[Sex inversion and epigenetic regulation in Vertebrates].

This review discusses issues related to the regulation of sex determination and differentiation in various groups of Vertebrates. Special attention was paid to factors of external and internal control for various genetic systems of sex determination, as well as to the epigenetic control of this process. Opportunities for sex inversion in various animals were also discussed.

[Effect of sex inversion in embryos of domestic chicken (Gallu gallus domesticus) by influence of letrozole and tamoxifen].

Realization of program of sex formation in multicellular organisms is a complex multistage process. The role of the inductor in this process is assigned to sex hormones synthesized by cells of the emerging gonads. The action of androgens on the formation of the male is now well understood. However, little is known about the involvement of estrogen the female gonad formation and the formation of a female as a whole. Here we present the results of experimental sex inversion in female chickens produced by aromatase inhibition and by the action of tamoxifen on chicken embryos. We have shown various masculinizing effect depending on the dose of active substance and the number of injections. We have noted that inhibition of aromatase does not block meiotic prophase in oogoniums. We have suggested that there are differences in the mechanisms of action of retinoic acid and estrogens on oogenesis. We have first shown proteins and nucleoproteins that interact with the estrogen receptor 1 and provided maps of their gene localization in human and chicken genomes.

[The effect of retinoic acid on the meiosis in the chick embryo (Gallus gallus domesticus)].

In this study it was shown that the injection of retinoic acid (RA) into incubated eggs on day 9 or 14 induced entry the males germ cells into preleptotene stage of prophase I on day 17, which are absent in the control embryos. At the same time the meiosis marker SCP3 was detected in the germ cells. Which was also absent at control embryos. On day 19 in male embryos the number of male germ cells at the stage preleptoteny increased, but there were no germ cells in the following stages of the prophase of meiosis. In 20-day-old chicks meiotic germ cells were absent. Thus, white it is shown that the influence of RA on the developing chicken embryos induces the entry of germ cells into preleptotene stage of prophase I meiosis. However, further meiotic transformations don't occur. Thus RA is only one of many factors providing meiotic cell division.

[Problems of sex determination in birds exemplified by Gallus gallus domesticus].

The current views of sex determination in birds are considered mostly with the example of Gallus gallus domesticus, the species best studied in this respect. Data on the appearance of primordial germ cells, their migration to the primordial gonads, the role of hormonal factors in the regulation of sex differentiation, the sex chromosomes, putative genetic mechanisms of sex determination, and a possible contribution of dosage compensation are described. The review discusses the two best-grounded hypotheses on the roles of the Z and W chromosomes in sex determination.

[Urinary prostaglandin levels in patients with arterial hypertension with benign and malignant course]. / Soderzhanie prostaglandinov v moche u bol'nykh arterial'noi gipertoniei dobrokachestvennogo i zlokachestvennogo techeniia.

With radioimmunoassay, daily urinary levels of prostaglandins E2 and F2 alpha (PGE2, FGF2 alpha were measured in 45 patients with hypertensive disease, 13 patients with chronic diffuse glomerulonephritis and 14 healthy persons. A progressive reduction in urinary PGE2 excretion was found to accompany the occurrence of labile arterial hypertension (AH), its stabilization, and development of malignant AH in patients with hypertensive disease or chronic diffuse glomerulonephritis. When labile AH developed, urinary PGF2 alpha excretion was increased, but when AH stabilized, its excretion became increased up to the baseline level. The specific features of malignant AH are significantly higher urinary PGF2 alpha and sharply greater PGF2 alpha/PGE2 coefficient. The identified abnormal metabolism of renal prostaglandins may contribute to the stabilization of blood pressure at a high level and to the development of malignant AH.

[Mechanisms of the development of arterial hypertension in hypertonic nephritis]. / Mekhanizmy razvitiia arterial'noi gipertonii pri gipertonicheskom nefrite.

