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Biomedical subjects

K Horký

Publications and source records attributed to K Horký.

At least 19 recordsLinked to original sources
PubMed2006

[Nitric oxide synthase, typical flavohemoproteins and their complicated enzymology].

Nitric oxide is a diatomic gaseous molecule with unpaired electron in the molecule. Physical properties such as solubility, diffusibility and half-life decide the chemical reactivity of nitric oxide. Nitric oxide is the unstable free radical in vessels, immune system and central nervous system. The reactivity of nitric oxide under physiological and pathological conditions depends upon its concentration and site of production. Nitric oxide is thought to play a role in many pathological situations: septic shock, cardiovascular diseases, arthritis, diabetes, multiple sclerosis, asthma, and hypertension. Nitric oxide synthase is a self-sufficient flavohemoprotein capable of producing nitric oxide from L-arginine by two successive monooxygenation steps. Although the N-terminal heme domain functionally resembles cytochromes P450, no structural similarities exist between cytochrome P450 and nitric oxide synthases heme domains. The C-terminal domain of nitric oxide synthases containing flavin adenine dinucleotide and flavin mononucleotide as cofactors exhibits a high degree of sequence similarity with NADPH-cytocrome P450 reductase. The reductase domains serve as an intermediary for the transfer of electrons from NADPH for the catalytic reaction. The connecting domain between the oxygenase and the reductase domains of nitric oxide synthase isoforms binds calmodulin in the presence of calcium. The binding of calmodulin to all nitric oxide synthase isoforms is obligatory for the production of nitric oxide. At the same time, the presence of one or more phosphorylation sites in nitric oxide synthase puts them among the kinase-mediated signaling pathways. This also means that nitric oxide synthases are regulated indirectly by the events that regulate kinases. This field of research of nitric oxide synthase regulation has become one of the most actively pursued and much has been learned from basic biochemical mechanisms to physiological processes and to medical applications, but many more questions still remain to be answered.

Animals↗
PubMed2005

[Recommendations for the treatment of tobacco dependence].

This first Czech version of guidelines formulated by the working group of mentioned medical associations is based on current literature and international guidelines. They are aimed mainly on clinical medicine and on incorporation of this treatment into the health care system according to WHO recommendations. They should serve to the treatment of tobacco dependence at any level: during any contact with the smoking patient (short intervention), in specialised centres or for the health care providers or health system itself.

Humans↗
PubMed2002

Circulating intercellular cell adhesion molecule-1, endothelin-1 and von Willebrand factor-markers of endothelial dysfunction in uncomplicated essential hypertension: the effect of treatment with ACE inhibitors.

The aim of the study was to examine whether the circulating cell adhesion molecules, von Willebrand factor (vWf) and endothelin-1, are elevated in patients with essential hypertension with no other risk factors for atherosclerosis and thus may serve as a markers of endothelial dysfunction in uncomplicated hypertension. Furthermore, the effect of treatment with the ACE inhibitor, quinapril, on levels of endothelial dysfunction markers were studied. The levels of adhesion molecules (intercellular cell adhesion molecule-1 [ICAM-1], E-selectin, P-selectin), von Willebrand factor (vWf) and endothelin-1 were measured in patients with hypertension without any other risk factors of atherosclerosis before and after treatment with quinapril (n = 22) and in normotensive controls (n = 22). Compared with normotensive subjects, the hypertensive patients had significantly higher levels of ICAM-1 (238 vs 208 ng/ml, P = 0.02), vWf (119 vs 105 IU/dl, P < 0.05) and endothelin-1 (5.76 vs 5.14 fmol/ml, P < 0.05). Three-month treatment of hypertensive patients with quinapril led to a significant decrease in the levels of endothelin-1 (5.76 vs 5.28 fmol/ml, P < 0.01). We did not observe significant changes in the levels of adhesion molecules and vWf after ACE inhibitor treatment, although a trend toward a decrease was apparent with all these parameters. Patients with uncomplicated hypertension with no other risk factors of atherosclerosis had significantly elevated levels of ICAM-1, vWf, and endothelin-1. Our data suggest that these factors may serve as markers of endothelial damage even in uncomplicated hypertension. In hypertensive patients, treatment with the ACE inhibitor quinapril resulted in a significant decrease in endothelin-1 levels. These findings indicate a beneficial effect of ACE inhibitors on endothelial dysfunction in hypertensive patients.

