We hypothesized that hypertension-related myocardial remodeling characterized by hypertrophy and fibrosis might be accompanied by cell-to-cell gap junction alterations that may account for increased arrhythmogenesis. Intercellular junctions and expression of gap junction protein connexin-43 were analyzed in rat heart tissues from both spontaneous (SHR) and L-NAME model of hypertension. Isolated heart preparation was used to examine susceptibility of the heart to lethal ventricular fibrillation induced by low potassium perfusion. Ultrastructure observation revealed enhanced neoformation of side-to-side type while internalization of end-to-end type (intercalated disc-related) of gap junctions prevailed in the myocardium of rats suffering from either spontaneous or L-NAME-induced hypertension. In parallel, immunolabeling showed increased number of connexin-43 positive gap junctions in lateral cell membrane surfaces, particularly in SHR. Besides, focal loss of immunopositive signal was observed more frequently in hearts of rats treated with L-NAME. There was a significantly higher incidence of hypokalemia-induced ventricular fibrillation in hypertensive compared to normotensive rat hearts. We conclude that adaptation of the heart to hypertension-induced mechanical overload results in maladaptive gap junction remodeling that consequently promotes development of fatal arrhythmias., M. Fialová, K. Dlugošová, L. Okrouhlicová, F. Kristek, M. Manoach, N. Tribulová., and Obsahuje bibliografii a biblioigrafické údaje
The aldosterone synthase gene (CYP11B2) is an important candidate gene region in essential hypertension. We therefore studied the association of -344T/C polymorphism of the CYP11B2 gene with the presence and severity of hypertension in a case-control study. We studied 369 individuals, of whom 213 were hypertensive patients (139 controlled hypertensive, 74 resistant hypertensive) and 156 were healthy normotensive subjects. The -344T/C polymorphism of the CYP11B2 gene was determined using polymerase chain reaction - restriction fragment length polymorphism analysis. The distribution of genotypes in normotensive controls and hypertensive subjects were: TT 25.6 vs. 31.9 %, TC 51.9 vs. 57.3 % and CC 22.4 vs. 10.8 %. The -344T/C variant was associated with hypertension. Subjects carrying the -344T allele had a greater risk of hypertension compared to those having C allele (χ2=5.89, p<0.05). The frequency of CC genotype was significantly lower in hypertensive patients than in normotensive controls ( χ2=9.44, p<0.01). A stepwise logistic regression analysis confirmed these findings. We did not find an association of -344T/C variant with the resistance of hypertensive patients to combination therapy, but we observed an association of -344T/C polymorphism of aldosterone synthase gene with increased risk of hypertension. These results support a potential role of -344T/C CYP11B2 gene polymorphism in genetic predisposition to develop hypertension., Z. Hlubocká ... [et al.]., and Obsahuje seznam literatury
The production of the pineal hormone melatonin is synchronized with day-night cycle via multisynaptic pathway including suprachiasmatic nucleus linking several physiological functions to diurnal cycle. The recent data indicate that impaired melatonin production is involved in several cardiovascular pathologies including hypertension and ischemic heart disease. However, the mechanisms of melatonin effect on cardiovascular system are still not completely understood. The activation of melatonin receptors on endothelial and vascular smooth muscle cells and antioxidant properties of melatonin could be responsible for the melatonin effects on vascular tone. However, the data from in vitro studies are controversial making the explanation of the melatonin effect on blood pressure in vivo difficult. In vivo, melatonin also attenuates sympathetic tone by direct activation of melatonin receptors, scavenging free radicals or increasing NO availability in the central nervous system. The central and peripheral antiadrenergic action of chronic melatonin treatment might eliminate the mechanisms counter-regulating decreased blood pressure, providing thus additional cardioprotective mechanism. The extraordinary antioxidant activity and antilipidemic effects of melatonin may enhance the modulation of blood pressure by melatonin and probably play the most important role in the amelioration of target organ damage by chronic melatonin treatment. Further investigation of these mechanisms should provide novel knowledge about pathophysiological mechanisms of cardiovascular diseases, additional explanation for their circadian and seasonal variability and potentially generate new impulses for the development of therapeutic arsenal., Ľ. Paulis, F. Šimko., and Obsahuje bibliografii a bibliografické odkazy
