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Scientists
Jaroslav Kunes, PhD, DSc.
Milada Dobiasova, M.D., Ph.D., DSc.
Zdenka Dobesova, Ph.D.
Hana Rauchova, M.D., Ph.D.
Michaela Kadlecova, Ing.
Martina Vokurkova, M.D.

Technical Assistants
Natalie Hanova
Iva Nahodilova
Marketa Krupkova
Marie Schutzova

PhD students
Mgr. Silvie Hojna, MSc
Maria Pinterova, M.D.

 
Department: Experimental Hypertension
Head: Josef Zicha, M.D., Ph.D., DSc.
   
Contact phone/fax number: +420 24106 2420, +420 24106 2488
e-mail: zichabiomed.cas.cz
kunesbiomed.cas.cz
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Background

Hypertension and atherosclerosis are frequently coexisting chronic diseases, which are significant risk factors for cardiovascular morbidity and mortality. Both are polygenic clinical entities that include subgroups of subjects differing in the response to various dietary and pharmacological interventions. This indicates the presence of multiple mechanisms participating in the pathogenesis and/or maintenance of high blood pressure or atherosclerosis. One of them might be the abnormal metabolism of glucose, insulin and lipoprotein that occurs more frequently in hypertensive than in normotensive subjects.

The abnormal composition of cellular membranes, which cause the changes of membrane fluidity, have been shown to interfere with various cell functions including membrane transport. The abnormal function of membrane proteins in hypertension could thus result in part from changes of their lipid environment. This hypothesis is partially supported by the hypotensive effects of dietary unsaturated fatty acids as well as by the effects of changes in membrane lipids on cell calcium handling or various sodium transport systems.

The appropriate balance between vasoconstrictor and vasodilator systems is the necessary prerequisite for the maintenance of a normal level of blood pressure. The endotheliumderived relaxing factor, which is identical with nitric oxide (NO), represents a major vasodilator system opposing the hypertensive effects of pressor agents (e.g. norepinephrine, angiotensin II, etc.). NO is eliminated by interaction with superoxide radicals. The excess formation of these radicals in the endothelium could decrease the vasodilating potential of NO. Diminished NO availability demonstrated in spontaneously hypertensive rats is caused by the excess formation of superoxide radicals that could probably explain the apparent "NO deficiency" in this form of genetic hypertension leading to higher vasoconstrictor activity.

Hypertension is a good example of a quantitative trait that is controlled by multigenic systems. Several selective breeding procedures are used (F2 hybrids, backcross, etc.) to search for candidate genes of hypertension. In spite of the fact that these approaches have some limitations, there is a tendency to rigorously characterize, in both phenotypic and genetic terms, animal models for hypertension and to use genetic linkage analysis to identify genetic markers for the pathogenesis of this disease.


Main research topics of the department

- Age-dependent interactions of genetic and environmental factors in the pathogenesis of experimental hypertension.
 - Search for genes responsible for high blood pressure and metabolic disturbances in spontaneous and saltinduced forms of hypertension.
 - Alterations of particular cellular ion transport mechanisms in genetic and experimental hypertension.
-  The role of disturbances in intracellular calcium and pH regulations as well as in membrane fluidity and lipid metabolism in pathogenesis of genetic and experimental hypertension.
 -Sex-dependent differences in growth and calcium handling of smooth muscle cells isolated from hypertensive or normotensive animals.
 - The role of vasoactive systems in the maintenance of genetic and experimental hypertension.
-  Interaction of oxygen free radicals and nitric oxide in the pathogenesis of agedependent experimental hypertension.
 - Metabolism of high density lipoproteins (HDL) in relation to composition of HDL subclasses and cholesterol esterification by lecithin cholesterol acyltransferase.
 - Relationship between renal failure and plasma lipid profile in human.
- Evaluation of antioxidant status with special attention to the age of experimental animals, study of antioxidant protective effect of carnitine and other agents which could improve the antioxidant status of the organism.

The longterm goal of our work is better understanding of pathophysiological mechanisms governing hypertension and atherosclerosis development (including their complications).