Adult↗
PubMed2002

Association analysis of Arg16Gly polymorphism of the beta2-adrenergic receptor gene in offspring from hypertensive and normotensive families.

OBJECTIVE: Since beta2-adrenergic receptors (beta2AR) can influence blood pressure not only by vasodilation, but also participate in noradrenaline release from sympathetic nerve endings, we have studied whether Arg16Gly polymorphism of the beta2AR gene is associated with predisposition to essential hypertension and increased plasma noradrenaline concentration in offspring from normotensive (SN) and hypertensive parents (SH). DESIGN AND METHODS: The study population consisted of 105 young SN and 101 SH subjects matched for age and body mass index. Arg16Gly polymorphism of the beta2AR gene was determined by polymerase chain reaction (PCR) technique and subsequent incubation with NcoI restriction enzyme. Resulting fragments were separated using electrophoresis on a 4.2% Metaphor agarose gel. RESULTS: SH already had significantly higher systolic BP, and a tendency to higher diastolic BP than the SN group. The frequency of Arg/Arg homozygotes was significantly increased in SH when compared to SN (25% vs 15%). Results of logistic regression analysis showed the highest relative risk for the Arg/Arg genotype and suggested a recessive action of the Arg16 variant. There was an increased diastolic BP in Arg/Arg homozygotes of the SN group (p = 0.029). This genotype also had a tendency to increased heart rate in both groups (p = 0.049). There was no relationship of this polymorphism with plasma noradrenaline concentration. CONCLUSION: Our findings suggest that genetic variability of the beta2AR gene is implicated in predisposition to essential hypertension. However, the contradictory results between individual studies indicate that the action of the beta2AR gene is indirect, through multiple intermediate phenotypes and gene interactions.

Adult↗
PubMed2002

[Is mild essential hypertension without obvious organ complications and risk factors associated with increased levels of circulating markers of endothelial dysfunction? Effect of ACE inhibitor therapy].

The objective of the investigation was to assess whether circulating adhesion molecules, von Willebrand factor (vWf) and endothelin-1 are elevated in patients with mild uncomplicated essential hypertension without further risk factors of atherosclerosis and whether they could serve as indicators of endothelial dysfunction in this form of hypertension. Furthermore the authors investigated the effect of ACE inhibitor treatment (ACEI), quinapril, on the level of these markers of endothelial dysfunction. The level of adhesion molecules [intercellular cytoadhesion molecule-1 (ICAM-1), E-selectin, P-selectin], von Willebrand s factor (vWf) and endothelin-1 were assessed in patients with mild essential hypertension without further cardiovascular risk factors or clinical manifestations of atherosclerosis before and after quinapril treatment (n = 25) and compared with normotensive controls (n = 29). The results of the examinations provided evidence that contrary to controls the hypertensive subjects had significantly higher ICAM-1 levels (237.8 vs. 207.8 ng/ml, P = 0.02) vWf (118 vs. 106 IU/dl, p < 0.05) and endothelin-1 (5.81 vs. 5.15 fmol/ml, p < 0.05). Three-month treatment of hypertensive patients with ACEI led to a significant drop of endothelin-1 levels (5.81 vs. 5.26 fmol/ml, p = 0.01). The authors proved also an unequivocal declining trend of other cytoadhesion molecules and vWf after ACEI treatment, the changes however were not statistically significant. From the investigation it may be concluded that also patients with uncomplicated essential hypertension without other cardiovascular risk factors or clinical manifestations of atherosclerosis have significantly elevated plasma levels of ICAM-1, vWf and endothelin-1. Higher concentrations of these factors suggest endothelial dysfunction already in mild forms of essential hypertension without further risk factors or cardiovascular complications. A significant drop of endothelin-1 and declining trend of the other investigated indicators suggest that ACEI treatment can favourably influence endothelial dysfunction in hypertensive patients also independently on reduction of the BP.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

[The beginnings of electrocardiography at the Prague Medical School].

