RESUMEN

The review compiled mainly from the works of the author's laboratory continues to develop a new area in arterial hypertension studies. The author considers the major manifestation of the pathology, i. e. the stable increase in systemic blood pressure (BP), is in a direct causal relationship to cell and tissue energy deficiency. The energy deficiency is caused by impaired energy conversion in the cell mitochondria, uncoupling of oxidation and phosphorylation, and decreased ATP production. The cause of the latter in primary hypertension may be a mitochondrial calcium overload resulting from generalized abnormalities in membranous cytosol Ca2+ concentration regulation. In secondary forms of hypertension, uncoupling agents, such as thyroid hormones, angiotensin II, cyclosporine II, low temperatures, etc., may act as triggers of mitochondrial dysfunction. Hypertension begins with the activation of an efferent component of the sympathetic nervous system that supplies the vascular periphery. The sympathetic centers in the medulla oblongata seem to be involved in the activation process. Elevated systemic BP develops in order to compensate for ATF deficiency as a measure for correcting metabolic disturbances. Further systemic BP stabilization occurs with the involvement of the kidney that, exposed to elevated BP, begins functioning in a special switching (shifting) mode. Such a mode allows the kidney to avoid salt and water losses and at the same time to maintain the required (elevated) systemic BP, by affecting the mechanism of intrarenal regulation on the feedback principle. Resetting fixation takes place with the development of sclerotic changes in the kidney and hyalinosis in the renal medulla. Vascular system remodeling, including myocardial hypertrophic changes and capillary network rarefaction, is an essential element of BP stabilization. Hypertension becomes irreversible, by losing the features of compensatory and adaptive nature, and refractory to antihypertensive therapy.

Asunto(s)

RESUMEN

This review deals with the cellular mechanisms underlying decreased energy status documented in different tissues from experimental rat models of primary and secondary hypertension as well as the involvement of these abnormalities in the pathogenesis of the disease. Such analyses allow us to hypothesize that dysfunction of mitochondrial energy conversion, caused by distinct stimuli, including generalized disturbances of intracellular Ca2+ handling and mitochondria calcium overload found in primary hypertension, leads to uncoupling of oxidation and phosphorylation and attenuated ATP synthesis. Examples of arterial hypertension accompanied by mitochondrial uncoupling and cell ATP depletion (hyperthyroidism, cold hypertension, cyclosporine A intake, etc.) may be considered as an additional argument supporting this opinion. It means also that despite of differences in triggering mechanisms of mitochondrial dysfunction in all these models, the final outcome, i.e. decreased mitochondrial ATP production, is similar. Attenuated intracellular ATP content, in turn, results in the long-term maintenance of elevated BP by increased sympathetic outflow, whereas augmented ROS production following mitochondrial dysfunction lowers the capacity of the NO-dependent vascular relaxation. In the light of these data the cause of stationary elevated BP in chronic arterial hypertension should be regarded as a compensatory response to decreased mitochondrial ATP synthesis.

Asunto(s)

RESUMEN

The author develops previously expressed hypothesis of causative relationship between primary hypertension and altered mitochondrial energy production, reduced ATP synthesis and tissue energy deficit. These deviations in energy metabolism originate on the basis of generalized alteration of membrane regulation of intracellular Ca(2+) distribution leading to mitochondrial calcium overload and lowering of ATP synthesis. Critical factor determining mitochondrial calcium overload is the development of functional insufficiency of mPT pores of inner mitochondrial membrane facilitate Ca(2+) outflow from matrix of organelles. Elevation of systemic blood pressure is associated with emergence of energy deficit in brain tissue which stimulate vasomotor centers of brain stem and efferent activity of sympathetic nervous system supplying cardiovascular system. Stationary elevated blood pressure level in long term is supported by structural-functional rearrangement of circulation. Important component of the latter is reduction of capillary net and related centralization of circulation. Blood pressure in the central part of the arterial system is determined by demands of new level of energy metabolism in cells.

