E F F E C T O F D R U G S B L O C K I N G a - A N D / ~ - A D R E N E R G I C

R E C E P T O R S ON C H A N G E S I N L I P O L Y S I S P R O D U C E D

B Y E X T R A O R D I N A R Y S T I M U L A T I O N

N. G. Nikul'cheva UDC 615.221.015.42:612.015.32

Ex t r ao rd ina ry (electr ical) s t imulat ion of r a t s was shown to i nc r ea se the concentra t ion of non- es te r i f i ed fat ty acids (NEFA) in the blood s e r u m and adipose (ependymal) t i ssue. All ~ - adrenoly t ics t es ted (sympatholytin, phenoxybenzamine, phentolamine) cons iderab ly weakened the act ivat ion of l ipolys is , and reduced the i nc r ea se in NEFA concent ra t ion in the adipose t i s sue and blood. However , against the background of i so la ted blocking of f l -adrenerg ic s y s t e m s by propranolo l , a lprenolol , and t r a s i e o r , the NEFA-mobi l i za t ion reac t ion to e x t r a - o rd inary s t imulat ion of the an imals took p lace to the same degree as in the contro l ra ts .

Ex t r ao rd ina ry s t imulat ion of an animal s t imula tes l ipolys is and i n c r e a s e s the concentra t ion of non- es te r i f i ed fatty acids (NEFA) in the adipose t i s sue and blood. Some w o r k e r s r e g a r d this reac t ion as a manifes ta t ion of a s ta te of s t r e s s [9, 17]. The extensive l i t e r a t u r e d e m o n s t r a t e s the impor tan t role of the sympathe t ic nervous s y s t e m and of the ca techolamines in the physiologica l regula t ion of l ipolys is [13, 22, 25]. A number of inves t iga t ions have been made of NEFA mobi l izat ion in r e sponse to e x t r a o r d i n a r y s t imu- lat ion [1, 6, 15, 18, 21]. However , insufficient work has been done to study a d r e n o r e c e p t o r s of adipose t i s sue whose exci ta t ion leads to mobil izat ion of NEFA during e x t r a o r d i n a r y s t imulat ion.

The f i r s t inves t igat ion was accordingly c a r r i e d out in o r d e r to study the role of the sympathe t ic nervous s y s t e m in the regulat ion of NEFA me tabo l i sm during e x t r a o r d i n a r y s t imulat ion of an imals by the use of ad reno recep to r blocking drugs.

Sympatholytin, phenoxybenzamine (dibenzylin) and phentolamine (regitin) were used as ~ - a d r e n o - r e cep to r blocking drugs. As f l -adrenolyt ics , the thoroughly inves t iga ted compound proprano lo l (inderal) was used, and also two compara t ive ly new drugs blocking f i - ad r ene rg i c s y s t e m s , namely a lprenolol (H5~28, aptin), s i m i l a r to p roprano lo l in the s t rength of its action [5], and also t r a s i c o r (Ciba 39,089/Ba) [24].

E X P E R I M E N T A L M E T H O D

Male r a t s were immobi l i zed by a t tachment to a f r a m e and then s t imula ted by an e l ec t r i c cu r r en t (2.5-3 V, 50 Hz) for 2 h. The content of NEFA in the blood s e r u m and adipose (ependymal) t i s sue was de- t e rmined by Dole ' s method [11]. The compounds for tes t ing were given in the following doses: sympatho- lytin 5 mg/kg , phenoxybenzamine 10 mg/kg, phentolamine 10 mg/kg , p roprano lo l 2, 5, 10, 20, and 40 mg/kg , a lprenolol 5 and 20 mg/kg , and t r a s i c o r 2, 10, and 20 mg/kg . The conditions of the i r a d m i n i s t r a - tion a re given in the caption to Fig. 1. Rats of the control g roups r ece ived the s a m e volumes of the c o r - responding solvents and were sac r i f i ced along with the expe r imen ta l an imals . In a spec ia l s e r i e s of exper i - ments the effect of these compounds on NEFA me tabo l i sm was studied in intact an imals kept under ident i - cal conditions with the expe r imen ta l ra ts .

Depar tment of Pha rmaco logy , Insti tute of Exper imenta l Medicine, Academy of Medical Sciences of the USSR, Leningrad. (Presen ted by Academic ian of the Academy of Medical Sciences of the USSR S. V. Anichkov.) T rans l a t ed f r o m Byulle ten ' ~ ,ksper imental 'noi Biologii i Meditsiny, Vol. 71, No. 2, pp. 55-58, February , 1971. Original a r t ic le submit ted July 27, 1970.

