Accumulating evidence indicates that hypertension is associated with "ion channel remodeling" of vascular smooth muscle cells (VSMCs). The objective of this study was to determine the effects of exercise intensity/volume on hypertension-associated changes in large-conductance Ca2+-activated K+ (BKCa) channels in mesenteric arteries (MAs) from spontaneously hypertensive rats (SHR). Male SHRs were randomly assigned to three groups: a low-intensity aerobic exercise group (SHR-L: 14 m/min), a moderate-intensity aerobic exercise group (SHR-M: 20 m/min), and a sedentary group (SHR). Age-matched Wistar-Kyoto rats (WKYs) were used as normotensive controls. Exercise groups completed an 8-week exercise program. Elevation of the α and β1 proteins was unequal in MA myocytes from SHRs, with the β1 subunit increasing more than the α subunit. BKCa contribution to vascular tone regulation was higher in the myocytes and arteries of SHRs compared to WKYs. SHR BKCa channel subunit protein expression, β1/α ratio, whole cell current density and single-channel open probability was also increased compared with WKYs. Aerobic exercise lowered systemic blood pressure and normalized hypertension-associated BKCa alterations to normotensive control levels in the SHRs. These effects were more pronounced in the moderate-intensity group than in the low-intensity group. There is a dose-effect for aerobic exercise training in the range of low to moderate-intensity and accompanying volume for the correction of the pathological adaptation of BKCa channels in myocytes of MAs from SHR., Y. Zhang, Y. Chen, L. Zhang, N. Lu, L. Shi., and Obsahuje bibliografii
Considerable evidence demonstrates that phenotypic switching of vascular smooth muscle cells (VSMCs) is influenced by aging and hypertension. During phenotypic switching, VSMCs undergo a switch to a proliferative and migratory phenotype, with this switch being a common pathology in cardiovascular diseases. The aim of this study was to explore the joint influence of age and hypertension on thoracic aortic smooth muscle phenotypic switching and the balance of Akt and mitogen-activated protein kinase (MAPK) signaling during this switch. Different ages of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were used to establish hypertension and aging models. The phenotypic state was determined by detecting the marker proteins α-SM-actin, calponin, and osteopontin (OPN) via immunohistochemical staining and Western blot. Signaling proteins associated with the Akt and MAPK pathways were detected in rat thoracic aorta using Western blot. Both aging and hypertension caused a decrease in contractile (differentiated) phenotype markers (α-SM-actin and calponin), while the synthetic (proliferative or de-differentiated) phenotype maker was elevated (OPN). When combining hypertension and aging, this effect was enhanced, with Akt signaling decreased, while MAPK signaling was increased. These results suggested that VSMCs phenotype switching is modulated by a balance between Akt and MAPK signaling in the process of aging and hypertension., Lin Zhang, Zhaoxia Xu, Ying Wu, Jingwen Liao, Fanxing Zeng, Lijun Shi., and Obsahuje bibliografii
Matrix metalloproteinases (MMPs) play an important role in the pathogenesis of heart failure (HF). Our aim was to determine the activities of circulating MMP-2 and MMP-9 in patients with HF in respect of gender, comorbidities and treatment (n=51). We did not reveal any differences in circulating pro-MMP-2 and pro-MMP-9 activities between the patients with HF and without it. However, there was a decrease in activity of pro-MMP-2 in treated hypertensive participants versus healthy ones. In contrast, we observed increased pro-MMP-2 activity in hypertensive participants with coexistent HF versus hypertensive participants without HF. In addition, a decrease in pro-MMP-2 activity was shown in women suffering from HF versus men suffering from HF. In conclusion, potential inhibitory effect of antihypertensive treatment on pro-MMP-2 activity was found. Coexistent HF with hypertension probably reduces the inhibitory effect of antihypertensive treatment on pro-MMP-2 activity. Our data also suggest the role of potential cardioprotective factors influencing the activity of pro-MMP-2 in women., E. Giannakos, E. Vardali, M. Bartekova, M. Fogarassyova, M. Barancik, J. Radosinska., and Obsahuje bibliografii