Asunto(s)

RESUMEN

BACKGROUND: Disturbances of ionic homeostasis of cells and recently discovered cellular energy deficiency due to reduced ATP-synthesizing ability of mitochondria are the most important components of pathogenesis of primary hypertension. Therefore it is essential to elucidate relationship between functioning of ionic transport systems especially that of calcium transport and ATP-synthesizing ability of mitochondria. AIM: To study calcium induced calcium release from liver mitochondria of spontaneously hypertensive rats at various initial calcium concentrations in medium. RESULTS: We observed 30% lowering of maximal level of calcium uptake from the medium with unchanged rate of calcium uptake. Under conditions of calcium overload the rate of calcium release into the medium was 30% higher than in control. INTERPRETATION: These results evidenced for changes of functioning of mitochondrial permeability transition pores (MPT-pores) during calcium overload appearing as acceleration of their switch to high conductance mode and equilibration of all ionic gradients on internal mitochondrial membrane. This can negatively affect ATP-synthesizing ability of mitochondria. Thus the presence of linkage between disturbance of ionic homeostasis and intracellular energy deficit was confirmed.

Asunto(s)

RESUMEN

UNLABELLED: It has been shown previously that a decrease of ATP amount and changed balance of other macroergic phosphates occurs in different tissues of spontaneously hypertensive rats (SHR) compared with control normotensive rats (WKY). AIM: To assess the ability of SHR brain isolated mitochondria to synthesize ATP and to elucidate its relation to extramitochondrial calcium concentration. RESULTS: The present work shows for the first time that SHR brain mitochondria initially differ from WKY ones by decreased (by 30%) ATP synthesis rate. When calcium concentration is increased up to 20 or 40 micromole/l ATP synthesis rates in WKY and SHR mitochondria are about one half compared with the condition when the medium does not contain calcium, but the differences between SHR and WKY remain the same. CONCLUSION: Decreased ATP synthesis rate in SHR mitochondria may be considered as the main cause of cell energy deficiency observed in experimental variant of primary arterial hypertension.

Asunto(s)

RESUMEN

There are accumulated evidences on existence of an imbalance between energy production and consumption in tissues in primary hypertension resulting in insufficient compensation of energy and its deficiency in cells (human essential hypertension, spontaneous hypertension in rats, SHR). An origin of these abnormalities resides in an alteration of cell mitochondrion ATP-synthetic function which ground is calcium overload of mitochondria due to increased cytosolic calcium redundantly entering into mitochondria and development of insufficiency of mPT pore removing calcium from matrix of the organells. There is an energy production deficiency in brain tissue of individuals with primary hypertension that is not initially caused by alteration of cerebral blood circulation of ischemic type. The mentioned energy abnormality is determined by decreased ability of brain mitochondria to synthesize ATP as a result of their calcium overload due to altered cell calcium handling in hypertension (so called membrane defect). In these conditions the registered normal or insignificantly changed cerebral blood flow in primary hypertension may be a result of systemic blood pressure increase in response to energy deficiency in brain tissue. Mechanisms mediating development of systemic hypertension include as the most important activation of vasomtor centers of brain stem. Other systems influencing vascular flow and peripheral resistance also contribute. Among those redundant (under conditions of calcium overload) production of oxidative radicals by mitochondria canceling vasorelaxing effect of NO should be specifically mentioned. The structural remodeling of peripheral circulation including rarefaction of capillary network provides for irreversibility of hypertension.

Asunto(s)

RESUMEN

It has been shown previously, that a decrease of ATP amount and changed balance of the other macroergic phosphates are observed in different tissues of spontaneously hypertensive rats (SHR) compared with the normotensive controls (WKY). The aim of the present study was to assess the ability of SHR liver isolated mitochondria to synthesize ATP and to clarify its dependence on extramitochondrial calcium concentration. Macroergic phosphate concentrations were measured by high performance liquid chromatography (HPLC). The present work shows for the first time, that SHR liver mitochondria initially differ from WKY ones by decreased (by 30%) ATP synthesis rate. Respiratory control coefficient and phosphorylation rate in SHR and WKY mitochondria change in different manner when extramitochondrial calcium concentration increases from 0 to 50 microM. When calcium concentration is increased up to 50 microM both parameters in WKY mitochondria are about one half compared with the condition when the medium does not contain calcium. In the conditions, when the medium contains 50 microM of calcium, complete uncoupling of oxidation and phosphorylation in SHR mitochondria is observed. Thus the decrease of ATP synthesis rate in SHR mitochondria in conjunction with reduced tolerance to calcium overload (by respiratory control coefficient and phosphorylation rate) in comparison with WKY may be considered as the main cause of cell energy deficiency, observed in experimental variant of primary arterial hypertension.