�9 1971 Consultants Bureau,. a division of Plenum Publishing Corporation, 227 West 17th Street, New York, N. Y. 10011. All rights reserved. This article cannot be reproduced for any purpose whatsoever without permission of the publisher. A copy of this article is available from the publisher for $15.00.

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Fig. 1. Effect of ad reno recep to r b lock- ing drugs of NEFA mobil izat ion during ex t r ao rd ina ry s t imulat ion of ra t s : A) NEFA concentra t ion in adipose t i ssue , in pe rcen t of control 2; B) NEFA concen- t ra t ion in blood se rum, in pe rcen t of control 2; 1) control 2; 2, 3) sympa tho ly - t in 5 mg/kg , in t raper i tonea l ly 1 and 24 h r e spec t ive ly before s t imulat ion; 4,5) phenoxybenzamine, 10 mg/kg , i n t r a p e r i - toneal ly 1 and 24 h before s t imulat ion; 6) phentolamine, 10 mg/kg , i n t r a m u s c u - l a r ly 40 rain before s t imulat ion; 7, 8, 9, 10, 11) propranolo l 2, 5, 10, 20, and 40 mg /kg respec t ive ly , in t raper i tonea l ly 30 min before st imulat ion; 12, 13) alprenolol 5 and 20 mg /kg respec t ive ly , i n t r ape r i t o - neal ly 30 min before s t imulat ion; 14, 15, 16) t r a s i c o r 2, 10, and 20 mg/kg , i n t r a m u s - cular ly 40 min be fo re s t imulat ion; P) s igni - f icance of d i f fe rences re la t ive to control .

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Effect of ad reno recep to r blocking agents on NEFA concen t ra - tion in adipose t i s sue and blood s e r u m of in tact animals : 1) control 1. All r e su l t s e x p r e s s e d in pe rcen t of con- t ro l 1. Rema inde r of legend as in Fig. 1.

The r e su l t s of the exper imenta l s e r i e s were c o m - pared with those of the two control groups: t) intact r a t s rece iv ing the solvent and sac r i f i ced along with the cor responding exper imen ta l r a t s ; 2) an imals rece iv ing the cor responding solvent and then connected to e l ec - t r i ca l s t imulat ion. The indices of the two control groups were taken as 100%.

E X P E R I M E N T A L R E S U L T S

A N D D I S C U S S I O N

The combined action of immobi l i za t ion and e l e c - t r ica l s t imulat ion on the an imals was accompanied by an apprec iab le i n c r e a s e in the NE FA concentra t ion in the adipose t i s sue and blood se rum. Fo r example , the absolute content of NEFA in the adipose t i s sue of r a t s belonging to di f ferent control groups va r i ed f r o m 1.9 to 2.4 peq /g , and rose a f te r s t imulat ion by 1.0-1.9 p e q / g ,

i .e. , by 50-80%. The s e r u m NEFA level rose by 0.18-0.33 p e q / m l , or by 60-100% compared with the NEFA concentra t ion in the control r a t s (control 1).

The r e su l t s given in Fig. 1 show that all compounds blocking o~-adrenergic s y s t e m s reduced to some extent the inc rease in NEFA concentra t ion in the blood s e r u m and had a pa r t i cu l a r ly marked effect in de- p r e s s i n g the i r accumulat ion in the adipose t issue. The s t ronges t inhibi tory action on NEFA mobil izat ion was seen when sympatholyt in was injected 24 h before s t imulat ion. The s e r u m NEFA concentra t ion was 29% lower , and its content in adipose t i s sue 37% lower than in an imals exposed to e x t r a o r d i n a r y s t imulat ion but rece iv ing cor responding solvent instead of the compound. When sympatholyt in was given 1 h before e l ec t r i ca l s t imulat ion, i ts blocking p rope r t i e s were weaker in the i r effect. Phenoxybenzamine had a s im i l a r action as sympatholyt in, but d i f fe red f rom it in that the degree of i ts p ro tec t ive effect was p rac t i ca l ly the same wha tever t ime it was given. Of the group of compounds blocking p - a d r e n o r e c e p t o r s phentolamine was the leas t active, for it reduced the i nc r ea se in NEFA only in adipose t i ssue. The r e su l t s regard ing the i nc rea se in NEFA concentra t ion in the blood s e r u m were not s ta t i s t ica l ly significant.

150

The effect of the compounds blocking f i - ad r eno recep to r s on l ipolys is differed sharp ly f r o m the action of those blocking a - a d r e n e r g i c s y s t e m s {Fig. 1). Propranolo l , in a dose of 2 mg/kg , sl ightly reduced the i nc rea se in NEFA concentra t ion in the blood s e r u m but not in adipose t issue. This compound in la rge doses , and also alprenolol and t r a s i c o r in all doses tes ted, led to v i r tua l ly no reduct ion in the inc rease of NEFA in e i ther blood s e r u m or adipose t i s sue during e x t r a o r d i n a r y s t imula t ion of the ra ts .