The authors describe the beginnings of development of electrocardiography at the Prague Medical Faculty of Charles-Ferdinand and Charles University resp. The first results of the new method came from the physiological laboratory of Ewald Karl Konstantin Hering (1834-1918), who contributed to electrocardiography by explaining the mechanism of atrial fibrillation and to Richard Hans Kahn (1876-1941) who was the first to publish electrocardiographic changes after temporary block of coronary artery blood flow in the dog. Clinical application and the promotion of electrocardiography in this country is among others in particular from Václav Libenský (1877-1938), Klement Weber (1890-1971) and Frantisek Herles (1900-1991) whose name became for half a century the synonym for electrocardiography.

Czech Republic↗
PubMed2001

Association of the Glu298Asp polymorphism in the endothelial nitric oxide synthase gene with essential hypertension resistant to conventional therapy.

Endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO) which, after diffusing into vascular smooth muscle cells, activates guanylate cyclase leading to vasodilatation. A polymorphism (894G to T) in exon 7 of the eNOS gene causes the conversion of Glu to Asp in position 298. The recently described crystal structure of the heme domain of eNOS protein shows that Glu298 is fully solvent accessible and distant from regions integral to enzyme function. Searching for phenotypic expression of eNOS gene variants, we genotyped a group of patients with essential hypertension (H, n = 119) for the Glu298Asp polymorphism and compared them with age- and sex-matched healthy normals (N, n = 85). To specify phenotypic expression further, the hypertensive patients were subdivided into one group that responded well to regular antihypertensive therapy (CH, n = 45) and one group that was resistant to the therapy (RH, n = 74). Patients with BP higher than 140/90 mmHg when on adequate lifestyle modification and triple-combination therapy (including diuretics) were considered resistant. In RH and H groups, a significantly higher frequency of T alleles (P = 0.022 and P = 0.046, respectively) was found compared to normotonics (N). In well-controlled hypertonics, the same tendency was found, but did not reach statistical significance. The Glu298Asp polymorphism may contribute to the complex pathogenesis of essential hypertension and may be a factor in the resistance of these patients to conventional antihypertensive therapy. The presence of this allele may thus be predictive of the patients' therapeutic response.

Adrenergic beta-Antagonists↗
PubMed2001

Blood pressure, endothelial function and circulating endothelin concentrations in liver transplant recipients.

OBJECTIVES: To study candidates for liver transplant before and 6 weeks after transplant, and to elucidate the role of endothelial dysfunction and plasma endothelin concentrations in the development of hypertension. DESIGN PROSPECTIVE: follow-up study. SETTING: Institutional, outpatient. PATIENTS: and controls Fifteen patients (11 men, four women, mean age 46.7+/-13.2 years) with end-stage liver disease (ESLD) and healthy volunteers of comparable age and sex. METHODS: We performed office blood pressure readings and 24 h ambulatory blood pressure monitoring (ABPM), measurements of endothelial-dependent vasodilatation using high-resolution ultrasound in the brachial artery at rest and during reactive hyperemia, and plasma endothelin-1 assays 3 months before and 6 weeks after the transplant. RESULTS: Office systolic and diastolic blood pressures increased significantly 6 weeks after liver transplantation (from 116.6+/-14.1 to 139.9+/-19.5 mmHg and from 68.6+/-9.5 to 84.1+/-9.8 mmHg, respectively; both P < 0.001). Hypertension based on office blood pressure readings increased from 6.7 to 40% (P < 0.05). Mean 24 h systolic blood pressure increased from 118.7+/-10.3 to 140.0+/-19.0 mmHg (P < 0.001), mean 24 h diastolic blood pressure increased from 86.0+/-7.7 to 104.8+/-13.9 mmHg (P < 0.001) and heart rate increased from 74.8+/-10.2 to 80.2+/-8.2 beats/min (P < 0.05). Brachial artery flow-mediated dilatation did not change throughout the study (before transplant: 4.2+/-4.0%; after transplant: 6.3+/-5.4%; NS) and did not differ from that in controls (5.2+/-3.8%). Plasma endothelin-1 was increased in patients with ESLD (15.3+/-2.6 pg/ml) compared with controls (5.6+/-0.4 pg/ ml; P < 0.001) and remained unchanged 6 weeks after liver transplantation (14.1+/-3.7 pg/ml). CONCLUSION: Our results show increased blood pressure with suppressed circadian blood pressure variability in liver graft recipients 6 weeks after transplant and no change in endothelial function and plasma endothelin concentrations. Therefore, the blood pressure increase documented in our study cannot be explained by endothelial dysfunction. Twenty-four hour ABPM should be performed routinely in patients who have undergone liver transplant.

