Hypertension and atherosclerosis are frequently coexisting chronic
diseases, which are significant risk factors for cardiovascular
morbidity and mortality. Both are polygenic clinical entities that
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
- 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
- Relationship between renal failure and plasma lipid profile in
- 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 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
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
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.
(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
esterification rate or the size of lipoprotein particles.