Some ad reno reeep to r blocking drugs t hemse lves had a l ipomobil iz ing effect when injected into intact r a t s , i .e . , they i nc rea sed the NEFA concentra t ion in the adipose t i s sue and blood (Fig. 2). This effect was mos t c l ea r ly seen a f te r adminis t ra t ion of phentolamine: the s e r u m NEFA concent ra t ion was doubled, and i ts concentra t ion in the adipose t i s sue v e r y nea r ly doubled. In the case of phenoxybenzamine, these lipo - mobil izing p r o p e r t i e s also were c l ea r ly marked , but were slightly weaker than with phentolamine. Unlike these two compounds, sympatholyt in had no such effect on adipose t i ssue. Of the a - a d r e n o r e c e p t o r blocking agents, t r a s i c o r gave a v e r y sl ight i nc rease in the NEFA level , but this i n c r e a s e in the blood s e r u m was not s ta t i s t i ca l ly significant.

Blocking the di f ferent ad reno recep to r s of adipose t i s sue was not equally re f l ec ted in the c h a r a c t e r of the changes in NEFA metabo l i sm produced by the combined action of immobi l i za t ion and e l ec t r i c a l s t im- ulation of the r a t s . For ins tance, compounds blocking a - a d r e n o r e c e p t o r s (sympatholyt in, phenoxybenza- mine, and phentolamine) cons iderably d e p r e s s e d the act ivat ion of l ipolys is , reduced the i nc rea se in the NEFA concentra t ion of the adipose t i s sue and, as a resul t , reduced the i n c r e a s e in the concentra t ion in the blood se rum. It is in te res t ing to note that this p ro tec t ive action was mani fes ted even with the use of phen- to lamine, which i t se l f had a m a rked l ipomobil iz ing effect, as other authors also have desc r ibed [7]. How- ever , it must be pointed out that phentolamine was weaker in i ts ant i l ipemic action than sympatholyt in and phenoxybenzamine. The l a s t compound also had a l ipomobil iz ing effect on adipose t i ssue , but to a l e s s e r degree than phentolamine. According to the l i t e r a tu re , both these blocking agents s t imula te the synthes is of ca techo lamines and inc rea se the i r blood concentrat ion, and this was evidently one r ea son for the i r s y m - pa thomimet ic effects [10].

None of the f i - r e c e p t o r blocking agents which were tes ted (propranolol , a lprenolol , t r a s i co r ) p r e - vented the i nc r e a s e in NEFA concentra t ion in the adipose t i s sue and blood. Nei ther p roprano lo l nor a l - prenolol reduced the s t imulat ion of l ipolys is , even when given in l a rge doses such as 20 and 40 mg/kg , which had a marked sedat ive ef fec t (some of the animals lay down on the i r side).

Af te r d i scover ing a high degree of s p e c i f c antagonism between the metabol ic e f fec ts of exogenous ea techolamines and blocking agents, many inves t iga tors have concluded that the regulat ion of l ipolysis in adipose t i s sue is effected through f l - ad r ene rg i c s y s t e m s [3, 12, 16, 20, 26]. However , this view is not shared by o ther w o r k e r s [2, 4, 14, 19].

The resu l t s of the p r e s e n t invest igat ion conf i rm the g r e a t e r impor t ance of the a - a d r e n e r g i c s y s t e m s of adipose t i s sue in the reac t ion of NEFA mobil izat ion to ex t r ao rd ina ry s t imulat ion in ra t s . This ag r ee s with the findings of Le i tes and Chou Su [1], who demons t r a t ed that e rgo tamine effect ively b locks the s t imu- lation of l ipolysis in s t r e s s ( immobil izat ion of ra ts) .

The high inhibi tory act ivi ty of a - a d r e n o l y t i c s with r e s p e c t to NEFA mobil izat ion in r e sponse to e x t r a - o rd inary s t imulat ion, demons t ra t ed in these exper imen t s , could be the r e su l t of t he i r speci f ic antagonism with the media to r l ibe ra ted at sympathe t ic ne rve endings. On the o ther hand, the p ro tec t ive ef fec t could be influenced by the exis tence of nonspecif ic antagonism which has been es tab l i shed for (x -ad renorecep to r blocking agents and va r ious l ipolyt ic agents (such as ACTH, growth hormone , g lueocor t ico ids , etc.) [8, 12, 16, 23].

L I T E R A T U R E C I T E D

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