Ganchev, T.

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Varna Medical University Press: Journals

E F F E C T OF T H E A L P H A - A D R E N E R G I G B L O C K A D E ON ERYTHROPOIESIS AND PLASMA E R Y T H R O P O I E T I N IN RATS T. Ganchev Key-words: alpha-adrenoblockade — phenoxybenzamine — erythropoiesis — erythropoietin According to literature data alpha-adrenoceptor activation suppresses stem cell proliferation and differentiation. It is done by erythropoiesis inhibitor and realized through intracellular cAMP inhibition (4). Other authors (5) failed to prove if alpha-adrenoceptors could serve for DNA-synthesis elimination in spleen colony-forming units (CFU) with "in vitro" experiments. The interest in the problem is roused by numerous facts that presynaptic alpha-adrenoreceptors intermediate the negative feed-back in adrenergic media­tor releasing, i . e. they participate in the self-regulation of the adrenergic media­tion (11, 16). Having in mind the controversity of the data available we'decided to study the effect of 6-day adrenergic blockade with phenoxybenzamine (РВА) on ery­thropoiesis and plasma erythropoietin activity (EP) in white rats in conditions "in vivo". It could provide an additional information about the adrenergic regulation of erythrocyte homeostasis and partially about the role of alpha-adreno-ceptors — an integral part of the adrenergic mediator unit. Material and methods Experiments were carried out on 84 white female rats of Wistar breed. Expe* rimental animals were treated once daily with РВА injected intraperitoneal^ in a dose of 5 mg/kg b. w. (diluted in saline) while control ones were treated with saline only. Before starting and after finishing of the experiment both erythrocyte and reticulocyte count "pro mili" and in absolute values, hemoglobin, hematocrit levels were determined while only at the end of the experiment myelokaryocyte (MKC) count, 59Fe-incorporation in the newly formed erythrocytes and plasma E P activity.was estimated. A total of 38 polycytemic hypoxic mice were used to determine E P activity. Radioisotope and other methods used were already described elsewhere (1 , 8). Results and discussion The data received are presented on table 1 and 2. A slight erythrocyte and hemoglobin reduction in PBA-treated animals at the end of the experiment is established while there is an insignificant increase of these levels in the control ones. Hematocrit is also insignificantly reduced in both animal groups. Reticulo­cytes are considerably increased "pro mili" and in absolute values in experimental rats. MKC and 5 9 Fe incorporated in newly formed erythrocytes are also signifi­cantly increased (table 1). Plasma E P activity is with 99,69 per cent higher in PBA-treated animals as compared with that of the control plasma (table 2). « с о csT + о +1 СО см о II о о с о о II ю см ю 0 0 о со о + CN II 1> со +1 1> со +1 со' ОС ю 1—1 ш Х 5 о со о о" +1 о о о I ! ю о" о CN со со I о °1 +1 со о" 0 0 ю 00 ю +1 си о Г 0 СО 0 I _ со о о СО о о" II о" о CN ОС СО II с о см — о + V ср ю с о II о CN ^ 5 2 d + У CN СО ю СО II со о СО о о о II ОС с* >> о о >. 1— О) 2 2 Effect of the alpha-adrenergic.. 41 T a b l e 2 EP activity determined by the percentage of 5 9 F e incorporated in newly formed erythrocytes of test-polycytemic hypoxic mice N Percentage of incorporated *»Fe Per cent difference Plasma from PBA-treated rats 13 6 ,47-1 .57 +99,69 p<0,02 Control plasma 9 3 ,24-1 ,01 + 165,57 p<0,01 Saline (basis of ery­thropoiesis) 7 1,22-0,33 — E P standard " C " 0,5 U 9 9 , 1 8 - 1 5 — Data are presented as x+Sx . Per cent difference for PBA-treated rats is calculated as compared to the ontrol pUs ma and for the latter — as compared to the initial erythropoiesis. N = number