MI on post-ischemic left ventricular function, myocardial fibrosis and inflammation were analyzed. As EET-based therapies can attenuate the progression of HF by mechanisms involving activation of heme oxygenase-1, its immunopositivity in viable myocytes of the ischemic myocardium was also determined. We demonstrated that EET-B treatment improved post-ischemic left ventricular function, markedly increased heme oxygenase-1 immunopositivity in cardiomyocytes subjected myocardial infarction and reduced cardiac inflammation and fibrosis. These findings suggest that EET analog EET-B has beneficial therapeutic actions to reduce remodeling in SHR subjected to myocardial infarction.

8.Neckář, Jan - Khan, M. A. H. - Gross, G. J. - Cyprová, Michaela - Hrdlička, Jaroslav - Kvasilová, A. - Falck, J. R. - Campbell, W. B. - Sedláková, Lenka - Škutová, Šárka - Olejníčková, Veronika - Gregorovičová, Martina - Sedmera, David - Kolář, František - Imig, J. D. Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats. Clinical science. Roč. 133, č. 8 (2019), s. 939-951. ISSN 0143-5221, IF: 5,237 (2018).

Small amounts of inorganic nitrate or beetroot provide substantial protection from salt-induced Increases in blood pressure (4.4. 2019)

Adding tiny amounts of beetroot or dietary nitrate to salty food products might help prevent high blood pressure, according to a preliminary study of rats.

To reduce the risk of salt-induced hypertension, medical authorities have emphasized dietary guidelines promoting high intakes of potassium and low intakes of salt that provide molar ratios of potassium to salt of ≥1:1. However, during the past several decades, relatively few people have changed their eating habits sufficiently to reach the recommended dietary goals for salt and potassium. Thus, new strategies that reduce the risk of salt-induced hypertension without requiring major changes in dietary habits would be of considerable medical interest. In the current studies in a widely used model of salt-induced hypertension, the Dahl salt-sensitive rat, we found that supplemental dietary sodium nitrate confers substantial protection from initiation of salt-induced hypertension when the molar ratio of added nitrate to added salt is only ≈1:170. Provision of a low molar ratio of added nitrate to added salt of ≈1:110 by supplementing the diet with beetroot also conferred substantial protection against salt-induced increases in blood pressure. The results suggest that on a molar basis and a weight basis, dietary nitrate may be ≈100× more potent than dietary potassium with respect to providing substantial resistance to the pressor effects of increased salt intake. Given that leafy green and root vegetables contain large amounts of inorganic nitrate, these findings raise the possibility that fortification of salty food products with small amounts of a nitrate-rich vegetable concentrate may provide a simple method for reducing risk for salt-induced hypertension.

Effects of supplemental sodium nitrate or beetroot on salt-induced increases in blood pressure. A, Time course of 24-h averages of systolicarterial pressure. B, Time course of 24-h averages of diastolic arterial pressure. C, Mean changes in systolic arterial pressure induced by salt loading. D, Mean changes in diastolic arterial pressure induced by salt loading. *P < 0.05.

Morris Jr, R. Curtis - Pravenec, Michal - Šilhavý, Jan - DiCarlo, E. Stephen - Kurtz, W. Theodore: Small amounts of inorganic nitrate or beetroot provide substantial protection from salt-induced increases in blood pressure. Hypertension. Roč. 73, 2019. doi: 10.1161/HYPERTENSIONAHA.118.12234. [Epub ahead of print]. ISSN 0194-911X, IF: 6.857.

The effect of gut microbiome on expression of genes involved in regulation of stress response in chronic stress (11.2. 2019)

The scientists from the Institutes of Physiology and Microbiology CAS have shown, that absence of gut microbiota leads to altered behavior in social conflict and changes of expression of genes involved in regulation of stress response in chronically stressed mice.

Mammals are naturally colonized by microorganisms, commonly referred as the microbiome. Substantial fraction of the microbiome represent bacteria. Some bacteria are capable of synthetizing chemical substances, such as hormones or neurotransmitters, and thus influence the host both on local and whole-organism level. Disruption of the microbiome is associated with several immune and neuropsychiatric disorders and stress may disrupt the balance between the host and the microbiome. When facing potential danger, stress response acts towards maintaining the homeostasis by activating variety of mechanisms such as sympatho-adrenal system or the hypothalamo-pituitary-adrenal (HPA) axis. Acute stress is generally not harmful, however when prolonged or poorly managed, it can lead to serious side effects.

For studying the effects of microbiome on the host the germ-free mice are used as animal model. It is known that microbiome alters the behavior and can alter humoral response to acute stress. In collaboration with our colleagues from the Institute of Microbiology CAS we have focused on the effects of chronic psychosocial stress in germ-free mice. Our results have shown that the absence of microbiome affects the murine behavior in social conflicts (Fig. 1) and modulates the expression of genes involved in regulation of stress response in adrenal gland (Fig. 2), local paracrine signalization in colon and expression of cytokines in mesentery lymph nodes and colon. This study contributes to understanding the crosstalk between microbiota and the host brain, especially during chronic stress.

Fig. 1. Time spent in individual defensive behavioral patterns (upright posture, freezing and escape/flight) and in total defensive behavior (B) of specific pathogen-free (SPF) and germ-free (GF) mice. Data are expressed as the means ± SEM; *P < 0.05.

