Current status and prospects for arterial hypertension research in the Soviet Union.

Research on arterial hypertension is being conducted in the Soviet Union under a program organized by the National Cardiology Research Center. Four program directions are included: (a) basic research on the pathophysiologic mechanisms in the development of hypertension, including vascular wall viscosity and elasticity, associated regulatory mechanisms, and molecular and cellular mechanisms of vascular tone; (b) clinical research on the pathophysiology of hypertension and the mechanisms responsible for the course and prognosis of the disease, including biobehavioral and psychological aspects and the effects of sodium kinetics and a sodium-limiting diet; (c) approaches to treatment, both pharmacologic and nonpharmacologic; and (d) population studies of children, adolescents, and adults.

Platelets as a model for studying the action of antihypertensive drugs.

The action of different antihypertensive drugs on Ca2+ concentration in human platelets was studied under in vitro conditions and during the treatment of hypertensive persons. Several calcium antagonists (verapamil, nifedipine, and nicardipine) acted to block an increase of Ca2+ concentration in platelets which was induced by platelet activating factor (PAF), adenosine diphosphate, and U46619, the stable analog of thromboxane A2. All calcium antagonists suppressed dose-dependent calcium responses induced by each agonist. In a group of stable hypertensive patients, the basal Ca+ level in platelets was significantly higher than the level in mildly hypertensive or normotensive individuals. The induced increase in Ca2+ in the platelets of stable hypertensive patients was also higher, but this difference was not significant. Treatment of hypertensive patients with nifedipine for 3 weeks led to a decrease in calcium responses induced by all activators, but this decrease was significant only when PAF was used for platelet stimulation. Nifedipine added to platelets induced a nearly identical decrease in PAF-dependent calcium responses before and after therapy. Treatment with nifedipine in combination with furosemide and propranolol led to a more significant decrease in calcium responses than that expressed with monotherapy. In vitro experiments showed that furosemide has a calcium-blocking action on platelets, but that it is less expressed than the action of calcium antagonists. Low doses of propranolol did not influence calcium platelet responses, but high doses potentiated them slightly. A significant correlation was found between the percentage change in mean arterial pressure and in the PAF-induced responses with either monotherapy or combination drug therapy. Measurement of calcium responses before and after intravenous infusion of prostaglandin E2 showed that this procedure leads to a decrease in calcium responses that lasts for several days. The data suggest that platelets may be used as a model for investigating the action of drugs that influence calcium exchange when these drugs are administered chronically.

Beta-blocker action on lymphocyte proliferative response in essential hypertension.

The proliferative response of phytohaemagglutinin (PHA) - stimulated lymphocytes of healthy donors and hypertensive subjects was analysed according to 3H-thymidine incorporation and cell cycle phase position on a flow cytofluorimeter. 3H-thymidine uptake and the percentage of cells in (S + G2) phase were significantly lower in hypertensive patients. After short-term propranolol administration the lymphocyte blastogenic response in essential hypertension increased by 30--100%. The data suggest that the change in mitogenic response of lymphocytes in essential hypertension results from changes in the distribution of lymphocyte subclasses. The connection between the sympathoadrenal and immune system is discussed.

Primary hypertension: left ventricular mass and function, sympathetic nervous system activity, and therapy.

Left ventricular (LV) mass is a predictor of morbidity in patients with hypertension. To elucidate the mechanisms of left ventricular hypertrophy (LVH) in primary hypertension, we examined the relationships of LV mass, arterial blood pressure, and plasma norepinephrine--as a marker of sympathetic nervous system tone--in three populations of patients with mild or moderate hypertension. We found linking of neural tone with (a) arterial blood pressure in mild and moderate hypertension, (b) LV mass in moderate hypertension, and (c) diastolic function in mild hypertension, suggesting that neural tone is a factor in both the pathogenesis and the sequelae of hypertension. Additionally, elevated norepinephrine level may reflect subtle loss of diastolic function before hypertrophy is manifest. Both nondrug and drug therapy may regress LV mass after blood pressure reduction with disparate effects on neural tone.

Morphological changes in the adrenal cortex in different variants of low-renin hyperaldosteronism. Comparison with the functional state of certain hormonal systems.

On the basis of morphological and histochemical examination of adrenal tissue of 45 patients with arterial hypertension and low-renin hyperaldosteronism, the following five morphological variants of this disease were differentiated: 1) with adenoma of the adrenal cortex and atrophy of surrounding cortical tissue; 2) with adenoma and hyperplasia of elements of the zona glomerulosa and(or) the zona fasciculata and the zona reticularis; 3) with multiple adenomatosis of the adrenal cortex; 4) with isolated diffuse or focal hyperplasia of the zona glomerulosa; 5) with nodal, diffuse-nodal or diffuse hyperplasia of all cortical zones. In tumours, three structural variants, corresponding to their histogenesis, were identified. A correlation was found between morphological variants and hormonal diagnosis of different forms of low-renin hyperaldosteronism.