Adult↗
PubMed2001

[Portal hypertension and the endothelium].

Portal hypertension is defined as a rise in the pressure gradient between the portal vein and the inferior vena cava by more than 10 mmHg. The basic factors in the development of portal hypertension include increased resistance in intrahepatic circulation, increased portal blood flow, and development of the hyperdynamic syndrome. Apart from structural changes in the hepatic tissue, the major role in the pathogenesis of portal hypertension is played by endothelial dysfunction. In patients with portal hypertension, endothelial dysfunction reduced the activity of vasodilator, anti-aggregation, and anti-adhesion substances (NO/EDRF, prostacyclin, CO) and to increased production of vasoconstrictor and proliferative substances (endothelins in particular) in intrahepatic the circulation. On the other hand, vasodilator agents become predominant in splanchnic and systemic circulation. As a result, the intrahepatic vascular resistance and portal blood flow rise. It was followed by a subsequent increase in portal pressure and the development of hyperdynamic circulation. Identification of the pathophysiological mechanisms of portal hypertension has paved the way to new trends in pharmacological therapy. The aim of effective treatment of portal hypertension is the permanent reduction of the portal pressure, which markedly decreases the risk for complications, and the risk for esophageal variceal bleeding in particular. The currently most preferred agents are those with vasodilator and vasoconstrictor effects.

Endothelium, Vascular↗
PubMed2000

[Humoral profile of patients with severe aortic stenosis].

BACKGROUND: While the effect of neurohormones is often studied in congestive heart failure, their role in aortic stenosis needs to be elucidated. METHODS: 54 consecutive patients with symptomatic aortic stenosis without overt heart failure were studied at the age of 64.4 +/- 9.3 yrs with echocardiography, x-ray and catheterization. Levels of circulating atrial natriuretic factor endothelin-1, catecholamines, plasma renin activity, immunoreactive insulin and C-peptide were assessed, related to hemodynamic data and compared to those in 23 healthy controls, aged 59.2 +/- 12.8 yrs. RESULTS: Patients had significantly higher plasma levels of endothelin-1 (z-value 0.64 +/- 1.19, p = 0.019), atrial natriuretic factor (z-value 2.46 +/- 2.46, p < 0.001) and dopamine (z-value 0.91 +/- 2.33, p = 0.02). Levels of endothelin-1 and ANF positively correlated with mean (r = 0.631, p < 0.001) and wedged pulmonary artery pressures and with left atrial diameter index (r = 0.602, p < 0.001). Endothelin-1 levels correlated negatively with aortic valve area (r = -0.306, p = 0.041). No correlation was found between neurohumoral plasma concentrations and left ventricular mass index. CONCLUSIONS: In patients with symptomatic aortic stenosis without overt heart failure, elevated plasmatic levels of endothelin-1, atrial natriuretic factor and dopamine were documented. The increase of ET-1 levels is related to pulmonary hypertension and severity of the disease. Left ventricular hypertrophy is not related to neurohormonal levels. Neither circulating system renin-angiotensin nor noradrenaline are activated in these patients.

Adult↗
PubMed2000

Association analysis of two tyrosine hydroxylase gene polymorphisms in normotensive offspring from hypertensive families.

OBJECTIVE: We have studied possible association between predisposition to essential hypertension, plasma noradrenaline level and two polymorphisms of the gene for tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis. DESIGN AND METHODS: One hundred and one normotensive sons from normotensive parents (SN) and 107 normotensive sons of hypertensive families (SH) were studied. Tetranucleotide TCAT repeat and Va181Met polymorphisms of the TH gene were determined by polymerase chain reaction (PCR) technique. RESULTS: SH had higher systolic BP and plasma noradrenaline concentration than the SN group. No significant difference was found between the allele and genotype frequencies in the SH and SN groups for both polymorphisms. The two polymorphisms were in tight linkage disequilibrium. The CD genotype of the microsatellite marker was associated with increased plasma noradrenaline concentration in both groups. Genotypes AB, AE and BB of the TCAT repeat polymorphism and genotypes VM and MM of the Va181Met polymorphism exhibited the greatest difference in plasma noradrenaline concentration between the SH and SN groups. CONCLUSION: The studied TH polymorphisms do not appear to be associated with family history of essential hypertension. Nevertheless, some genotypes of TH might be related to disturbance of plasma noradrenaline concentration.