Fig. 2. Responses of genes encoding adrenal steroidogenesis, catecholamine biogenesis and glucocorticoid metabolism following social defeat in specific pathogen-free (SPF) and germ-free (GF) mice. MC2R, melanocortin 2 receptor; StAR, steroidogenic acute regulatory protein; Cyp11a1, cholesterol side-chain cleavage enzyme; TH, tyrosine hydroxylase; PNMT, phenylethanolamine N-methyltransferase; 11HSD1 and 11HSD2, 11b-hydroxysteroid dehydrogenase type 1 and type 2. The data are expressed as the means ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001.

Vodička, Martin - Ergang, Peter - Hrnčíř, Tomáš - Mikulecká, Anna - Kvapilová, Pavlína - Vagnerová, Karla - Šestáková, Blanka - Fajstová, Alena - Hermanová, Petra - Hudcovic, Tomáš - Kozáková, Hana - Pácha, Jiří: Microbiota affects the expression of genes involved in HPA axis regulation and local metabolism of glucocorticoids in chronic psychosocial stress. Brain Behavior and Immunity. Roč. 73, Oct 2018 (2018), s. 615-624. ISSN 0889-1591, IF: 6.306, 2017.

Alignment of mother and offspring body clock could prevent diseases such as heart disease and obesity (9.1. 2019)

The scientists from the Institute of Physiology CAS found out that the care provided by a mother can impact the body clock and health of offspring after birth. By reducing abnormalities in the body clock of offspring, it may be possible to develop therapies for serious lifestyle-related diseases, such as heart disease and obesity.

The body has an internal clock that regulates sleepiness over a 24 hour period, called your circadian rhythm. The circadian system is important so that processes in our body are synchronised with day and night, i.e. when it is light or dark outside. Disturbances in these mechanisms can lead to poor health, such as heart disease.

The mother-offspring interaction is very important for health later in adulthood. This is the first study to provide compelling evidence that the circadian characteristics of a mother may positively affect the likelihood of disease developing in offspring. Providing better maternal care significantly reduced abnormalities in the circadian system and resulted in a lower likelihood of development of heart disease.

The study conducted by the Institute of Physiology of the Czech Academy of Sciences was performed in two strains of laboratory rats, in which the maternal care and synchrony of their circadian clocks with external day/night cycle differed. The effect of maternal care provided by the genetic mother of these pups was compared with maternal care of the foster mother. The pups either had an aberrant circadian system and were genetically determined to develop disease in adulthood or they were healthy controls. The researchers tested the effect of maternal care on the body clock before and just after weaning, and on their activity rhythms, heart rate and blood pressure in adulthood. Proper maternal care provided to pups genetically predisposed to develop disease led to improvement of their clock function and abolished the rise in their heart rate in adulthood.

The data obtained in pups before weaning were based on population samples because the researchers could not assess circadian rhythms of the clocks in each individual pup within the body without disturbing maternal behaviour. Additionally, in the rat strain spontaneously developing disease, the molecular mechanisms connecting the circadian clock and the pathology is not understood.

These results point to a real possibility to reduce abnormalities in the offspring’s body clock and therefore limit the progression of disease in order to improve health. The future research will be directed at understanding in more detail how an aberrant circadian system contributes to the progression of disease. This research is worth future explorations as it may provide novel therapies for serious life-style related diseases in humans.

Olejníková, Lucie - Polidarová, Lenka - Behuliak, Michal - Sládek, Martin - Sumová, Alena: Circadian alignment in a foster mother improves the offspring's pathological phenotype.  Journal of Physiology. Roč. 596, č. 23 (2018), s. 5757-5775. ISSN 0022-3751, IF: 4.540, 2017.

Anti-epileptic drug gabapentin decreases blood pressure through the attenuation of sympathetic nerve transmission (6.12. 2018)

Our study reveals an important role of sympathetic nervous system in blood pressure lowering by acute administration of gabapentin in spontaneously hypertensive rats (SHR) which is the most widely used model of human hypertension.

Gabapentin (GBP) is an anticonvulsant drug used for the treatment of epilepsy and it is also often used as analgesic in the treatment of chronic neuropathic pain. Gabapentin acts as an inhibitor of voltage-dependent calcium channels (VDCCs) containing the auxiliary α2δ subunit. VDCCs play important role in blood pressure regulation of mammals – the elevated vascular smooth muscle tone is mediated via the L-type VDCCs while the augmented activity of sympathetic nervous system via the N-type VDCCs. The sympathetic nervous system plays an important role in the regulation of blood pressure. The increased sympathetic nerve activity has been observed in both hypertensive humans and animal models of hypertension. Our study revealed that acute administration of gabapentin lowered blood pressure and heart rate more in SHR than in normotensive control WKY rats (Fig. 1). Hypotensive effect of gabapentin was accompanied by a reduction of several indirect measures of sympathetic nerve activity. In agreement with previous results, sympathectomy prevented the blood pressure-lowering effect of gabapentin (Fig. 1). These findings suggest that gabapentin administration lowers blood pressure of SHR mainly through the attenuation of sympathetic nerve transmission. Therefore, sympatholytic effect of gabapentin should be considered in patients subjected to gabapentin treatment.

Fig. 1 The effects of intravenous application of gabapentin on the mean arterial pressure (MAP) in control non-sympathectomized (Control) or guanethidine-sympathectomized (Sympx) SHR and WKY rats. The vertical dotted lines represent the time of drug administration.

Behuliak, Michal - Bencze, Michal - Polgárová, Kamila - Kuneš, Jaroslav - Vaněčková, Ivana - Zicha, Josef. Hemodynamic Response to Gabapentin in Conscious Spontaneously Hypertensive Rats: The Role of Sympathetic Nervous System. Hypertension 2018, vol. 72, 3, p. 676-685 . IF = 6.823