There exists no examination of what is the minimum anti - hypertensive threshold intensity for isometric exercise training. Twenty two normotensive participants were randomly assigned to training intensities at either 5 % or 10 % of their maximal contraction. Twenty participants completed the study. Clinical meaningful, but not statistically significant, reductions in systolic blood pressure were observed in both 5 % and 10 % groups -4.04 mm Hg (95 % CI -8.67 to +0.59, p=0.08) and -5.62 mm Hg (95 % CI -11.5 to +0.29, p=0.06) respectively after 6 weeks training. No diastolic blood pressure reductions were observed in either 5 % -0.97 mm Hg (95 % CI -2.56 to +0.62, p=0.20) or 10 % MVC +1.8 mm Hg (95 % CI -1.29 to +4.89, p=0.22) groups respectively after training. In those unable to complete isometr ic exercise at the traditional 30 % intensity, our results suggest there is no difference between 5 and 10 % groups and based on the principle of regression to the mean, this could mean both interventions induce a similar placebo-effect., N. C. L. Hess, D. J. Carlson, J. D. Inder, E. Jesulola, J. R. McFarlane, N. A. Smart., and Obsahuje bibliografii
We assessed the effect of the previously uncovered gap junctio n protein alpha 8 (Gja8) mutation present in spontaneously hypertensive rat - dominant cataract (SHR - Dca ) strain on blood pressure, metabolic profile, and heart and renal transcriptomes. Adult, standard chow-fed male rats of SHR and SHR - Dca strains were used. We found a significant, consistent 10-15 mmHg decrease in both systolic and diastolic blood pressures in SHR - Dca compared with SHR (P<0.01 and P<0.05 , respectively; repeated measures analysis of variance (ANOVA)). With immunohistochemistry, we were able to localize Gja8 in heart, kidney, aorta, liver, and lungs, mostly in endothelium; with no differences in expression between strains. SHR - Dca rats showed decreased body weight, high-density lipoprotein cholesterol concentrations and basa l insulin sensitivity in muscle. There were 21 transc ripts common to the sets of 303 transcripts in kidney and 487 in heart showing >1.2-fold difference in expression between SHR and SHR - Dca. Tumor necrosis factor was the most significant upstream regulato r and glial cell-derived neurotrophic factor family ligand-receptor interactions was the common enriched and downregulated canonical pathway both in heart and kidney of SHR - Dca. The connexin 50 mutation L7Q lowers blood pressure in the SHR - Dca strain, decr eases high-density lipoprotein cholesterol, and leads to substantial transcriptome changes in heart and kidney., O. Šeda, F. Liška, M. Pravenec, Z. Vernerová, L. Kazdová, D. Křenová, V. Zídek, L. Šedová, M. Krupková, V. Křen., and Obsahuje bibliografii
We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the followup period was 50 weeks. RAS was blocked using angiotensinconverting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF., P. Kala, L. Sedláková, P. Škaroupková, L. Kopkan, Z. Vaňourková, M. Táborský, A. Nishiyama, S. H. Hwang, B. D. Hammock, J. Sadowski, V. Melenovský, J. D. Imig, L. Červenka., and Obsahuje bibliografii
Proximal resistance vessels, such as the mesenteric arteries, contribute substantially to the peripheral resistance. The reactivity of resistance vessels to vasoactive substance like natriuretic peptides plays an important role in the regulation of blood pressure. In current study, we investigated the reactivity of mesenteric arteries to atrial natriuretic peptide (ANP), a well known vasodilating factor, in spontaneously hypertensive rats (SHR), as well as the effects of exercise training on it. As a result, ANP-induced vasorelaxation was attenuated in SHR with significantly increased phosphodiesterase type 5 (PDE5), and decreased cGMP/ANP ratio, compared with WKY rats as control. Intriguingly, the decreased reactivity to ANP in SHR was markedly reversed by exercise training. In addition, ANP resistance of in vitro mesenteric arteries was diminished by sildenafil a potent selective inhibitor of PDE5. In conclusion, ANP resistance occurs in resistance vessels of SHR, suggesting predisposition to hypertension, which can be reversed by exercise., Jun Yu, Bing Zhang, Xing-Lu Su, Ru Tie, Pan Chang, Xue-Ce Zhang, Jian-Bang Wang, Ge Zhao, Miao-Zhang Zhu, Hai-Feng Zhang, Bao-Ying Chen., and Obsahuje bibliografii
Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long-term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered. The immunosuppressive effects of CNIs result from the inhibition of interleukin-2 synthesis and reduced proliferation of T cells due to calcineurin blockade. The considerable side effects that are associated with CNIs therapy include arterial hypertension and nephrotoxicity. The focus of this article was to review the available literature on the pathophysiological mechanisms of CNIs that induce chronic nephrotoxicity and arterial hypertension. CNIs lead to activation of the major vasoconstriction systems, such as the reninangiotensin and endothelin systems, and increase sympathetic nerve activity. On the other hand, CNIs are known to inhibit NO synthesis and NO-mediated vasodilation and to increase free radical formation. Altogether, these processes cause endothelial dysfunction and contribute to the impairment of organ function. A better insight into the mechanisms underlying CNI nephrotoxicity could assist in developing more targeted therapies of arterial hypertension or preventing CNI nephrotoxicity in organ transplant recipients, including heart transplantation., L. Hošková, I. Málek, L. Kopkan, J. Kautzner., and Obsahuje bibliografii
Gap junction connexin channels are important determinants of myocardial conduction and synchronization that is crucial for coordinated heart function. One of the main risk factors for cardiovascular events that results in heart attack, congestive heart failure, stroke as well as sudden arrhythmic death is hypertension. Mislocalization and/or dysfunction of specific connexin-43 channels due to hypertension-induced myocardial remodeling have been implicated in the occurrence of lifethreatening arrhythmias and heart failure in both, humans as well as experimental animals. Recent studies suggest that downregulation of myocardial connexin-43, its abnormal distribution and/or phosphorylation might be implicated in this process. On the other hand, treatment of hypertensive animals with cardioprotective drugs (e.g. statins) or supplementation with non-pharmacological compounds, such as melatonin, omega-3 fatty acids and red palm oil protects from lethal arrhythmias. The antiarrhythmic effects are attributed to the attenuation of myocardial connexin-43 abnormalities associated with preservation of myocardial architecture and improvement of cardiac conduction. Findings uncover novel mechanisms of cardioprotective (antihypertensive and antiarrhythmic) effects of compounds that are used in clinical settings. Well-designed trials are needed to explore the antiarrhythmic potential of these compounds in patients suffering from hypertension., T. Egan Benova, B. Szeiffova Bacova, C. Viczenczova, E. Diez, M. Barancik, N. Tribulova., and Obsahuje bibliografii
Drugs interfering with the renin-angiotensin-aldosterone system (RAAS) improved the prognosis in patients with hypertension, heart failure, diabetes and chronic kidney disease. However, combining different drugs brought no further benefit while increasing the risk of hyperkalemia, hypotension and acute renal failure. This was so with combining angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptors type 1 antagonists (ARB). Dissimilarly, in animal disease models this dual therapy proved clearly superior to single drug treatment and became the optimal standard regime for comparison with other treatments. This review analyzes the causes of the discrepancy of effects of the dual therapy between animal experiments versus clinical studies, and is focused on the outcomes in chronic kidney disease. Discussed is the role of species differences in RAAS, of the variability of the disease features in humans versus relative stability in animals, of the genetic uniformity in the animals but not in humans, and of the biased publication habits of experimental versus clinical studies. We attempt to understand the causes and reconcile the discordant findings and suggest to what extent dual RAAS inhibition should be continued in animal experiments and why its application in the clinics should be limited to strictly selected groups of patients., V. Čertíková Chábová, L. Červenka., and Obsahuje bibliografii