Adult↗
PubMed2000

Lack of association of angiotensin-converting enzyme and angiotensinogen genes polymorphisms with left ventricular structure in young normotensive men.

Left ventricular (LV) hypertrophy is a strong predictive factor for cardiovascular morbidity and mortality. LV structure and function are influenced by many variables, including genetic background. The potential role of gene polymorphisms of different components of the renin angiotensin system remains controversial. The aim of this study was to determine the influence of deletion/insertion (D/I) polymorphism of the angiotensin-converting enzyme (ACE) gene and M235-->T polymorphism of the angiotensinogen (AG) gene on left ventricular morphology and function in young normotensive men. The study included 110 normotensive healthy males (mean age 24 +/- 4 years, age range 18 to 34 years) who were assessed by echocardiography for LV structure and function. In all subjects ACE D/I polymorphism was evaluated using a polymerase chain reaction (PCR) method. M235-->T polymorphism assessment was available in 98 individuals. Significant differences between groups according to ACE I/D or AG M235-->T polymorphisms were not found for parameters of LV morphology or for parameters of systolic and diastolic function. When subjects with DD or ID genotypes were grouped, their LV mass index was higher than that in subjects with II genotypes (86 +/- 14 vs 79 +/- 15, r = 0.033, p = 0.05). There were no significant differences among other variables. In a population of young normotensive men where the influence of confounding variables such as age, gender and associated pathological conditions is minimized, the gene polymorphisms of ACE I/D and AG M235-->T are not important determinants of LV structure and function.

Adult↗
PubMed2000

[Dual endopeptidase inhibitors--a new direction in the development of hypertensive agents].

Endogenous peptidases participate in a major way in the formation of peptide pressor substances such as angiotensin II (A II) and endothelin (ET) as well as in the degradation of depressor substances, e.g. atrial natriuretic peptide (ANP) or bradykinin. They include on the one hand the angiotensin converting enzyme (ACE) and endothelin converting enzyme (ECE), on the other hand kinase II for bradykinin and neutral endopeptidase 24.11 (NEP) for ANP. Inhibition of these enzymatic reactions leads to a decline of vasopressors A II and ET and conversely delays the break-down of vasodilatating bradykinin and ANP. The main haemodynamic consequence of this double inhibition is a reduced peripheral vascular resistance and decline of the blood pressure. The concurrent block of both systems (dual inhibition) is more effective than the isolated block of one substance. The first dual endopeptidase inhibitors were ACE inhibitors blocking the conversion of angiotensin I to A II and inhibiting at the same time the degradation of bradykinin by kininase II which is identical with ACE. At present further substances were synthetized with a dual inhibitory effect e.g. on ECE and on NEP (phosphoramidone, thiorphan, ecadatril etc.). Under experimental conditions they have a long-term antihypertensive effect on the vascular wall and heart muscle. The development of another dual ACE and NEP inhibitor has reached already the stage of clinical tests and the first clinical studies. The preparation omapatrilate in amounts of 2.5-80 mg significantly reduced the BP in a dose-dependent way in mild and medium advanced essential hypertension. Normalization of the blood pressure, i.e. a drop below 140/90 mm Hg, was achieved with omapatrilate monotherapy in as many as 83% of patients with hypertension stage I and in 53% patients with essential hypertension stage II. The drop of blood pressure after 20-80 mg/day depended on the degree of hypertension and was comparable or better than monotherapy with lisonopril 20 mg/day or amlodipine 10 mg/day. Treatment with omapatrilate was well tolerated. Dual peptidase inhibitors interfering with the formation of pressor substances and with the degradation of depressor substances seem to be a perspective class of antihypertensives also useful in the treatment of other cardiovascular diseases (heart failure, primary pulmonary hypertension). Before its final inclusion in the therapeutic pattern, further comparative and clinical mortality studies must be implemented.

Antihypertensive Agents↗