of poiycytemic mice It is evident that PBA-induced alpha-adrenoblockade causes a more consi­derable increase of incorporated 5 9 Fe (with 34,52 per cent) (p <0,05) — a fact that probably reflects the enhanced young erythrocyte production. Relative and absolute reticulocytosis are better outlined in PBA-treated rats, too: 3,26 times or with 226,10 per cent (p<0,01) and 2,95 times or with 194,20 per cent (p<0,001), respectively, while in control rats relative reticulocytosis is more mode­rate (2,29 times or an increase with 129,83 per cent — p <0,01), and absolute one shows an increase of 2,33 times or with 132,70 per cent (p <0,001). There is, therefore, an intensive erythroid regeneration in PBA-treated rats. According to us, plasma erythropoietin increase (with 99,69 per cent — p <0,02> which is a basic and specific erythropoiesis regulator underlies this stimulation (3, 7). Working on Byron's data (5) we are inclined to exclude the direct action of alpha-adrenoblockade on erythroid bone marrow. It is obviously that alpha-adrenergic receptor elimination stimulates E P production and does not inhibit endogenic E P realization from the erythron. The increased reticulocyte and mye-lokaryocyte production and the elevated percentage of 5 9 Fe incorporated in newly forrried erythrocytes testifies in favour of this statement (table 1). The following considerations can be mentioned in the interpretation of plas­ma E P activity increase in PBA-treated rats: Proceeding from the data that РВА removes a series of effects of adrenaline and noradrenaline including those on renal circulation (6, 13) we are not inclined to exclude completely the consequences of a adrenoblockade influence on it. It is, however, an important factor in E P biogenesis. This is confirmed by the data of some authors (17) that renal РВА infusion reduces strongly its medullar and moderately its cortical fractions even if it increases relatively the total renal blood flow. The role of the kidney itself and of the changes of its blood flow for E P formation is well-known (7). It is possible that the increased E P production is directly stimulated by BA through unkown mechanisms acting on the renal "sensory" structures which re responsible for that. It is known that some РВА effects are independent of s alpha-adrenoblocking action (18). 42 . Т . Ganchev On the other hand, increased catecholamines after PBA-treatment (18) through stimulation of the system adenylate cyclase/cAMP can also stimulate E P formation as far as there is no doubt that cAMP plays a positive role in E P biogenesis (15). Besides it is rather probably that catecholamine increase through intensifying tissue respiration (higher oxygen consumption) induces relative re­nal hypoxia and thus an increased E P production (2). Blocking of alpha-adrenoceptors in stem cell, comiting cells and later sta­ges' erythroid representatives diminishes in our opinion the possibility for mani­festing of the action of an eventual erythropoiesis inhibitor that could additio­nally potentiate E P effect. It is known that alpha-adrenoblockade in some tissues makes (J-adrenoceptors more sensitive. We suppose that on this basis it is pos­sible that under the influence of endogenically increased E P a poten­tial |3-adrenostimulation of EP-sensitive erythroid cells can be realized in so far as it is presumed that E P activates stem cells through p-adrenoreceptors (4). The participation of P-receptor activation in the regulation of proliferative pro­cesses and differentiation of erythroid cells, respectively, in the erythropoiesis regulation, can be considered surely proven (5, 8, 10, 12, 14). On the basis of our results we can conclude that we can accept the undoubted participation of alpha-adrenoreceptors