The rat strain transgenic for the murine Ren-2 renin gene (TGR) is defined as a monogenic model of angiotensin II-dependent hypertension with endogenous activation of the renin-angiotensin system. Homozygous males TGR develop malignant hypertension with a strong salt-sensitive component. These animals show severe hypertension, proteinuria and high mortality. Morphological changes of renal parenchyma correspond to chronic ischemic glomerular changes. Heterozygous TGR develop only mild hypertension and thus provide a more suitable model of hypertension regarding to clinic al studies. Within the renal parenchyma, secondary focal segmental glomerulosclerosis (FSGS) predominates. High-salt diet in heterozygous animals induces transition from benign to malignant phase of hypertension. In this case, ischemic glomerular changes are superimposed on preexisting secondary FSGS. In the regression model of hypertension (late-onset treatment) the effect of salt intake is attenuated. In homozygous TGR, early selective ET A receptor blockade decreased blood pressure and ameliorated end-organ damage. Late selective ET A receptor blockade reduced podocyte injury despite final severe hypertension. Survival rate was markedly improved in both regimens with ETA selective blockade, while there was only partial improvement with early non-selective blockade. Both bosentan and atrasentan decreased ET-1 levels in both regimens. In heterozygous TGR, early and late ETA treatment substantially while ETA/ETB treatment partially improved survival rate. Significant effect on BP was found with early and late ETA blockade, while ETA/ETB blockade had no effect. Bosentan and at rasentan similarly decreased ET-1 levels on both regimens. In conclusion, selective ETA receptor blockade is superior to nonselective ETA/ETB receptor blockade in attenuating hypertension and end-organ damage. Its effect is more pronounced when applied early in the life., Z. Vernerová ... [et al.]., and Obsahuje seznam literatury
Treatment with pertussis toxin (PTX) which eliminates the activity of Gi proteins effectively reduces blood pressure (BP) and vascular resistance in spontaneously hypertensive rats (SHR). In this study we have compared the functional characteristics of isolated arteries from SHR with and without PTX-treatment (10 μg/kg i.v., 48 h before the experiment). Rings of thoracic aorta, superior mesenteric artery and main pulmonary artery were studied under isometric conditions to measure the reactivity of these vessels to receptor agonists and to transmural electrical stimuli. We have found that the treatment of SHR with PTX had no effect on endothelium-dependent relaxation of thoracic aorta induced by acetylcholine. In PTX-treated SHR, the maximum contraction of mesenteric artery to exogenous noradrenaline was reduced and the dose-response curve to cumulative concentration of noradrenaline was shifted to the right. Similarly, a reduction in the magnitude of neurogenic contractions elicited by electrical stimulation of perivascular nerves was observed in the mesenteric artery from PTX-treated SHR. PTX treatment of SHR also abolished the potentiating effect of angiotensin II on neurogenic contractions of the main pulmonary artery. These results indicate that PTX treatment markedly diminishes the effectiveness of adrenergic stimuli in vasculature of SHR. This could importantly affect BP regulation in genetic hypertension., A. Zemančíková, J. Török, J. Zicha, J. Kuneš., and Obsahuje bibliografii a bibliografické odkazy
We studied the effect of thiazide-like diuretic – indapamide on fibrosis development in the left ventricle of young spontaneously hypertensive rats (SHR) and assessed the involvement of nitric oxide in this process. Six-week-old male SHR were treated with indapamide (1 mg/kg/day) for six weeks. Age-matched SHR were used as hypertensive and Wistar-Kyoto rats (WKY) as normotensive control. Systolic blood pressure was measured by tail-cuff plethysmography. Nitric oxide synthase (NOS) activity, protein expressions of endothelial (eNOS) and inducible NOS (iNOS), myocardial fibrosis and collagen type I and III were determined in the left ventricle. Indapamide treatment partially prevented SBP increase in SHR (SHR+Indapamide: 157±4, SHR: 171±3, WKY: 119±3 mmHg). Indapamide prevented myocardial fibrosis development in SHR, but without affecting collagen type I to type III ratio. Indapamide did not affect NOS activity as well as eNOS and iNOS protein expressions in the left ventricles evaluated by both Western blot and immunohistochemically. In conclusion, our results indicate that indapamide-induced prevention of myocardial fibrosis is not mediated by nitric oxide-related mechanism., P. Janega, S. Kojšová, L. Jendeková, P. Babál, O. Pecháňová., and Obsahuje bibliografii a bibliografické odkazy
Spontaneously hypertensive rats (SHR) are characterized by enhanced nifedipine-sensitive component of sympathetic vasoconstriction. Our study tried to elucidate the mechanisms responsible for long-term reduction of blood pressure (BP) in SHR subjected to early transient captopril treatment. Adult untreated SHR aged 30-34 weeks were compared with animals subjected to chronic captopril treatment for 6 weeks either in youth (between 4 and 10 weeks of age) or in adulthood (between 24 and 30 weeks of age). Antihypertensive effects of captopril were more pronounced in young than adult SHR. This was due to greater attenuation of sympathetic and nifedipine-sensitive BP components and prevention of residual BP rise in young captopril-treated SHR in which the reductions of nifedipine-sensitive BP component and residual BP persisted for 20 weeks after captopril withdrawal. The magnitude of nifedipine-sensitive component of sympathetic vasoconstriction is decisive for BP maintenance not only in untreated SHR but also in SHR during active captopril treatment by or after its withdrawal., J. Zicha, Z. Dobešová,J. Kuneš., and Obsahuje bibliografii a bibliografické odkazy