Asunto(s)

RESUMEN

The author proceeds that increased arterial blood (BP) pressure, reflecting the shift of the threshold blood pressure controlling system, is conditioned by underlying energy deficiency at the cellular level, caused by a decrease of the mitochondrial energy generating function. Elevation of systemic BP in hyperthyroidism resultant from oxidation-phosphorylation uncoupling, leading to decrease of ATP production by mitochondria, is an example of energy dependence of the hypertension phenomenon. In primary hypertension (essential hypertension in humans and spontaneous hypertension in rats) one can speak about genetically determined characteristics of cell membranes (so-called membrane defect) leading to insufficient regulation of intracellular calcium and increased concentrations of free calcium in the cytosol under physiological actions on cell calcium homeostasis mechanisms. Elevation of BP mediated by increased efferent sympathetic activity occurs as far as the excess of the cytosolic calcium accumulates in the mitochondria and their energy generating function decreases, which results in alteration of the ion transporting function of cell membranes. Hence, increased systemic BP in primary hypertension should be considered as an inherent feature of circulation corresponding to altered cell energetics.

Asunto(s)

RESUMEN

Genetic determining factors of essential hypertension seems to involve a dynamic mutation or a similar process. The mobile elements of the genome: moderately recurrent sequences, play a special role in initiation of such a process. A possible molecular mechanism of the initiation and development of the dynamic mutation, is described.

Asunto(s)

RESUMEN

Ultrastructure of vegetative ganglions (neck-thoracic, intracardial and intestinal) of Wistar and SHR rats, 26-28 months of age was studied electron-microscopically. The most pronounced changes were found in the neck-thoracic ganglions where, apart from lipofuscin deposits, lamellar bodies were frequently found. Redistribution of neuromediators in the neuron body and an increase of the neuroactive substances release into the intercellular space of the ganglion occur with age. The data on possible postsynaptic influence on the presynapse by means of neuromediators are presented. Nissl bodies hypertrophy was observed in the neck-thoracic and intracardial ganglions of old SHR rats.

Asunto(s)

RESUMEN

The study was made of early autopsies of 20-55-year-old victims deceased because of trauma. Incubation of sections in 2% glyoxylic acid and luminescent microscopy were used. The density of the adrenergic fibers in the central aortic zones which are most frequently affected with atherosclerosis was 2.8 +/- 0.2%, while in the distal rarely affected zones was 5.0 +/- 0.4%. In the abdominal aorta, the least density (2.1 +/- 2%) of the adrenergic plexuses was over the site of the celiac artery effluence, i.e. at the zones of the intensive atherosclerosis development while the density in the regions slightly affected with atherosclerosis it was 3.8 +/- 0.3%. The results indicate possible permissive role of the sympathetic nervous system in the development of local atherosclerotic alterations.

Asunto(s)

RESUMEN

Developing the idea of the membrane origin of primary hypertension, we proceed from the following: this form of hypertension is based on widespread (i.e., not limited to one type of cells) abnormalities in the ion transport function of the plasma membrane and its structure, leading to changes in the values of several constraints regulated by the plasma membrane (in particular, pHi, Cai2+); plasma membrane alterations apparently have a genomic source and are initiated by a factor whose impact is mediated by the protooncogenes of the genome: the specific functions of the cell are preserved in these conditions by means of a mechanism of cell adaptation, revealed in the example of adipose tissue and called "cell resetting"; the development of cell resetting simultaneously initiates changes in hormone-target relations which manifest themselves, in particular, in augmented corticosteroid secretion (adrenal cortex hypertrophy), in increased activity of the sympathetic nervous system, and in the phenomenon of hyperinsulinemia; considering membrane alterations as the source of primary hypertension, the author proceeds from the assumption of the role of the blood circulation system as an "intermediate link" between two basic systems (effectors) of water-salt homeostasis at the cellular level and at the level of the whole body, i.e., between the cell plasma membrane and the kidney; under conditions of "membrane defect" the functional equilibrium indicated in the previous item occurs at a new level of hormone-target interaction and is achieved via the development of chronic arterial hypertension and the kidney resetting (kidney shifting after Guyton) that prevents water and salt loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

RESUMEN

When the whole erythrocytes were exposed to LaCl3, A--23187, ionomycin, orthovanadate and saponin, there was Ca2+ binding only following La3+ treatment of the cells. The binding was evident at a wide range (0.1 microM--1.OmM) of La3+ concentrations. Iodoacetamide-induced (incubation for 3 hours, 37 degrees C) decrease in erythrocyte ATP levels was found to result in a 3-fold reduction in Ca2+ binding to the cytoskeleton. La(3+)-induced Ca2+ binding enhanced the incorporation of 14C-glucose and/or its metabolites into the red cell skeleton. Thus, the detected new type of Ca2+ binding to the cytoskeleton of human and rat erythrocytes is likely to be due to the cumulative process: direct binding of La3+ to the outer surface of a membrane and the metal-induced trigger of nucleotide--dependent intracellular process.