HLA antigens and the complement system in essential hypertension.

Heredity factors are of great importance in the pathogenesis of essential hypertension, but their role was until recently not reliably proved. It was only after research into histocompatibility antigens that it was possible to discover the genetic determination of a number of diseases. The purpose of the study was to reveal the genetic factors raising the risk of essential hypertension (EH). In the population of Russian nationality in Moscow, suffering from EH, HLA antigens and certain complement components were investigated. The results showed an increased frequency of HLA-A11, HLA-B13 and HLA-Bw22. However, blood C3c and C4 concentration was in the studied group of patients significantly elevated, which attests to a possible participation of the complement system in the development of EH as a factor causing vasoconstriction. The results confirm the need for further study of the immunogenetic profile of patients with EH in order to clarify certain aspects of the pathogenesis of EH.

Left ventricular function, haemodynamics and certain indicators of neurohumoral control during submaximal exercise in patients with essential hypertension.

The study was carried out in 22 men with essential hypertension, stage I B-II B, aged 25 to 46 years, and in 10 healthy volunteers of the same age. The authors investigated indicators of systemic and intracardiac haemodynamics by echocardiography, determined the blood plasma catecholamine concentration, catecholamine excretion, renin and cyclic nucleotides activity in plasma, both at rest and during continuous submaximal graded exercise on a bicycle ergometer. The haemodynamic response to exercise differed in patients with stable HPT from healthy subjects and patients with labile HPT by an increase in diastolic blood pressure, a lesser drop in end-systolic volume and in total peripheral vascular resistance, a lesser rise in cardiac output, and by a substantially higher left ventricular mass. The left ventricular ejection fraction did not rise in patients with stable hypertension. In these patients, no statistically significant concentration of urine catecholamines and their urine excretion was observed, in contrast to the other two groups where these indicators were increased. A negative correlation was found between the left ventricular mass and the ejection fraction during exercise, which attests to a negative influence of left ventricular hypertrophy on the pump function of the heart during exercise in patients with essential hypertension.

Blood antidiuretic activity and selected haemodynamic indicators in patients with essential hypertension.

In patients with essential hypertension the blood antidiuretic activity was studied in relation to the haemodynamics. It was found that the blood antidiuretic activity increased in parallel with the rise in the total peripheral resistance, and with the decreases in the blood and plasma volumes, stroke volume, and end-diastolic heart volume. The role of antidiuretic hormone in the regulation of haemodynamics in hypertensive patients is discussed.

The renal kallikrein-kinin system in various types of diuresis and under the effects of inhibitors of prostaglandin synthesis in rats.

In rats with water load, rats with high-salt diet, rats treated with furosemide, and rats treated with indomethacin in low doses (2 mg/kg orally per day for five consecutive days) an enhanced urinary excretion of kallikrein was observed. Higher dosage of indomethacin (5 mg/kg), on the contrary, markedly reduced the urinary kallikrein excretion. The degree of activation of the renal kallikrein-kinin system was lowest in water diuresis, and highest at the high-salt diet. In salt- and furosemide-induced diuresis, positive correlations were found between the urinary kallikrein excretion, sodium excretion, urine flow rate, and renal concentration capacity. In water diuresis, a positive correlation was found solely between the kallikrein excretion and the urine flow rate. Indomethacin at low dosages elevated, and at high dosages reduced the activity of the renal kallikrein-kinin system; analogous effects were exerted on the urine flow rate and on sodium excretion.

Resetting of aortic baroreceptors in experimental hypertension and atherosclerosis.

The dependence of aortic baroreceptor activity on aortic pressure and aortic distension was studied in isolated preparations "aortic arch--aortic nerve", obtained from normal rabbits and from rabbits with experimental hypertension and atherosclerosis varying in duration. It was found that in both atherosclerosis and hypertension the reactivity thresholds of aortic baroreceptors shifted toward higher pressures. In initial stages of hypertension and atherosclerosis this resetting results from changes in the baroreceptive zone itself, and aortic distensibility does not differ from the normal state. In later stages of hypertension and atherosclerosis the aortic distensibility decreases; in consequence of this the shift of baroreceptor reactivity threshold increases. Possible mechanism of baroreceptor resetting and its role in the regulation of arterial pressure in hypertension and atherosclerosis are discussed.

Venous tone in essential hypertension.

Peripheral venous tone was measured in 124 patients with essential hypertension and in 20 healthy persons by digital electroplethysmography according to B. E. Votchal. In patients with hypertension stage II, the venous tone significantly decreased with increasing arterial tone; in patients in stage I this tendency was statistically not significant. In orthostasis the increase in venous tone was much lesser than that in arterial tone. The close positive correlation between venous capacity and the degree of decrease in systolic and pulse pressure make it possible to assess the systemic venous pressure on the basis of findings obtained from occlusion plethysmographic measurements. In patients with hypertensive disease in stage IIA, treated with reserpine, the arterial tone and pressure decreased, whereas the venous tone significantly increased (normalized).