We studied the relationship between blood pressure (BP), body mass index (BMI, kg/m2) and baroreflex sensitivity (BRS, ms/mmHg) in adolescents. We examined 34 subjects aged 16.2±2.4 years who had repeatedly high causal BP (H) and 52 controls (C) aged 16.4±2.2 years. Forty-four C and 22 H were of normal weight (BMI between 19-23.9), and 8 C and 12 H were overweight (BMI between 24-30). Systolic BP was recorded beat-to-beat for 5 min (Finapres, controlled breathing 0.33 Hz). BRS was determined by the cross-spectral method. The predicting power of BMI and BRS for hypertension was evaluated by sensitivity, specificity, and receiver operating curve (ROC - plot of sensitivity versus specificity). H compared with C had lower BRS (p<0.01) and higher BMI (p<0.05). Multiple logistic regression analysis (p<0.001) revealed that a decreased BRS (p<0.05) and an increased BMI (p<0.01) were independently associated with an increased risk of hypertension. No correlation between BMI and BRS was found either in H or in C. Following optimal critical values by ROC, the sensitivity, specificity and area under ROC were determined for: BMI - 22.2 kg/m2, 61.8 %, 69.2 %, 66.0 %; BRS - 7.1 ms/mmHg, 67.7 %, 69.2 %, 70.0 %; BMI and BRS - 0.439 a.u., 73.5 %, 82.7 %, and 77.3 %. Decreased BRS and overweight were found to be independent risk factors for hypertension., K. Krontorádová, N. Honzíková, B. Fišer, Z. Nováková, E. Závodná, H. Hrstková, P. Honzík., and Obsahuje bibliografii a bibliografické odkazy
This review concerns the role of nitric oxide (NO) in the pathogenesis of different models of experimental hypertension (NO-deficient, genetic, salt-dependent), which are characterized by a wide range of etiology. Although the contribution of NO may vary between different models of hypertension, a unifying characteristic of these models is the presence of oxidative stress that participates in the maintenance of elevated arterial pressure and seems to be a common denominator underlying endothelial dysfunction in various forms of experimental hypertension. Besides the imbalance between the endothelial production of vasorelaxing and vasoconstricting compounds as well as the relative insufficiency of vasodilator systems to compensate augmented vasoconstrictor systems, there were found numerous structural and functional abnormalities in blood vessels and heart of hypertensive animals. The administration of antihypertensive drugs, antioxidants and NO donors is capable to attenuate blood pressure elevation and to improve morphological and functional changes of cardiovascular system in some but not all hypertensive models. The failure to correct spontaneous hypertension by NO donor administration reflects the fact that sympathetic overactivity plays a key role in this form of hypertension, while NO production in spontaneously hypertensive rats might be enhanced to compensate increased blood pressure. A special attention should be paid to the modulation of sympathetic nervous activity in central and peripheral nervous system. These results extend our knowledge on the control of the balance between NO and reactive oxygen species production and are likely to be a basis for the development of new approaches to the therapy of diseases associated with NO deficiency., J. Török., and Obsahuje bibliografii a bibliografické odkazy
Renin-angiotensin system (RAS) plays a key role in the regulation of renal function, volume of extracellular fluid and blood pressure. The activation of RAS also induces oxidative stress, particularly superoxide anion (O2-) formation. Although the involvement of O2- production in the pathology of many diseases is known for long, recent studies also strongly suggest its physiological regulatory function of many organs including the kidney. However, a marked accumulation of O2- in the kidney alters normal regulation of renal function and thus may contribute to the development of salt-sensitivity and hypertension. In the kidney, O2- acts as vasoconstrictor and enhances tubular sodium reabsoption. Nitric oxide (NO), another important radical that exhibits opposite effects than O2-, is also involved in the regulation of kidney function. O2- rapidly interacts with NO and thus, when O2- production increases, it diminishes the bioavailability of NO leading to the impairment of organ function. As the activation of RAS, particularly the enhanced production of angiotensin II, can induce both O2- and NO generation, it has been suggested that physiological interactions of RAS, NO and O2- provide a coordinated regulation of kidney function. The imbalance of these interactions is critically linked to the pathophysiology of salt-sensitivity and hypertension., L. Kopkan, L. Červenka., and Obsahuje seznam literatury