The patients suffering from hypertonic nephritis were examined for renal hemodynamics, the activity of the renin-angiotensin-aldosterone system (RAAS), excretion of PGE2 and PGF2 alpha, and for a number of the parameters of water-electrolyte homeostasis. In A series, the patients suffering from latent and hypertonic nephritis (n = 11 in each group) were compared. In B series, two groups of the patients (n = 13 in each group) suffering from hypertonic nephritis associated with moderate or grave arterial hypertension were compared. The patients under comparison belonging to A and B series did not differ as regards the sex, age, nephritis standing, serum creatinine or proteinuria. As compared with the patients suffering from latent nephritis (A series), the patients with hypertonic nephritis showed a lower effective renal plasma flow, a greater resistance of the renal vessels, lesser PGE2 secretion, and a higher serum sodium concentration. As compared with the patients suffering from moderate hypertension (B series), the patients with associated hypertonic nephritis and grave hypertension demonstrated a higher resistance of the renal vessels, a higher activity of plasma renin, a larger concentration of plasma aldosterone and its excretion with urine, as well as a greater volume of the circulating blood. It is assumed that the development of arterial hypertension associated with hypertonic nephritis may be caused by renal hemodynamics deterioration, by relative activation of the renin-angiotensin system, inhibition of the depressor prostaglandin system and sodium retention. The progression of hypertension may be related to further deterioration of renal hemodynamics attended by RAAS activation and hypervolemia.

[Receptor-dependent regulation of the concentration of Ca2+ in the cytoplasm of thrombocytes in hypertensive patients]. / Retseptorzavisimaia reguliatsiia kontsentratsii Ca2+ v tsitoplazme trombotsitov bol'nykh gipertonicheskoi bolezn'iu.

Platelet activation factor (PAF)-, ADP and vasopressin-induced increments of platelet Ca2+ concentration were measured by quin-2 in 64 patients with essential hypertension and 16 normal donors. Basal concentration of free Ca2+ was 87 +/- 4 nM in donors, 106 +/- 5 nM in patients with labile hypertension (LH) and 122 +/- 6 nM in those with stable hypertension (SH) (p less than 0.01). PAF, ADP and vasopressin, added to platelets, increased [Ca]in by 448 +/- 58, 397 +/- 66, and 277 +/- 50 nM, respectively, in the donors, by 473 +/- 57, 479 +/- 54 and 195 +/- 32 nM, in LH patients, and by 607 +/- 85, 584 +/- 73 and 245 +/- 41 nM in SH patients. There were no significant variations between the three samples, using the ANOVA test. In 20 patients, whose both parents had essential hypertension, [Ca]in increment was 738 +/- 8 nM for PAF, 682 +/- 90 nM for ADP, and 320 +/- 61 nM for vasopressin. In 19 patients, who admitted to no essential hypertension in the family, these parameters were significantly lower: 310 +/- 40 nM for PAF, 389 +/- 61 nM for ADP, and 147 +/- 26 nM for vasopressin. The demonstrated changes may be making an important contribution to the maintenance of elevated vascular tone and provide an evidence in favor of a genetically-predetermined EH variety.

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.

[New mechanisms of a positive effect of curantyl in chronic nephritis]. / Novye mekhanizmy polozhitel'nogo deistviia kurantila pri khronicheskom nefrita.

The effects of curantyl (dipiridamole) on the excretion of prostaglandins E2 and F2 alpha (PGF2 alpha and PGF2 alpha) and renal hemodynamics (RHD) were studied in patients with hypertensive nephritis in an acute test and during prolonged (up to 21 mos) single-agent therapy. In the acute test curantyl increased PG excretion in 15 out of 18 patients by 86.8 +/- 17.6%, mainly at the expense of PGE2 (133.2 +/- 33.1%), and renal blood flow in 11 out of 12 patients by 32.1 +/- 7.7%. During prolonged therapy curantyl also raised PGE2 excretion and improved RHD (raised renal blood flow, glomerular filtration and decreased renal vascular resistance). Besides, during prolonged single-agent therapy curantyl reduced renin plasma activity, increased circulating blood volume, insignificantly reduced BP, and possessed an antiproteinuric and antihematuric effect. It is concluded that curantyl can stimulate PG renal biosynthesis improving RHD in hypertensive nephritis that can have a beneficial effect on a course of this disease.