in erythropoiesis regulation at normoxia as far as alpha-adrenoblockade with РВА increases its most important characte­ristic indices: reticulocytes, 5 9 Fe incorporated in newly formed erythrocytes, myelokaryocytes and plasma erythropoietin activity. Besides the fact is to be noted that alpha-adrenoblockade does not hinder an increased endogenic E P utilization. The latter namely influences favourably upon erythropoiesis. The exact mechanism by which blocked alpha-adrenoceptors increase plasma E P ac­tivity with concrete experimental conditions is complex and difficult to explain, in our opinion, for the present. R E F E R E N C E S 1. Г а н ч е в , Т. Върху някои въпроси от адренергичната регулация на еритропое-зата и плазмената еритропоетинова активност у плъхове. Канд. дис. Варна, 1975. — 2. У ж а н с к и й, Я. Г. Физиологические механизмы регенерации крови. Москва, Ме­дицина, 1968, 210—212. — З. Ч е р н и г о в с к и й , В. Н. , О. И. М о и с е е в а . Усп. физиол. наук, 13, 1982, 2 7 — 4 4 . - 4. B r u c k n e r , V . Zywietz. Umschau aus Wissenschaft und Technik, 73, 1973, 7 6 6 — 7 6 7 . - 5. B y r o n , J . W. Experitn. HematoL, 3, 1975,44— 5 3 . — 6 . Е п е г о , M. A. , S. Z. L a n g e r . B r i t . J . Pharmacol., 49, 1973, 214—225.— 7. F i s h e r , J . W. Proc. Soc. Experim. Biol. Med., 173, 1983, 289—305. — 8. G a n ­c h e v , T . Agressology, 16, 1975, 301—305. — 9. H a f f n е r, I . F . , I . L i a v a g, I . S t e e l i e v . Scand. J. Gastroenterol.; 4, 196Э, 1 4 5 - 1 5 0 . - 10. J e l k m a n n W . , C. B a u e r . Experim. HematoL, 8, 1980, 742—748. — 11. L a n g е г S. Z . — I n : The re­lease of catecholamines from adrenergic neurons. Pergamon Press, 1979, 59—82. — 12. M 1 a -<jl е n о v i c, J . , J . W. A d a m s о n. Brit. J. Haematol., 56, 1984, З2З—ЗЗ2. — 13. N a -g y, Z . , A. M a s z a r o s , L . V a s l a k i . Acta Physiol. Acad. Sci. Hung., 40, 1971, 129 — 137. — 14. P r z a 1 a, F . , D. M. G r o s s , В. В e с k m a n, J . W . F i s h e r . Amer. J. Physiol., 236, 1979, H422—H426. — 15. R о d g e r s, G . M . , J . W . F i s h е r, W . J . G e o r g e . ATer . J . Physiol., 229, 1975, 1387—1393. — 16. S t j a r n e , L . Acta Phy­siol. Scand., 95, 1975, 18A. — 17. R o s t i v a l l , L . , J . W a l t e r , L . H a r s i n g . Acta Physiol. Acad. Sci. Hung., 51, 1978, З4З—351. — 18. Z i m m е r m a n, B . G . , J . C . L i a o, J . G i s s l e n . J . Pharmacol. Experim. Ther., 176, 1971, 603—610. Effect of the alpha-adrenergic blockade. 43 ВЛИЯНИЕ АЛЬФА-АДРЕНЕРГИЧЕСКОЙ БЛОКАДЫ НА ЭРИТРОПОЭЗ И НА ПЛАЗМЕННЫЙ ЭРИТРОПОЭТИН У КРЫС Т. Ганчев Р Е З Ю М Е Изучаются эритропоэз и плазменный эритропоэтин у крыс после шестидневной аль-фа-адреноблокады феноксибензамином (ФБА). Устанавливается значительное увеличение s^Fe включения (34,52 % р<0,05) в новообразовавшиеся эритроциты у крыс, третированных ФБА. Отмечается увеличение ретикулоцитов у животных обеих групп, причем в первой группе оно более значительно. Плазменная эритропоэтиновая активность у третированных ФБА животных увеличена на 99,69 % ( р < 0 , 0 2 ) . По всей вероятности причина увеличения эритропоэтина после альфа-адреноблокады связана с непосредственным влиянием ФБА на почки (измене­ния в токе крови) или с влиянием освободившихся катехоламинов на ток крови и на ткане­вый метаболизм. Вероятно это вызывает релятивную почечную гипоксию и увеличенную эрит-ропоэтиновую продукцию. 

EFFECT OF THE ALPHA-ADRENERGIG BLOCKADE ON ERYTHROPOIESIS AND PLASMA ERYTHROPOIETIN IN RATS

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EFFECT OF THE ALPHA-ADRENERGIG BLOCKADE ON ERYTHROPOIESIS AND PLASMA ERYTHROPOIETIN IN RATS

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Varna Medical University Press: Journals