Asunto(s)

RESUMEN

The paper outlines a new La(3+)-induced mechanism of Ca2+ binding to rat red blood cells. Other compounds elevating intracellular Ca2+ concentrations, such as A-23187, ionomycin, and orthovanadate, and some activators of phosphotransferases (TPA, dibutyryl cAMP) fail to initiate the binding. Inhibitors of calmodulin-dependent processes, such as calmidazolium and trifluoroperazine, diminish La-dependent Ca2+ binding. La(3+)-induced Ca2+ binding is followed by an increased cytoskeleton incorporation rate of 14C metabolites of glucose. The rate of Ca2+ binding and 14C metabolite incorporation was 30% and 80% higher, respectively, but Ca+ binding capacity was increased by 45% in SHR as compared to WKY rats. Due to the fact that La3+ enhances the phosphorylation of proteins with molecular masses of 14, 36, and 58 kD, it is suggested that Ca2+ binding alterations should be determined by changes in phosphorylation and glucose metabolic disturbances in spontaneously hypertensive rats.

Asunto(s)

RESUMEN

Literature and authors' own data on the diagnostic value of endomyocardial biopsy in cases with clinical diagnosis of dilatation cardiomyopathy are analysed. It is shown that due to this biopsy the diagnosis of more than 20 heart diseases becomes possible. Myocarditis, the diagnosis of which is particularly difficult, is most frequently masked under dilatation cardiomyopathy. Ultrastructural studies are of great importance allowing to diagnose a number of heart diseases including alcoholic cardiomyopathy and viral myocardial lesions. The authors advocate wider use of endomyocardial biopsy which is sufficiently safe and informative.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

26 male F2 hybrids between spontaneously hypertensive (SHR) and normotensive control (WKY) rats (SHRxWKY)F2 were segregated according to their c-src genotype into SS and WW homozygous groups, corresponding to SHR or WKY and WS heterozygous group. Na, K cotransport in erythrocytes in the WW group was equal to that of WKY and differs significantly from that of WS and SS groups (the rate of Na, K cotransport in latter groups was close to that of SHR). Ca content of RBC in WW group was equal to that of WKY, lower than that of WS and SS groups which in turn was significantly lower than in SHR, indicating polygenic control of the trait. Authors conclude that the c-src locus itself or some other loci inherited in conjunction with c-src determines both the increase of Na, K cotransport and calcium content in erythrocytes of SHR.

Asunto(s)

RESUMEN

The erythrocytes from two spontaneously hypertensive rat strains (SHR and MHS) differ from those of control strains such as WKY and MNS in showing lower values of the mean volume and higher Na,K-cotransport rates. After 4-hour incubation in the presence of orthovanadate 45Ca levels in the erythrocytes from SHR was twice as high as in those from WKY. Under the same conditions, hemoglobin crystallization occurred, this process in SHR erythrocytes took place more intensively. No difference was found in these parameters between MNS and MHS. The fractions enriched with young and old cells remained to display variations in the mean volume of cells, Na,K-cotransport rates, 45Ca levels and hemoglobin crystallization, which were recorded between SHR and WKY. The WKY-SHR hybrids of second generation indicated that only Na,K-cotransport rates of the parameters examined positively correlated with blood pressures. From the findings it was concluded that the differences in the volume of erythrocytes and their permeability for cations were not due to the changed time course of cell aging in the blood bed, but to the specific characteristics of cytoskeleton protein arrangement, which were primarily typical of a rat reticulocytic membrane.

Asunto(s)

RESUMEN

Protein kinase C activities in the brain tissue of spontaneously hypertensive rats (SHR) and normotensive control rats (WKY) were studied. Protein kinase C activity in SHR was found to be 35% higher than that in normotensive control rats. It is suggested that the increase in protein kinase C activity is involved in the mechanism of membrane alterations in primary hypertension.

Asunto(s)