[Effect of hypotensive therapy on a receptor-dependent increase in Ca2+ in the thrombocytes of patients with hypertension]. / Vliianie gipotenzivnoi terapii na retseptorzavisimoe povyshenie soderzhaniia Ca2+ v trombotsitakh bol'nykh gipertonicheskoi bolezn'iu.

The effect of antihypertensive drugs on receptor-dependent increase in Ca2+ basal level and its changes under stimulators action (thrombocytes activating factor, ADP and vasopressin) were studied by means of a fluorescent calcium probe "quin-2". Nifedipine blocked receptor-dependent increase of Ca2+ in thrombocytes in vitro as well as by oral administration, which was accompanied by decrease in vascular tone and BP. The degree of BP decrease correlated with that of depression of receptor-dependent increase of Ca2+ in thrombocytes. Combined therapy including nifedipine, propranolol and a diuretic resulted in more manifest inhibition of receptor-dependent calcium channels than monotherapy with nifedipine. Effect of antihypertensive drugs evidently depends on their influence on receptor-dependent Ca2+ cellular entrance.

[The vasodilator minoxidil in the treatment of hypertension]. / Vazodilatator minoksidil v lechenii gipertonicheskoi bolezni.

A new vasodilating agent, minoxidil, was used in 17 patients with essential hypertension that had not responded sufficiently to combined treatment with 3 or 4 conventional hypotensive agents. After minoxidil was added, mean arterial BP dropped by 50 +/- 2.4 mmHg, the effect persisting for 3-4 months. Discontinuation of minoxidil after a short-term administration of 20 +/- 3.8 mg daily was accompanied with a BP rise eventually reaching baseline values, while gradual replacement with nifedipine after daily doses of minoxidil had been reduced smoothly over 3 or 4 weeks allowed to maintain mean arterial BP about 34 +/- 1.8 mm Hg below the baseline. The use of minoxidil in combination with beta-blockers and diuretics for 6 weeks resulted in a significant increase of left-ventricular myocardial weight, while cardiac contractility and pump function remained intact, as evidenced by electrocardiography. After 3 weeks of treatment, peripheral vascular resistance diminished in the forearm owing to reduced arterial and arteriolar tone, yet no reverse development of the vascular-wall adaptive structural changes could be seen at venous occlusion plethysmography.

[Platelet aggregation in severe and malignant forms of hypertension: effect of treatment with prostaglandin E2]. / Agregatsiia trombotsitov pri tiazhelykh i zlokachestvennykh formakh arterial'noi gipertonii: vliianie lecheniia prostaglandinom E2.

Platelet aggregation was studied in patients with high and stable arterial hypertension that was mostly associated with the malignant syndrome, and the effect of PGE2 introduced into the blood flow as repeated intravenous infusions on platelet activity was assessed. The addition of low-dose inductor produced the greatest changes in platelet aggregation following platelet exposure to different ADP doses in the patients, as compared to normal subjects. Stimulation with 0.1 mumol ADP produced a 7-fold increase in platelet aggregation in hypertensive patients, as compared to the controls. Repeated administration of 1.2-1.5 mg PGE2 normalizes cell sensitivity to ADP. Mean arterial BP dropped by 15-45 mm Hg during the infusions and remained low for several days afterwards.

[Use of prostenon in the treatment of severe and malignant forms of hypertension]. / Primenenie prostenona dlia lecheniia tiazhelykh i zlokachestvennykh form arterial'noi gipertonii.

Forty-five patients with high arterial hypertension (AH) refractory to hypotensive therapy were treated with 3 or 4 prostaglandin E2 (PGE2) infusions (Prostenon). Twenty-two of those had the malignant AH syndrome. The hypotensive effect of prostenon was most pronounced in patients with essential hypertension, less marked in those with chronic glomerulonephritis and pyelonephritis and virtually nonexistent in cases of renovascular hypertension. It persisted until the discharge in most patients, and for several months in some. In severe AH, prostenon improved blood supply to the brain, kidneys and, less notably, the limbs, normalized venous dilatability and the cardiac index, brought down total peripheral resistance, particularly in cases where pretreatment values had been high, reduced platelet aggregation 1.8-fold, and contributed to reverse development of eyeground changes in some patients with malignant AH syndrome.