The genetic (spontaneously hypertensive [SHR], hypertriglyceridemic [HTG], Dahl salt-sensitive [SS/Jr] and salt-resistant [SR/Jr], Sabra salt-sensitive [SBH] and salt-resistant [SBN], etc.) and experimental (e.g. DOCA-salt, renal, NO-deficient) rat models are used in our experiments. F2 hybrids are constructed as a standard genetic tool to search for genetic loci. This experimental work is combined with clinical research concerning lipid metabolism and ion transport in patients with hypertension, diabetes, atherosclerosis and renal failure.

HTG rats are characterized by a reduction in the initial rate and maximal aggregation of platelets after stimulation with thrombin. This is in accordance with the attenuation of other thrombininduced responses, e.g. [Ca2+]i mobilization, pHi rise or Mn2+ entry through receptoroperated Ca2+ channels. Thus lower responsiveness to thrombin stimulation is a major alteration found in platelets of HTG rats. Although there were no strain differences in basal cytosolic [Ca2+ ]i levels or Ca2+ influx, cell Ca2+ handling was strongly dependent on circulating levels of triacylglycerols (triglycerides, TG). It should be noted that the slope of the relationship between plasma TG and membranerelated parameters (microviscosity, Ca2+ influx, thrombininduced Mn2+ entry, platelet aggregation) was always substantially steeper in normotensive normotriglyceridemic controls than in hypertensive HTG rats. Thus circulating TG modulates cell membrane properties through the changes in membrane lipid composition and membrane microviscosity. Na+ and K+ transport is enhanced in erythrocytes of HTG rats. Using F2 hybrids of HTG and Lewis rats we demonstrated cosegregation of plasma TG with blood pressure, red cell Na+ content and Na+ leak. Similar abnormalities of cell Ca2+ handling and red cell ion transport were also demonstrated in Lyon hypertensive rats that were selected for high BP but they also have elevated plasma triacylglycerols.

Long-term treatment of HTG or SHR rats with L-carnitine led to a significant decrease of systolic blood pressure in comparison with non-treated animals. This pharmacological intervention completely blocked the age-dependent increase of plasma levels of triacylglycerols and cholesterol seen in nontreated HTG rats. Our results suggest that L-carnitine might prevent some cardiovascular alterations by its influence on lipid metabolism.

It was demonstrated in SHR that specific growth rate was faster, whereas the doubling time and the cell cycle were shorter in vascular smooth muscle cells (VSMS) isolated from males than from females. Angiotensin II 

(10-7M) stimulated specific growth rate only in male cells during the exponential phase of growth. Moreover, the [Ca2+ ]i rise elicited by angiotensin II was more pronounced in cells isolated from males than in those from females. Such difference may be attributed to greater mobilization of intracellular calcium stores in male VSMC. These results could explain the higher sensitivity of males to hypertensive stimuli.

To test the balance between major vasoconstrictor and vasodilator systems, blood pressure (BP) changes after to the consecutive blockade of reninangiotensin (RAS), sympathetic nervous (SNS) and NO system were studied in the chronically instrumented HTG and control Lewis rats. The increased residual BP (after RAS and SNS blockade) was already found in prehypertensive 4-week-old HTG rats. Surprisingly, the NOdependent BP component was augmented in immature and adolescent HTG rats but this was not true in old animals (aged 24 - 28 weeks). The baseline BP level was positively associated with pentolinium-induced BP fall, with relative SNS contribution to BP maintenance and with the ratio of BP changes induced by ganglionic and NO synthase blockade in HTG ( Lewis F2 hybrids. The dysbalance between SNSdependent vasoconstriction and NO-dependent vasodilation could be responsible for the maintenance of elevated BP in HTG rats. Genetic analysis based upon more than 500 markers has localized the quantitative trait locus for BP changes after NO synthase blockade on the chromosome 1.

Analysis of our clinical data has shown that the rate of cholesterol esterification significantly correlated (r = 0.9) with atherogenic index of plasma triacylglycerols/cholesterol ratio. Average AIP values in nonrisk groups (children, healthy women etc.) were close or lower than zero, while they reached positive values in groups with higher risk. The highest AIP values were found in groups with a very high risk score, e.g. in patients with hypertension, diabetes, heart failure, etc. It is evident that AIP calculation could replace more expensive and technically more difficult determination of cholesterol esterification rate or the size of lipoprotein particles. 

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