[Comparative evaluation of prostaglandins E1 and E2 in patients with hypertension]. / Sravnitel'naia otsenka deistviia prostaglandinov E1 i E2 u bol'nykh gipertonicheskoi bolezn'iu.

Changes in ABP, ECG, cerebral and peripheral hemodynamics were examined in 29 patients with second-stage essential hypertension before and within 1 or 2 days after PGE1 and PGE2 infusions administered during follow-up or in the presence of a hypotensive therapy. PGE were shown to be active vasodilators increasing cerebral and peripheral circulation. Vascular PG effects persisted for 1 or 2 days after the administration. Hypertensive patients demonstrated two patterns of hemodynamic response to PGE. The patients with higher total peripheral resistance (TPR) and low stroke and cardiac indices (SI and CI) during follow-up or hypotensive treatment were more sensitive to PGE, their ABP falling because of declining TPR. The patients with high SI and normal or slightly elevated TPR were less sensitive to PGE, their ABP falling mostly at the expense of declining SI. Most patients showed changed end portion of the ventricular complex immediately after PGE administration that vanished within one or two days. In coronary patients, angina of effort occurred less frequently after PGE infusion.

[Renal prostaglandins and hypertension]. / Prostaglandiny pochek i gipertonicheskaia bolezn'.

A total of 154 patients with essential hypertension (EH), 24 patients with renovascular hypertension (RVH), and 130 Wistar rats were investigated. PGE2 and PGF2 alpha levels were assayed radioimmunologically in renal venous blood and urine of the patients, and the synthesis of PGE2 and PGF2 alpha in renal tissue, renal PGE-9-ketoreductase activity and urinary PG excretion were measured in rats. It was demonstrated that the PGE2 synthesis was depressed in the vascular channel and the renal uropoietic system, with elevated F/E rations, in patients with arterial hypertension. Clinical and experimental studies showed prolonged and excessive salt consumption to be a cause of these changes, rooted in suppressed renal biosynthesis of both PGs and increased conversion of PGE2 to PGF2 alpha. In addition, renal PGE2 inactivation was increased in EH patients, as compared to those with RVH. PGE2 produced in the kidneys of EH patients is always a depressor natriuretic substance, whereas the role of PGF2 alpha is dependent on the water-salt balance. Furosemide and, to a smaller extent, other diuretics, as well as some hypotensive agents, increase urinary PG excretion and depress the F/E ratio in the urine. Repeated PGE2 infusions are shown to enhance the sensitivity of EH patients to hypotensive drugs, so they can be used for the treatment of refractory EH cases.

[Characteristics of the water-electrolyte metabolism of hypertension patients with stable hypertension and the principles of diuretic therapy]. / Osobennosti vodno-élektrolitnogo obmena u bol'nykh gipertonicheskoi bolezn'iu so stabil'noi gipertenziei i nekotorye printsipy terapii diuretikami.

Different levels of water-salt metabolism control were studied in patients with stable essential hypertension (SEH). The sample was found to be highly heterogeneous in terms of the magnitude of the body's water-filled spaces in relation to plasma renin activity (PRA) and the cooking salt gustatory sensitivity threshold, examined in the presence of various salt diets and diuretic treatments. Three patterns of response to salt loads were identified in SEH patients with respect to sodium and water elimination by the kidneys: the first was identical to that of normal subjects, while the second one featured increased, and the third one, decreased, diuresis and natriuresis. Prostaglandin E2 and kallikrein were shown to be involved in the formation of the second- and third-type renal response to excessive salt. Differential treatment of EH patients with diuretics alone or, where necessary, in combinations with small-dose beta-blockers or vasodilators provides effective BP control for some 1.5 to 2 years in 65% of patients.